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Item The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration(American Society for Clinical Investigation, 2019-09-03) Uchida, Masaki; Maier, Bernhard; Waghwani, Hitesh Kumar; Selivanovitch, Ekaterina; Pay, S. Louise; Avera, John; Yun, EJun; Sandoval, Ruben M.; Molitoris, Bruce A.; Zollman, Amy; Douglas, Trevor; Hato, Takashi; Medicine, School of MedicineNature exploits cage-like proteins for a variety of biological purposes, from molecular packaging and cargo delivery to catalysis. These cage-like proteins are of immense importance in nanomedicine due to their propensity to self-assemble from simple identical building blocks to highly ordered architecture and the design flexibility afforded by protein engineering. However, delivery of protein nanocages to the renal tubules remains a major challenge because of the glomerular filtration barrier, which effectively excludes conventional size nanocages. Here, we show that DNA-binding protein from starved cells (Dps) — the extremely small archaeal antioxidant nanocage — is able to cross the glomerular filtration barrier and is endocytosed by the renal proximal tubules. Using a model of endotoxemia, we present an example of the way in which proximal tubule–selective Dps nanocages can limit the degree of endotoxin-induced kidney injury. This was accomplished by amplifying the endogenous antioxidant property of Dps with addition of a dinuclear manganese cluster. Dps is the first-in-class protein cage nanoparticle that can be targeted to renal proximal tubules through glomerular filtration. In addition to its therapeutic potential, chemical and genetic engineering of Dps will offer a nanoplatform to advance our understanding of the physiology and pathophysiology of glomerular filtration and tubular endocytosis.Item The Effects of Refractive Index Mismatch on Multiphoton Fluorescence Excitation Microscopy of Biological Tissue(2010-08-31T18:42:10Z) Young, Pamela Anne; Rubart, Michael; Decca, Ricardo S.; Bacallao, Robert L.; Dunn, Kenneth WilliamIntroduction: Multiphoton fluorescence excitation microscopy (MPM) is an invaluable tool for studying processes in tissue in live animals by enabling biologists to view tissues up to hundreds of microns in depth. Unfortunately, imaging depth in MPM is limited to less than a millimeter in tissue due to spherical aberration, light scattering, and light absorption. Spherical aberration is caused by refractive index mismatch between the objective immersion medium and sample. Refractive index heterogeneities within the sample cause light scattering. We investigate the effects of refractive index mismatch on imaging depth in MPM. Methods: The effects of spherical aberration on signal attenuation and resolution degradation with depth are characterized with minimal light absorption and scattering using sub-resolution microspheres mounted in test sample of agarose with varied refractive index. The effects of light scattering on signal attenuation and resolution degradation with depth are characterized using sub-resolution microspheres in kidney tissue samples mounted in optical clearing media to alter the refractive index heterogeneities within the tissue. Results: The studies demonstrate that signal levels and axial resolution both rapidly decline with depth into refractive index mismatched samples. Interestingly, studies of optical clearing with a water immersion objective show that reducing scattering increases reach even when it increases refractive index mismatch degrading axial resolution. Scattering, in the absence of spherical aberration, does not degrade axial resolution. The largest improvements in imaging depth are obtained when both scattering and refractive index mismatch are reduced. Conclusions: Spherical aberration, caused by refractive index mismatch between the immersion media and sample, and scattering, caused by refractive index heterogeneity within the sample, both cause signal to rapidly attenuate with depth in MPM. Scattering, however, seems to be the predominant cause of signal attenuation with depth in kidney tissue. Kenneth W. Dunn, Ph.D., ChairItem Evaluation of the follicular space volume of lower third molars with different impaction positions and angulations: A cone-beam computed tomography and histopathological study(Elsevier, 2023-03-30) Barroso, Marlene; Arriola-Guillén, Luis E.; Dutra, Vinicius; Rodríguez, Julio Escoto; Suárez, Gerardo Ruales; Oral Pathology, Medicine and Radiology, School of DentistryObjective: To quantify the volume of the follicular spaces of impacted lower third molars (ILTMs) with different impaction positions and angulations using cone-beam computed tomography (CBCT) and to determine its association with the histopathological findings. Study design: This study included 103 ILTMs of 33 men and 70 women aged 18-46 years (mean age, 29.18 years). The follicular space volumes were measured on CBCT by manual segmentation and correlated with the histopathological diagnosis of each ILTM having different impaction positions and angulations. Statistical Product and Service Solutions, version 24, was used for statistical analyses by applying the t-test and binary logistic regression and multiple linear regression tests (p < 0.05). Results: Overall, 83 (80.6%) dental follicles presented a non-pathological diagnosis (mean follicular volume, 0.10 cm3), whereas 20 (19.4%) presented a pathological diagnosis (mean follicular volume, 0.32 cm3; p = 0.001). Similarly, the impaction depth in Position C cases was associated with a pathological diagnosis (p = 0.010). Conclusion: The follicular volume of the ILTMs varied significantly in teeth with a histopathological diagnosis of a follicular cyst and was associated with the impaction depth, mainly in Position C cases, and its relationship with the mandibular ramus. A mean follicular volume of 0.32 cm3 was associated with a greater probability of a pathological diagnosis.Item Gastrointestinal carcinoma and sarcoma surgery(AME, 2019-06-05) Koniaris, Leonidas G.; Surgery, IU School of MedicineA number of advances in both earlier diagnostic imaging and better treatment options for patients with intra-abdominal malignancies have occurred. Frequently such newer therapies rely on the integration of established surgical and radiation approaches potentially with newer chemotherapies and immunomodulators. Unfortunately, with further study some newer therapies have proven less beneficial than initially suggested. Keeping up with the data supporting newer alternatives, and determining which therapies to provide patients can be a challenge. Nonetheless, integrating newer study data into beneficial therapeutic algorithms and understanding the molecular basis and rationale for new therapies remains a critically important role for treating physicians. To help provide busy clinicians and trainees with a current update for the management of intra-abdominal malignancies, this special issue of Translational Gastroenterology and Hepatology provides succinct reviews relevant to both diagnosis and treatment for patients with abdominal sarcoma or adenocarcinoma.Item Insurance Denials of Care Amount to Unlicensed Medical Practice(Academy of Managed Care Pharmacy, 2020) Bennett, William E.; Pediatrics, School of MedicineItem Mining brain imaging and genetics data via structured sparse learning(2015-04-29) Yan, Jingwen; Wu, Huanmei; Shen, Li; Fang, Shiaofen; Liu, XiaowenAlzheimer's disease (AD) is a neurodegenerative disorder characterized by gradual loss of brain functions, usually preceded by memory impairments. It has been widely affecting aging Americans over 65 old and listed as 6th leading cause of death. More importantly, unlike other diseases, loss of brain function in AD progression usually leads to the significant decline in self-care abilities. And this will undoubtedly exert a lot of pressure on family members, friends, communities and the whole society due to the time-consuming daily care and high health care expenditures. In the past decade, while deaths attributed to the number one cause, heart disease, has decreased 16 percent, deaths attributed to AD has increased 68 percent. And all of these situations will continue to deteriorate as the population ages during the next several decades. To prevent such health care crisis, substantial efforts have been made to help cure, slow or stop the progression of the disease. The massive data generated through these efforts, like multimodal neuroimaging scans as well as next generation sequences, provides unprecedented opportunities for researchers to look into the deep side of the disease, with more confidence and precision. While plenty of efforts have been made to pull in those existing machine learning and statistical models, the correlated structure and high dimensionality of imaging and genetics data are generally ignored or avoided through targeted analysis. Therefore their performances on imaging genetics study are quite limited and still have plenty to be improved. The primary contribution of this work lies in the development of novel prior knowledge-guided regression and association models, and their applications in various neurobiological problems, such as identification of cognitive performance related imaging biomarkers and imaging genetics associations. In summary, this work has achieved the following research goals: (1) Explore the multimodal imaging biomarkers toward various cognitive functions using group-guided learning algorithms, (2) Development and application of novel network structure guided sparse regression model, (3) Development and application of novel network structure guided sparse multivariate association model, and (4) Promotion of the computation efficiency through parallelization strategies.Item Radiologic Imaging of CAR T-Cell Therapy: Looking under the Hood to Move Us Forward(Radiological Society of North America, 2022) Langer, Mark P.; Radiation Oncology, School of MedicineItem Tau PET correlates with different Alzheimer’s disease‐related features compared to CSF and plasma p‐tau biomarkers(EMBO Press, 2021) Ossenkoppele, Rik; Reimand, Juhan; Smith, Ruben; Leuzy, Antoine; Strandberg, Olof; Palmqvist, Sebastian; Stomrud, Erik; Zetterberg, Henrik; Alzheimer’s Disease Neuroimaging Initiative; Scheltens, Philip; Dage, Jeffrey L.; Bouwman, Femke; Blennow, Kaj; Mattsson-Carlgren, Niklas; Janelidze, Shorena; Hansson, Oskar; Neurology, School of MedicinePET, CSF and plasma biomarkers of tau pathology may be differentially associated with Alzheimer's disease (AD)-related demographic, cognitive, genetic and neuroimaging markers. We examined 771 participants with normal cognition, mild cognitive impairment or dementia from BioFINDER-2 (n = 400) and ADNI (n = 371). All had tau-PET ([18 F]RO948 in BioFINDER-2, [18 F]flortaucipir in ADNI) and CSF p-tau181 biomarkers available. Plasma p-tau181 and plasma/CSF p-tau217 were available in BioFINDER-2 only. Concordance between PET, CSF and plasma tau biomarkers ranged between 66 and 95%. Across the whole group, ridge regression models showed that increased CSF and plasma p-tau181 and p-tau217 levels were independently of tau PET associated with higher age, and APOEɛ4-carriership and Aβ-positivity, while increased tau-PET signal in the temporal cortex was associated with worse cognitive performance and reduced cortical thickness. We conclude that biofluid and neuroimaging markers of tau pathology convey partly independent information, with CSF and plasma p-tau181 and p-tau217 levels being more tightly linked with early markers of AD (especially Aβ-pathology), while tau-PET shows the strongest associations with cognitive and neurodegenerative markers of disease progression.Item What the duct: Imaging ductular reaction spanning the fibrotic areas in primary sclerosing cholangitis (PSC)(Elsevier, 2022) Owen, Travis; Francis, Heather; Alpini, Gianfranco; Kennedy, Lindsey; Medicine, School of Medicine