13 results on '"Charles K. F. Chan"'
Search Results
2. Denervation during mandibular distraction osteogenesis results in impaired bone formation
- Author
-
Ruth Tevlin, Michelle Griffin, Kellen Chen, Michael Januszyk, Nick Guardino, Amanda Spielman, Shannon Walters, Garry Evan Gold, Charles K. F. Chan, Geoffrey C. Gurtner, Derrick C. Wan, and Michael T. Longaker
- Subjects
Medicine ,Science - Abstract
Abstract Mandibular distraction osteogenesis (DO) is mediated by skeletal stem cells (SSCs) in mice, which enact bone regeneration via neural crest re-activation. As peripheral nerves are essential to progenitor function during development and in response to injury, we questioned if denervation impairs mandibular DO. C57Bl6 mice were divided into two groups: DO with a segmental defect in the inferior alveolar nerve (IAN) at the time of mandibular osteotomy (“DO Den”) and DO with IAN intact (“DO Inn”). DO Den demonstrated significantly reduced histological and radiological osteogenesis relative to DO Inn. Denervation preceding DO results in reduced SSC amplification and osteogenic potential in mice. Single cell RNA sequencing analysis revealed that there was a predominance of innervated SSCs in clusters dominated by pathways related to bone formation. A rare human patient specimen was also analyzed and suggested that histological, radiological, and transcriptional alterations seen in mouse DO may be conserved in the setting of denervated human mandible distraction. Fibromodulin (FMOD) transcriptional and protein expression were reduced in denervated relative to innervated mouse and human mandible regenerate. Finally, when exogenous FMOD was added to DO-Den and DO-Inn SSCs undergoing in vitro osteogenic differentiation, the osteogenic potential of DO-Den SSCs was increased in comparison to control untreated DO-Den SSCs, modeling the superior osteogenic potential of DO-Inn SSCs.
- Published
- 2023
- Full Text
- View/download PDF
3. Sexually dimorphic estrogen sensing in skeletal stem cells controls skeletal regeneration
- Author
-
Tom W. Andrew, Lauren S. Koepke, Yuting Wang, Michael Lopez, Holly Steininger, Danielle Struck, Tatiana Boyko, Thomas H. Ambrosi, Xinming Tong, Yuxi Sun, Gunsagar S. Gulati, Matthew P. Murphy, Owen Marecic, Ruth Tevlin, Katharina Schallmoser, Dirk Strunk, Jun Seita, Stuart B. Goodman, Fan Yang, Michael T. Longaker, George P. Yang, and Charles K. F. Chan
- Subjects
Science - Abstract
Abstract Sexually dimorphic tissues are formed by cells that are regulated by sex hormones. While a number of systemic hormones and transcription factors are known to regulate proliferation and differentiation of osteoblasts and osteoclasts, the mechanisms that determine sexually dimorphic differences in bone regeneration are unclear. To explore how sex hormones regulate bone regeneration, we compared bone fracture repair between adult male and female mice. We found that skeletal stem cell (SSC) mediated regeneration in female mice is dependent on estrogen signaling but SSCs from male mice do not exhibit similar estrogen responsiveness. Mechanistically, we found that estrogen acts directly on the SSC lineage in mice and humans by up-regulating multiple skeletogenic pathways and is necessary for the stem cell’s ability to self- renew and differentiate. Our results also suggest a clinically applicable strategy to accelerate bone healing using localized estrogen hormone therapy.
- Published
- 2022
- Full Text
- View/download PDF
4. Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus
- Author
-
Yuxi Sun, Tatiana Boyko, Owen Marecic, Danielle Struck, Randall K. Mann, Tom W. Andrew, Michael Lopez, Xinming Tong, Stuart B. Goodman, Fan Yang, Michael T. Longaker, Charles K. F. Chan, and George P. Yang
- Subjects
fracture healing ,bone regeneration ,skeletal progenitor cells ,Del1 ,proliferation ,Microbiology ,QR1-502 - Abstract
Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.
- Published
- 2023
- Full Text
- View/download PDF
5. Cross-species comparisons reveal resistance of human skeletal stem cells to inhibition by non-steroidal anti-inflammatory drugs
- Author
-
L. Henry Goodnough, Thomas H. Ambrosi, Holly M. Steininger, M. Gohazrua K. Butler, Malachia Y. Hoover, HyeRan Choo, Noelle L. Van Rysselberghe, Michael J. Bellino, Julius A. Bishop, Michael J. Gardner, and Charles K. F. Chan
- Subjects
skeletal stem cells (SSCs) ,non-steroid antiinflamatory drugs ,species specificity ,bone regeneration ,inflammation ,fracture healing ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Fracture healing is highly dependent on an early inflammatory response in which prostaglandin production by cyclo-oxygenases (COX) plays a crucial role. Current patient analgesia regimens favor opioids over Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) since the latter have been implicated in delayed fracture healing. While animal studies broadly support a deleterious role of NSAID treatment to bone-regenerative processes, data for human fracture healing remains contradictory. In this study, we prospectively isolated mouse and human skeletal stem cells (SSCs) from fractures and compared the effect of various NSAIDs on their function. We found that osteochondrogenic differentiation of COX2-expressing mouse SSCs was impaired by NSAID treatment. In contrast, human SSCs (hSSC) downregulated COX2 expression during differentiation and showed impaired osteogenic capacity if COX2 was lentivirally overexpressed. Accordingly, short- and long-term treatment of hSSCs with non-selective and selective COX2 inhibitors did not affect colony forming ability, chondrogenic, and osteogenic differentiation potential in vitro. When hSSCs were transplanted ectopically into NSG mice treated with Indomethacin, graft mineralization was unaltered compared to vehicle injected mice. Thus, our results might contribute to understanding species-specific differences in NSAID sensitivity during fracture healing and support emerging clinical data which conflicts with other earlier observations that NSAID administration for post-operative analgesia for treatment of bone fractures are unsafe for patients.
- Published
- 2022
- Full Text
- View/download PDF
6. Optimizing Delivery of Therapeutic Growth Factors for Bone and Cartilage Regeneration
- Author
-
Eri Takematsu, Matthew Murphy, Sophia Hou, Holly Steininger, Alina Alam, Thomas H. Ambrosi, and Charles K. F. Chan
- Subjects
therapeutic growth factor delivery ,osteoarthritis ,osteoporosis ,controlled delivery ,osteoimmunology ,biomaterials ,Science ,Chemistry ,QD1-999 ,Inorganic chemistry ,QD146-197 ,General. Including alchemy ,QD1-65 - Abstract
Bone- and cartilage-related diseases, such as osteoporosis and osteoarthritis, affect millions of people worldwide, impairing their quality of life and increasing mortality. Osteoporosis significantly increases the bone fracture risk of the spine, hip, and wrist. For successful fracture treatment and to facilitate proper healing in the most complicated cases, one of the most promising methods is to deliver a therapeutic protein to accelerate bone regeneration. Similarly, in the setting of osteoarthritis, where degraded cartilage does not regenerate, therapeutic proteins hold great promise to promote new cartilage formation. For both osteoporosis and osteoarthritis treatments, targeted delivery of therapeutic growth factors, with the aid of hydrogels, to bone and cartilage is a key to advance the field of regenerative medicine. In this review article, we propose five important aspects of therapeutic growth factor delivery for bone and cartilage regeneration: (1) protection of protein growth factors from physical and enzymatic degradation, (2) targeted growth factor delivery, (3) controlling GF release kinetics, (4) long-term stability of regenerated tissues, and (5) osteoimmunomodulatory effects of therapeutic growth factors and carriers/scaffolds.
- Published
- 2023
- Full Text
- View/download PDF
7. Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis
- Author
-
Siddharth Menon, Ankit Salhotra, Siny Shailendra, Ruth Tevlin, Ryan C. Ransom, Michael Januszyk, Charles K. F. Chan, Björn Behr, Derrick C. Wan, Michael T. Longaker, and Natalina Quarto
- Subjects
Science - Abstract
Cranial sutures are major growth centers for the skull vault and premature fusion leads to pathological fusion, craniosynostosis. Here the authors isolate Wnt responsive skeletal stem and progenitor cells from sutures, that can be transplanted together with Wnt3a protein to repair craniosynostosis in a mouse model.
- Published
- 2021
- Full Text
- View/download PDF
8. A Revised Perspective of Skeletal Stem Cell Biology
- Author
-
Thomas H. Ambrosi, Michael T. Longaker, and Charles K. F. Chan
- Subjects
bone ,skeletal stem cell ,bone marrow/mesenchymal stromal/stem cell ,stem cell niche ,heterogeneity ,regeneration ,Biology (General) ,QH301-705.5 - Abstract
Bone-related maladies are a major health burden on modern society. Loss of skeletal integrity and regeneration capacity through aging, obesity, and disease follows from a detrimental shift in bone formation and resorption dynamics. Targeting tissue-resident adult stem cells offers a potentially innovative paradigm in the development of therapeutic strategies against organ dysfunction. While the essential role of skeletal stem cells (SSCs) for development, growth, and maintenance of the skeleton has been generally established, a common consensus on the exact identity and definition of a pure bona fide SSC population remains elusive. The controversies stem from conflicting results between different approaches and criteria for isolation, detection, and functional evaluation; along with the interchangeable usage of the terms SSC and “mesenchymal stromal/stem cell (MSC)”. A great number of prospective bone-forming stem cell populations have been reported with various characteristic markers, often describing overlapping cell populations with widely unexplored heterogeneity, species specificity, and distribution at distinct skeletal sites, bone regions, and microenvironments, thereby creating confusion that may complicate future advances in the field. In this review, we examine the state-of-the-art knowledge of SSC biology and try to establish a common ground for the definition and terminology of specific bone-resident stem cells. We also discuss recent advances in the identification of highly purified SSCs, which will allow detailed interrogation of SSC diversity and regulation at the single-cell level.
- Published
- 2019
- Full Text
- View/download PDF
9. A seed-and-soil theory for blood ageing
- Author
-
Thomas H. Ambrosi and Charles K. F. Chan
- Subjects
Cell Biology - Published
- 2023
10. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans
- Author
-
Robert C, Jones, Jim, Karkanias, Mark A, Krasnow, Angela Oliveira, Pisco, Stephen R, Quake, Julia, Salzman, Nir, Yosef, Bryan, Bulthaup, Phillip, Brown, William, Harper, Marisa, Hemenez, Ravikumar, Ponnusamy, Ahmad, Salehi, Bhavani A, Sanagavarapu, Eileen, Spallino, Ksenia A, Aaron, Waldo, Concepcion, James M, Gardner, Burnett, Kelly, Nikole, Neidlinger, Zifa, Wang, Sheela, Crasta, Saroja, Kolluru, Maurizio, Morri, Serena Y, Tan, Kyle J, Travaglini, Chenling, Xu, Marcela, Alcántara-Hernández, Nicole, Almanzar, Jane, Antony, Benjamin, Beyersdorf, Deviana, Burhan, Kruti, Calcuttawala, Matthew M, Carter, Charles K F, Chan, Charles A, Chang, Stephen, Chang, Alex, Colville, Rebecca N, Culver, Ivana, Cvijović, Gaetano, D'Amato, Camille, Ezran, Francisco X, Galdos, Astrid, Gillich, William R, Goodyer, Yan, Hang, Alyssa, Hayashi, Sahar, Houshdaran, Xianxi, Huang, Juan C, Irwin, SoRi, Jang, Julia Vallve, Juanico, Aaron M, Kershner, Soochi, Kim, Bernhard, Kiss, William, Kong, Maya E, Kumar, Angera H, Kuo, Rebecca, Leylek, Baoxiang, Li, Gabriel B, Loeb, Wan-Jin, Lu, Sruthi, Mantri, Maxim, Markovic, Patrick L, McAlpine, Antoine, de Morree, Karim, Mrouj, Shravani, Mukherjee, Tyler, Muser, Patrick, Neuhöfer, Thi D, Nguyen, Kimberly, Perez, Ragini, Phansalkar, Nazan, Puluca, Zhen, Qi, Poorvi, Rao, Hayley, Raquer-McKay, Nicholas, Schaum, Bronwyn, Scott, Bobak, Seddighzadeh, Joe, Segal, Sushmita, Sen, Shaheen, Sikandar, Sean P, Spencer, Lea C, Steffes, Varun R, Subramaniam, Aditi, Swarup, Michael, Swift, Will, Van Treuren, Emily, Trimm, Stefan, Veizades, Sivakamasundari, Vijayakumar, Kim Chi, Vo, Sevahn K, Vorperian, Wanxin, Wang, Hannah N W, Weinstein, Juliane, Winkler, Timothy T H, Wu, Jamie, Xie, Andrea R, Yung, Yue, Zhang, Angela M, Detweiler, Honey, Mekonen, Norma F, Neff, Rene V, Sit, Michelle, Tan, Jia, Yan, Gregory R, Bean, Vivek, Charu, Erna, Forgó, Brock A, Martin, Michael G, Ozawa, Oscar, Silva, Angus, Toland, Venkata N P, Vemuri, Shaked, Afik, Kyle, Awayan, Olga Borisovna, Botvinnik, Ashley, Byrne, Michelle, Chen, Roozbeh, Dehghannasiri, Adam, Gayoso, Alejandro A, Granados, Qiqing, Li, Gita, Mahmoudabadi, Aaron, McGeever, Julia Eve, Olivieri, Madeline, Park, Neha, Ravikumar, Geoff, Stanley, Weilun, Tan, Alexander J, Tarashansky, Rohan, Vanheusden, Peter, Wang, Sheng, Wang, Galen, Xing, Rebecca, Culver, Les, Dethlefsen, Po-Yi, Ho, Shixuan, Liu, Jonathan S, Maltzman, Ross J, Metzger, Koki, Sasagawa, Rahul, Sinha, Hanbing, Song, Bruce, Wang, Steven E, Artandi, Philip A, Beachy, Michael F, Clarke, Linda C, Giudice, Franklin W, Huang, Kerwyn Casey, Huang, Juliana, Idoyaga, Seung K, Kim, Mark, Krasnow, Christin S, Kuo, Patricia, Nguyen, Thomas A, Rando, Kristy, Red-Horse, Jeremy, Reiter, David A, Relman, Justin L, Sonnenburg, Albert, Wu, Sean M, Wu, and Tony, Wyss-Coray
- Subjects
B-Lymphocytes ,Multidisciplinary ,Cells ,RNA Splicing ,T-Lymphocytes ,T-Lymphocytes/metabolism ,Article ,Organ Specificity/genetics ,Atlases as Topic ,Organ Specificity ,Humans ,Cells/metabolism ,B-Lymphocytes/metabolism ,Single-Cell Analysis ,Transcriptome - Abstract
INTRODUCTION: Although the genome is often called the blueprint of an organism, it is perhaps more accurate to describe it as a parts list composed of the various genes that may or may not be used in the different cell types of a multicellular organism. Although nearly every cell in the body has essentially the same genome, each cell type makes different use of that genome and expresses a subset of all possible genes. This has motivated efforts to characterize the molecular composition of various cell types within humans and multiple model organisms, both by transcriptional and proteomic approaches. We created a human reference atlas comprising nearly 500,000 cells from 24 different tissues and organs, many from the same donor. This atlas enabled molecular characterization of more than 400 cell types, their distribution across tissues, and tissue-specific variation in gene expression. RATIONALE: One caveat to current approaches to make cell atlases is that individual organs are often collected at different locations, collected from different donors, and processed using different protocols. Controlled comparisons of cell types between different tissues and organs are especially difficult when donors differ in genetic background, age, environmental exposure, and epigenetic effects. To address this, we developed an approach to analyzing large numbers of organs from the same individual. RESULTS: We collected multiple tissues from individual human donors and performed coordinated single-cell transcriptome analyses on live cells. The donors come from a range of ethnicities, are balanced by gender, have a mean age of 51 years, and have a variety of medical backgrounds. Tissue experts used a defined cell ontology terminology to annotate cell types consistently across the different tissues, leading to a total of 475 distinct cell types with reference transcriptome profiles. The full dataset can be explored online with the cellxgene tool. Data were collected for the bladder, blood, bone marrow, eye, fat, heart, kidney, large intestine, liver, lung, lymph node, mammary, muscle, pancreas, prostate, salivary gland, skin, small intestine, spleen, thymus, tongue, trachea, uterus, and vasculature. Fifty-nine separate specimens in total were collected, processed, and analyzed, and 483,152 cells passed quality control filtering. On a per-compartment basis, the dataset includes 264,824 immune cells, 104,148 epithelial cells, 31,691 endothelial cells, and 82,478 stromal cells. Working with live cells, as opposed to isolated nuclei, ensured that the dataset includes all mRNA transcripts within the cell, including transcripts that have been processed by the cell’s splicing machinery, thereby enabling insight into variation in alternative splicing. The Tabula Sapiens also provided an opportunity to densely and directly sample the human microbiome throughout the gastrointestinal tract. The intestines from two donors were sectioned into five regions: the duodenum, jejunum, ileum, and ascending and sigmoid colon. Each section was transected, and three to nine samples were collected from each location, followed by amplification and sequencing of the 16S ribosomal RNA gene. CONCLUSION: The Tabula Sapiens has revealed discoveries relating to shared behavior and subtle, organ-specific differences across cell types. We found T cell clones shared between organs and characterized organ-dependent hypermutation rates among B cells. Endothelial cells and macrophages are shared across tissues, often showing subtle but clear differences in gene expression. We found an unexpectedly large and diverse amount of cell type–specific RNA splice variant usage and discovered and validated many previously undefined splices. The intestinal microbiome was revealed to have nonuniform species distributions down to the 3-inch (7.62-cm) length scale. These are but a few examples of how the Tabula Sapiens represents a broadly useful reference to deeply understand and explore human biology at cellular resolution.
- Published
- 2022
11. Aging of Skeletal Stem Cells
- Author
-
M Gohazrua K, Butler, Thomas H, Ambrosi, Matthew P, Murphy, and Charles K F, Chan
- Subjects
General Medicine - Abstract
The skeletal system is generated and maintained by its progenitors, skeletal stem cells (SSCs), across the duration of life. Gradual changes associated with aging result in significant differences in functionality of SSCs. Declines in bone and cartilage production, increase of bone marrow adipose tissue, compositional changes of cellular microenvironments, and subsequent deterioration of external and internal structures culminate in the aged and weakened skeleton. The features and mechanisms of skeletal aging, and of its stem and progenitor cells in particular, are topics of recent investigation. The discovery of functionally homogeneous SSC populations with a defined cell surface phenotype has allowed for closer inspection of aging in terms of its effects on transcriptional regulation, cell function, and identity. Here, we review the aspects of SSC aging on both micro- and macroscopic levels. Up-to-date knowledge of SSC biology and aging is presented, and directions for future research and potential therapies are discussed. The realm of SSC-mediated bone aging remains an important component of global health and a necessary facet in our understanding of human aging.
- Published
- 2022
12. Single-cell transcriptomic characterization of 20 organs and tissues from individual mice creates a Tabula Muris
- Author
-
Nicholas Schaum, Jim Karkanias, Norma F Neff, Andrew P. May, Stephen R. Quake, Tony Wyss-Coray, Spyros Darmanis, Joshua Batson, Olga Botvinnik, Michelle B. Chen, Steven Chen, Foad Green, Robert Jones, Ashley Maynard, Lolita Penland, Rene V. Sit, Geoffrey M. Stanley, James T. Webber, Fabio Zanini, Ankit S. Baghel, Isaac Bakerman, Ishita Bansal, Daniela Berdnik, Biter Bilen, Douglas Brownfield, Corey Cain, Min Cho, Giana Cirolia, Stephanie D. Conley, Aaron Demers, Kubilay Demir, Antoine de Morree, Tessa Divita, Haley du Bois, Laughing Bear Torrez Dulgeroff, Hamid Ebadi, F. Hernan Espinoza, Matt Fish, Qiang Gan, Benson M. George, Astrid Gillich, Geraldine Genetiano, Xueying Gu, Gunsagar S. Gulati, Yan Hang, Shayan Hosseinzadeh, Albin Huang, Tal Iram, Taichi Isobe, Feather Ives, Kevin S. Kao, Guruswamy Karnam, Aaron M. Kershner, Bernhard Kiss, William Kong, Maya E. Kumar, Jonathan Lam, Davis P. Lee, Song E. Lee, Guang Li, Qingyun Li, Ling Liu, Annie Lo, Wan-Jin Lu, Anoop Manjunath, Kaia L. May, Oliver L. May, Marina McKay, Ross J. Metzger, Marco Mignardi, Dullei Min, Ahmad N. Nabhan, Katharine M. Ng, Joseph Noh, Rasika Patkar, Weng Chuan Peng, Robert Puccinelli, Eric J. Rulifson, Shaheen S. Sikandar, Rahul Sinha, Rene V Sit, Krzysztof Szade, Weilun Tan, Cristina Tato, Krissie Tellez, Kyle J. Travaglini, Carolina Tropini, Lucas Waldburger, Linda J. van Weele, Michael N. Wosczyna, Jinyi Xiang, Soso Xue, Justin Youngyunpipatkul, Macy E. Zardeneta, Fan Zhang, Lu Zhou, Norma F. Neff, Paola Castro, Derek Croote, Joseph L. DeRisi, Angela Pisco, Bernhard M. Kiss, Christin S. Kuo, Benoit Lehallier, Patricia K. Nguyen, Serena Y. Tan, Bruce M. Wang, Hanadie Yousef, Philip A. Beachy, Charles K. F. Chan, Kerwyn Casey Huang, Kenneth Weinberg, Sean Wu, Ben A. Barres, Michael F. Clarke, Seung K. Kim, Mark A. Krasnow, Norma Neff, Roel Nusse, Thomas A. Rando, Justin Sonnenburg, Irving L. Weissman, and Sean M. Wu
- Subjects
Transcriptome ,Cell type ,medicine.anatomical_structure ,Single cell transcriptome ,ved/biology ,Gene expression ,Cell ,ved/biology.organism_classification_rank.species ,medicine ,Transcript analysis ,Biology ,Model organism ,Cell biology - Abstract
The Tabula Muris ConsortiumWe have created a compendium of single cell transcriptome data from the model organism Mus musculus comprising more than 100,000 cells from 20 organs and tissues. These data represent a new resource for cell biology, revealing gene expression in poorly characterized cell populations and allowing for direct and controlled comparison of gene expression in cell types shared between tissues, such as T-lymphocytes and endothelial cells from distinct anatomical locations. Two distinct technical approaches were used for most tissues: one approach, microfluidic droplet-based 3’-end counting, enabled the survey of thousands of cells at relatively low coverage, while the other, FACS-based full length transcript analysis, enabled characterization of cell types with high sensitivity and coverage. The cumulative data provide the foundation for an atlas of transcriptomic cell biology.
- Published
- 2017
- Full Text
- View/download PDF
13. Discussion: Regeneration of Vascularized Corticocancellous Bone and Diploic Space Using Muscle-Derived Stem Cells: A Translational Biologic Alternative for Healing Critical Bone Defects
- Author
-
Matthew P, Murphy, Charles K F, Chan, and Michael T, Longaker
- Subjects
Biological Products ,Wound Healing ,Bone Regeneration ,Stem Cells ,Humans ,Regeneration ,Bone and Bones ,Article - Published
- 2017
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.