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3. Supervised Parametric Learning in the Identification of Composite Biomarker Signatures of Type 1 Diabetes in Integrated Parallel Multi-Omics Datasets.

Author

Bonnell, Jerry, Alcazar, Oscar, Watts, Brandon, Buchwald, Peter, Abdulreda, Midhat H., and Ogihara, Mitsunori

Subjects
TYPE 1 diabetes, MULTIOMICS, SUPERVISED learning, AUTOIMMUNE diseases, BIOMARKERS, DATA augmentation
Abstract

Background: Type 1 diabetes (T1D) is a devastating autoimmune disease, and its rising prevalence in the United States and around the world presents a critical problem in public health. While some treatment options exist for patients already diagnosed, individuals considered at risk for developing T1D and who are still in the early stages of their disease pathogenesis without symptoms have no options for any preventive intervention. This is because of the uncertainty in determining their risk level and in predicting with high confidence who will progress, or not, to clinical diagnosis. Biomarkers that assess one's risk with high certainty could address this problem and will inform decisions on early intervention, especially in children where the burden of justifying treatment is high. Single omics approaches (e.g., genomics, proteomics, metabolomics, etc.) have been applied to identify T1D biomarkers based on specific disturbances in association with the disease. However, reliable early biomarkers of T1D have remained elusive to date. To overcome this, we previously showed that parallel multi-omics provides a more comprehensive picture of the disease-associated disturbances and facilitates the identification of candidate T1D biomarkers. Methods: This paper evaluated the use of machine learning (ML) using data augmentation and supervised ML methods for the purpose of improving the identification of salient patterns in the data and the ultimate extraction of novel biomarker candidates in integrated parallel multi-omics datasets from a limited number of samples. We also examined different stages of data integration (early, intermediate, and late) to assess at which stage supervised parametric models can learn under conditions of high dimensionality and variation in feature counts across different omics. In the late integration scheme, we employed a multi-view ensemble comprising individual parametric models trained over single omics to address the computational challenges posed by the high dimensionality and variation in feature counts across the different yet integrated multi-omics datasets. Results: the multi-view ensemble improves the prediction of case vs. control and finds the most success in flagging a larger consistent set of associated features when compared with chance models, which may eventually be used downstream in identifying a novel composite biomarker signature of T1D risk. Conclusions: the current work demonstrates the utility of supervised ML in exploring integrated parallel multi-omics data in the ongoing quest for early T1D biomarkers, reinforcing the hope for identifying novel composite biomarker signatures of T1D risk via ML and ultimately informing early treatment decisions in the face of the escalating global incidence of this debilitating disease. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Apolipoprotein CIII links islet insulin resistance to β-cell failure in diabetes

Author

Åvall, Karin, Ali, Yusuf, Leibiger, Ingo B., Leibiger, Barbara, Moede, Tilo, Paschen, Meike, Dicker, Andrea, Daré, Elisabetta, Köhler, Martin, Ilegems, Erwin, Abdulreda, Midhat H., Graham, Mark, Crooke, Rosanne M., Tay, Vanessa S. Y., Refai, Essam, Nilsson, Stefan K., Jacob, Stefan, Selander, Lars, Berggren, Per-Olof, and Juntti-Berggren, Lisa

Published
2015

13. Correction to: In vivo imaging of type 1 diabetes immunopathology using eye-transplanted islets in NOD mice

Author

Abdulreda, Midhat H., Molano, R. Damaris, Faleo, Gaetano, Lopez-Cabezas, Maite, Shishido, Alexander, Ulissi, Ulisse, Fotino, Carmen, Hernandez, Luis F., Tschiggfrie, Ashley, Aldrich, Virginia R., Tamayo-Garcia, Alejandro, Bayer, Allison S., Ricordi, Camillo, Caicedo, Alejandro, Buchwald, Peter, Pileggi, Antonello, and Berggren, Per-Olof

Published
2019
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14. High-resolution, noninvasive longitudinal live imaging of immune responses

Author

Abdulreda, Midhat H., Faleo, Gaetano, Molano, Ruth Damaris, Lopez-Cabezas, Maite, Molina, Judith, Tan, Yaohong, Echeverria, Oscar A. Ron, Zahr-Akrawi, Elsie, Rodriguez-Diaz, Rayner, Edlund, Patrick K., Leibiger, Ingo, Bayer, Allison L., Perez, Victor, Ricordi, Camillo, Caicedo, Alejandro, Pileggi, Antonello, and Berggren, Per-Olof

Published
2011

17. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans

Author

Rodriguez-Diaz, Rayner, Dando, Robin, Jacques-Silva, M. Caroline, Fachado, Alberto, Molina, Judith, Abdulreda, Midhat H., Ricordi, Camillo, Roper, Stephen D., Berggren, Per-Olof, and Caicedo, Alejandro

Subjects
Dextrose -- Physiological aspects -- Research, Islands of Langerhans -- Physiological aspects -- Research, Diabetes -- Drug therapy -- Research, Acetylcholine -- Physiological aspects -- Research, Glucose -- Physiological aspects -- Research, Biological sciences, Health
Abstract

Acetylcholine is a neurotransmitter that has a major role in the function of the insulin-secreting pancreatic beta cell (1,2). Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species (1,3,4), but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to the case in mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of human islets provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. Cholinergic signaling within islets represents a potential therapeutic target in diabetes (5), highlighting the relevance of this advance to future drug development., Acetylcholine is crucial for pancreatic beta cell function. It stimulates insulin secretion by increasing the cytoplasmic free [Ca.sup.2+] concentration, [[[Ca.sup.2+]].sub.i], via inositol phosphate production and enhancing the effects of [Ca.sup.2+] [...]

Published
2011
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18. Parallel Multi-Omics in High-Risk Subjects for the Identification of Integrated Biomarker Signatures of Type 1 Diabetes

Author

Alcazar, Oscar, primary, Hernandez, Luis F., additional, Nakayasu, Ernesto S., additional, Nicora, Carrie D., additional, Ansong, Charles, additional, Muehlbauer, Michael J., additional, Bain, James R., additional, Myer, Ciara J., additional, Bhattacharya, Sanjoy K., additional, Buchwald, Peter, additional, and Abdulreda, Midhat H., additional

Published
2021
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19. Supplemental_table - Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

Author

Tun, Sai Bo Bo, Chua, Minni, Riasat Hasan, Köhler, Martin, Xiaofeng Zheng, Ali, Yusuf, Abdulreda, Midhat H., Juntti-Berggren, Lisa, Veluchamy A. Barathi, and Per-Olof Berggren

Subjects
Medicine, Cell Biology
Abstract

Supplemental_table for Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate by Sai Bo Bo Tun, Minni Chua, Riasat Hasan, Martin Köhler, Xiaofeng Zheng, Yusuf Ali, Midhat H. Abdulreda, Lisa Juntti-Berggren, Veluchamy A. Barathi and Per-Olof Berggren in Cell Transplantation

Published
2020
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22. Donor Islet Endothelial Cells in Pancreatic Islet Revascularization

Author

Nyqvist, Daniel, Speier, Stephan, Rodriguez-Diaz, Rayner, Molano, R. Damaris, Lipovsek, Saša, Rupnik, Marjan, Dicker, Andrea, Ilegems, Erwin, Zahr-Akrawi, Elsie, Molina, Judith, Lopez-Cabeza, Maite, Villate, Susana, Abdulreda, Midhat H., Ricordi, Camillo, Caicedo, Alejandro, Pileggi, Antonello, and Berggren, Per-Olof

Published
2011
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23. Studying the biology of cytotoxic T lymphocytes in vivo with a fluorescent granzyme B-mTFP knock-in mouse

Author

Chitirala, Praneeth, primary, Chang, Hsin-Fang, additional, Martzloff, Paloma, additional, Harenberg, Christiane, additional, Ravichandran, Keerthana, additional, Abdulreda, Midhat H, additional, Berggren, Per-Olof, additional, Krause, Elmar, additional, Schirra, Claudia, additional, Leinders-Zufall, Trese, additional, Benseler, Fritz, additional, Brose, Nils, additional, and Rettig, Jens, additional

Published
2020
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24. Author response: Studying the biology of cytotoxic T lymphocytes in vivo with a fluorescent granzyme B-mTFP knock-in mouse

Author

Chitirala, Praneeth, primary, Chang, Hsin-Fang, additional, Martzloff, Paloma, additional, Harenberg, Christiane, additional, Ravichandran, Keerthana, additional, Abdulreda, Midhat H, additional, Berggren, Per-Olof, additional, Krause, Elmar, additional, Schirra, Claudia, additional, Leinders-Zufall, Trese, additional, Benseler, Fritz, additional, Brose, Nils, additional, and Rettig, Jens, additional

Published
2020
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26. Islet Transplantation to the Anterior Chamber of the Eye—A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate

Author

Tun, Sai Bo Bo, primary, Chua, Minni, additional, Hasan, Riasat, additional, Köhler, Martin, additional, Zheng, Xiaofeng, additional, Ali, Yusuf, additional, Abdulreda, Midhat H., additional, Juntti-Berggren, Lisa, additional, Barathi, Veluchamy A., additional, and Berggren, Per-Olof, additional

Published
2020
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27. Interplay between HGAL and Grb2 proteins regulates B-cell receptor signaling

Author

American Cancer Society, Miami University, National Institutes of Health (US), National Institute of General Medical Sciences (US), National Cancer Institute (US), Dwoskin Family Foundation, Jiang, Xiaoyu, Lu, Xiaoqing, Zhang, Yu, Lacaria, Leda, Schuchardt, Brett J., Mikles, David C., Magistri, Marco, García-Ramírez, Idoia, Sánchez García, Isidro, Farooq, Amjad, Verdun, Ramiro E., Abdulreda, Midhat H., Moy, Vincent T., Lossos, Izidore S., American Cancer Society, Miami University, National Institutes of Health (US), National Institute of General Medical Sciences (US), National Cancer Institute (US), Dwoskin Family Foundation, Jiang, Xiaoyu, Lu, Xiaoqing, Zhang, Yu, Lacaria, Leda, Schuchardt, Brett J., Mikles, David C., Magistri, Marco, García-Ramírez, Idoia, Sánchez García, Isidro, Farooq, Amjad, Verdun, Ramiro E., Abdulreda, Midhat H., Moy, Vincent T., and Lossos, Izidore S.

Abstract

Human germinal center (GC)–associated lymphoma (HGAL) is an adaptor protein expressed in GC B cells. HGAL regulates cell motility and B-cell receptor (BCR) signaling, processes that are central for the successful completion of the GC reaction. Herein, we demonstrate phosphorylation of HGAL by Syk and Lyn kinases at tyrosines Y80, Y86, Y106Y107, Y128, and Y148. The HGAL YEN motif (amino acids 107-109) is similar to the phosphopeptide motif pYXN used as a binding site to the growth factor receptor–bound protein 2 (Grb2). We demonstrate by biochemical and molecular methodologies that HGAL directly interacts with Grb2. Concordantly, microscopy studies demonstrate HGAL-Grb2 colocalization in the membrane central supramolecular activation clusters (cSMAC) following BCR activation. Mutation of the HGAL putative binding site to Grb2 abrogates the interaction between these proteins. Further, this HGAL mutant localizes exclusively in the peripheral SMAC and decreases the rate and intensity of BCR accumulation in the cSMAC. Furthermore, we demonstrate that Grb2, HGAL, and Syk interact in the same complex, but Grb2 does not modulate the effects of HGAL on Syk kinase activity. Overall, the interplay between the HGAL and Grb2 regulates the magnitude of BCR signaling and synapse formation.

Published
2019

29. Interplay between HGAL and Grb2 proteins regulates B-cell receptor signaling

Author

Jiang, Xiaoyu, primary, Lu, Xiaoqing, additional, Zhang, Yu, additional, Lacaria, Leda, additional, Schuchardt, Brett J., additional, Mikles, David C., additional, Magistri, Marco, additional, García-Ramírez, Idoia, additional, Sanchez-Garcia, Isidro, additional, Farooq, Amjad, additional, Verdun, Ramiro E., additional, Abdulreda, Midhat H., additional, Moy, Vincent T., additional, and Lossos, Izidore S., additional

Published
2019
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32. Apolipoprotein CIII links islet insulin resistance to beta-cell failure in diabetes

Author

Avall, Karin, Ali, Yusuf, Leibiger, Ingo B., Leibiger, Barbara, Moede, Tilo, Paschen, Meike, Dicker, Andrea, Dare, Elisabetta, Kohler, Martin, Ilegems, Erwin, Abdulreda, Midhat H., Graham, Mark, Crooke, Rosanne M., Tay, Vanessa S. Y., Refai, Essam, Nilsson, Stefan K., Jacob, Stefan, Selander, Lars, Berggren, Per-Olof, Juntti-Berggren, Lisa, Avall, Karin, Ali, Yusuf, Leibiger, Ingo B., Leibiger, Barbara, Moede, Tilo, Paschen, Meike, Dicker, Andrea, Dare, Elisabetta, Kohler, Martin, Ilegems, Erwin, Abdulreda, Midhat H., Graham, Mark, Crooke, Rosanne M., Tay, Vanessa S. Y., Refai, Essam, Nilsson, Stefan K., Jacob, Stefan, Selander, Lars, Berggren, Per-Olof, and Juntti-Berggren, Lisa

Abstract

Insulin resistance and beta-cell failure are the major defects in type 2 diabetes mellitus. However, the molecular mechanisms linking these two defects remain unknown. Elevated levels of apolipoprotein CIII (apoCIII) are associated not only with insulin resistance but also with cardiovascular disorders and inflammation. We now demonstrate that local apoCIII production is connected to pancreatic islet insulin resistance and beta-cell failure. An increase in islet apoCIII causes promotion of a local inflammatory milieu, increased mitochondrial metabolism, deranged regulation of beta-cell cytoplasmic free Ca2+ concentration ([Ca2+](i)) and apoptosis. Decreasing apoCIII in vivo results in improved glucose tolerance, and pancreatic apoCIII knockout islets transplanted into diabetic mice, with high systemic levels of the apolipoprotein, demonstrate a normal [Ca2+](i) response pattern and no hallmarks of inflammation. Hence, under conditions of islet insulin resistance, locally produced apoCIII is an important diabetogenic factor involved in impairment of beta-cell function and may thus constitute a novel target for the treatment of type 2 diabetes mellitus.

Published
2015
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33. Transplantation into the Anterior Chamber of the Eye for Longitudinal, Non-invasive In vivo Imaging with Single-cell Resolution in Real-time

Author

Abdulreda, Midhat H., Caicedo, Alejandro, and Berggren, Per-Olof

Subjects
Mice, Anterior Chamber, Islets of Langerhans Transplantation, Medicine, Animals, Single-Cell Analysis
Abstract

Intravital imaging has emerged as an indispensable tool in biological research. In the process, many imaging techniques have been developed to study different biological processes in animals non-invasively. However, a major technical limitation in existing intravital imaging modalities is the inability to combine non-invasive, longitudinal imaging with single-cell resolution capabilities. We show here how transplantation into the anterior chamber of the eye circumvents such significant limitation offering a versatile experimental platform that enables non-invasive, longitudinal imaging with cellular resolution in vivo. We demonstrate the transplantation procedure in the mouse and provide representative results using a model with clinical relevance, namely pancreatic islet transplantation. In addition to enabling direct visualization in a variety of tissues transplanted into the anterior chamber of the eye, this approach provides a platform to screen drugs by performing long-term follow up and monitoring in target tissues. Because of its versatility, tissue/cell transplantation into the anterior chamber of the eye not only benefits transplantation therapies, it extends to other in vivo applications to study physiological and pathophysiological processes such as signal transduction and cancer or autoimmune disease development.

Published
2013

34. In vivo imaging of kidney glomeruli transplanted into the anterior chamber of the mouse eye

Author

Kistler, Andreas D, Caicedo, Alejandro, Abdulreda, Midhat H, Faul, Christian, Kerjaschki, Dontscho, Berggren, Per-Olof, Reiser, Jochen, Fornoni, Alessia, Kistler, Andreas D, Caicedo, Alejandro, Abdulreda, Midhat H, Faul, Christian, Kerjaschki, Dontscho, Berggren, Per-Olof, Reiser, Jochen, and Fornoni, Alessia

Abstract

Multiphoton microscopy enables live imaging of the renal glomerulus. However, repeated in vivo imaging of the same glomerulus over extended periods of time and the study of glomerular function independent of parietal epithelial and proximal tubular cell effects has not been possible so far. Here, we report a novel approach for non-invasive imaging of acapsular glomeruli transplanted into the anterior chamber of the mouse eye. After microinjection, glomeruli were capable of engrafting on the highly vascularized iris. Glomerular structure was preserved, as demonstrated by podocyte specific expression of cyan fluorescent protein and by electron microscopy. Injection of fluorescence-labeled dextrans of various molecular weights allowed visualization of glomerular filtration and revealed leakage of 70 kDa dextran in an inducible model of proteinuria. Our findings demonstrate functionality and long-term survival of glomeruli devoid of Bowman's capsule and provide a novel approach for non-invasive longitudinal in vivo study of glomerular physiology and pathophysiology.

Published
2014

41. Letter about Coppetiers et. al

Author

Pileggi, Antonello, primary, Abdulreda, Midhat H., additional, Molano, R. Damaris, additional, Ricordi, Camillo, additional, Caicedo, Alejandro, additional, and Berggren, Per-Olof, additional

Published
2012
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50. TNF‐α and IFN‐γ promote lymphocyte adhesion to endothelial junctional regions facilitating transendothelial migration

Author

Jaczewska, Justyna, Abdulreda, Midhat H., Yau, Chi Y., Schmitt, Martin M., Schubert, Irene, Berggren, Per‐Olof, Weber, Christian, Koenen, Rory R., Moy, Vincent T., and Wojcikiewicz, Ewa P.

Abstract

JAM‐A redistribution on TNF‐α‐ and IFN‐γ‐treated endothelium promotes regions of enhanced adhesion measured by AFM that facilitate lymphocyte TEM. Inflammatory conditions induce redistribution of junctional adhesion receptors toward the apical regions of endothelial cells promoting lymphocyte TEM. Much of the molecular structures of TEM have been revealed; however, the biophysical mechanisms underlying this process remain to be fully elucidated. Here, we used immunofluorescence microscopy and AFM to study endothelial distribution of adhesion molecules upon lymphocyte activation and transmigration. Our immunofluorescence results revealed redistribution of JAM‐A and PECAM‐1 but not ICAM‐1 or VCAM‐1 toward the apical junctional regions of HUVECs following a 6‐h stimulation with TNF‐α and IFN‐γ. Consistently, our SCFS studies revealed that Jurkat cell adhesion to stimulated HUVEC monolayers was significantly greater in junctional regions. Enhanced adhesion was mediated mostly by JAM‐A receptors. Further AFM adhesion mapping of the homophilic JAM‐A/JAM‐A interaction on the surfaces of HUVECs revealed a greater number of JAM‐A receptors available for binding along junctional regions after TNF‐α and IFN‐γ stimulation. Our data reveal for the first time that adhesion “hot spots” of JAM‐A receptors are involved in initiating lymphocyte TEM under inflammatory conditions.

Published
2014
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