Digital Commons Network^™

Dopamine Buffering Capacity Imaging: A Pharmacodynamic Fmri Method For Staging Parkinson Disease, Kevin J Black, Haley K Acevedo, Jonathan M Koller

Open Access Publications

We propose a novel pharmacological fMRI (phMRI) method for objectively quantifying disease severity in Parkinson disease (PD). It is based on the clinical observation that the benefit from a dose of levodopa wears off more quickly as PD progresses. Biologically this has been thought to represent decreased buffering capacity for dopamine as nigrostriatal cells die. Buffering capacity has been modeled based on clinical effects, but clinical measurements are influenced by confounding factors. The new method proposes to measure the effect objectively based on the timing of the known response of several brain regions to exogenous levodopa. Such responses are robust …

Positive Allosteric Modulation Of Cd11b As A Novel Therapeutic Strategy Against Lung Cancer, Terese Geraghty, Anugraha Rajagopalan, Rabail Aslam, Alexander Pohlman, Ishwarya Venkatesh, Andrew Zloza, David Cimbaluk, David G Denardo, Vineet Gupta

Open Access Publications

Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMβ2), and plays an important role in recruitment and biological functions of these cells, …

Matriptase Cleaves Epcam And Trop2 In Keratinocytes, Destabilizing Both Proteins And Associated Claudins, Chuan-Jin Wu, Michael Lu, Xu Feng, Gaku Nakato, Mark C Udey

Open Access Publications

The homologs EpCAM and TROP2, which both interact with claudin-1 and claudin-7, are frequently coexpressed in epithelia including skin. Intestine uniquely expresses high levels of EpCAM but not TROP2. We previously identified EpCAM as a substrate of the membrane-anchored protease matriptase and linked HAI-2, matriptase, EpCAM and claudin-7 in a pathway that is pivotal for intestinal epithelial cells (IEC) homeostasis. Herein, we reveal that TROP2 is also a matriptase substrate. Matriptase cleaved TROP2 when purified recombinant proteins were mixed in vitro. TROP2, like EpCAM, was also cleaved after co-transfection of matriptase in 293T cells. Neither EpCAM nor TROP2 cleavage was …

Structural Mechanism For Gating Of A Eukaryotic Mechanosensitive Channel Of Small Conductance, Zengqin Deng, Grigory Maksaev, Angela M. Schlegel, Jingying Zhang, Michael Rau, James A. J. Fitzpatrick, Elizabeth S. Haswell, Peng Yuan

Open Access Publications

No abstract provided.

The Gut Microbiome Defines Social Group Membership In Honey Bee Colonies, Cassondra L Vernier, Iris M Chin, Boahemaa Adu-Oppong, Joshua J Krupp, Joel Levine, Gautam Dantas, Yehuda Ben-Shahar

Open Access Publications

In the honey bee, genetically related colony members innately develop colony-specific cuticular hydrocarbon profiles, which serve as pheromonal nestmate recognition cues. Yet, despite high intracolony relatedness, the innate development of colony-specific chemical signatures by individual colony members is largely determined by the colony environment, rather than solely relying on genetic variants shared by nestmates. Therefore, it is puzzling how a nongenic factor could drive the innate development of a quantitative trait that is shared by members of the same colony. Here, we provide one solution to this conundrum by showing that nestmate recognition cues in honey bees are defined, at …

Canonical Signaling By Tgf Family Members In Mesenchymal Stromal Cells Is Dispensable For Hematopoietic Niche Maintenance Under Basal And Stress Conditions, Joseph Ryan Krambs, Grazia Abou Ezzi, Juo-Chin Yao, Daniel C. Link

Open Access Publications

Mesenchymal stromal cells are an important component of the bone marrow hematopoietic niche. Prior studies showed that signaling from members of the transforming growth factor (TGF) superfamily in mesenchymal stromal cells is required for normal niche development. Here, we assessed the impact of TGF family signaling on niche maintenance and stress responses by deleting Smad4 in mesenchymal stromal cells at birth, thereby abrogating canonical TGF signaling. No alteration in the number or spatial organization of CXCL12-abundant reticular (CAR) cells, osteoblasts, or adipocytes was observed in Osx-Cre, Smad4fl/fl mice, and expression of key niche factors was normal. Basal hematopoiesis and stress …

Diet-Induced Metabolic Dysregulation In Female Mice Causes Osteopenia In Adult Offspring, Yu Shi, Jessica L. Saben, Guangxu He, Kelle H. Moley, Fanxin Long

Open Access Publications

Bone mass and quality in humans are controlled by numerous genetic and environmental factors that are not fully understood. Increasing evidence has indicated that maternal metabolic dysregulation impairs multiple physiological processes in the adult offspring, but a similar effect on bone health is yet to be established. Here, we have analyzed the bones of first-generation offspring from murine dams that present metabolic syndrome due to a high-fat and high-sugar (HF/HS) diet. Micro-CT analyses show that the long bones of HF/HS offspring possess lower cortical bone mass and weaker mechanical strength than normal, even though the trabecular bone is not affected. …

Rev-Erb Agonism Improves Liver Pathology In A Mouse Model Of Nash, Kristine Griffett, Gonzalo Bedia-Diaz, Bahaa Elgendy, Thomas P. Burris

Open Access Publications

Non-alcoholic fatty liver disease (NAFLD) affects a significant number of people worldwide and currently there are no pharmacological treatments. NAFLD often presents with obesity, insulin resistance, and in some cases cardiovascular diseases. There is a clear need for treatment options to alleviate this disease since it often progresses to much more the much more severe non-alcoholic steatohepatitis (NASH). The REV-ERB nuclear receptor is a transcriptional repressor that regulates physiological processes involved in the development of NAFLD including lipogenesis and inflammation. We hypothesized that pharmacologically activating REV-ERB would suppress the progression of fatty liver in a mouse model of NASH. Using …

Human Ipsc-Derived Neuronal Cells From Ctbp1-Mutated Patients Reveal Altered Expression Of Neurodevelopmental Gene Networks, S Vijayalingam, Eric Tycksen, Christina A Gurnett, Et Al

Open Access Publications

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Fenofibrate Prevents Iron Induced Activation Of Canonical Wnt/Β-Catenin And Oxidative Stress Signaling In The Retina, Ashok Mandala, Austin Armstrong, Becky Girresch, Jiyao Zhu, Aruna Chilakala, Sanmathi Chavalmane, Kapil Chaudhary, Pratim Biswas, Judith Ogilvie, Jaya P. Gnana-Prakasam

Open Access Publications

No abstract provided.

Hla‑A Alleles Including Hla‑A29 Affect The Composition Of The Gut Microbiome: A Potential Clue To The Pathogenesis Of Birdshot Retinochoroidopathy, Peter R. Sternes, Tammy M. Martin, Michael Paley, Sarah Diamond, Mark J. Asquith, Matthew A. Brown, James T. Rosenbaum

Open Access Publications

No abstract provided.

A Harmonized Meta-Knowledgebase Of Clinical Interpretations Of Somatic Genomic Variants In Cancer, Alex H. Wagner, Kilannin Krysiak, Malachi Griffith, Obi L. Griffith, Et Al.

Open Access Publications

No abstract provided.

Diet Modifies Pioglitazone’S Influence On Hepatic Pparγ-Regulated Mitochondrial Gene Expression, Sakil Kulkarni, Jiansheng Huang, Eric Tycksen, Paul F. Cliften, David A. Rudnick

Open Access Publications

No abstract provided.

Tumor Microenvironment-Targeted Nanoparticles Loaded With Bortezomib And Rock Inhibitor Improve Efficacy In Multiple Myeloma, Cinzia Federico, Kinan Alhallak, Jennifer Sun, Kathleen Duncan, Feda Azab, Gail P. Sudlow, Pilar De La Puente, Barbara Muz, Vaishali Kapoor, Luna Zhang, Fangzheng Yuan, Matea Markovic, Joseph Kotsybar, Katherine Wasden, Nicole Guenthner, Shannon Gurley, Justin King, Daniel Kohnen, Noha N. Salama, Dinesh Thotala, Dennis E. Hallahan, Ravi Vij, John F. Dipersio, Samuel Achilefu, Abdel Kareem Azab

Open Access Publications

No abstract provided.

Stretchable, Dynamic Covalent Polymers For Soft, Long-Lived Bioresorbable Electronic Stimulators Designed To Facilitate Neuromuscular Regeneration, Yeon Sik Choi, Ying Yan, Matthew R. Macewan, Wilson Z. Ray, Et Al.

Open Access Publications

No abstract provided.

A Feasibility Study To Evaluate Early Treatment Response Of Brain Metastases One Week After Stereotactic Radiosurgery Using Perfusion Weighted Imaging, Jiayi Huang, Mikhail Milchenko, Yuan J. Rao, Pamela Lamontagne, Christopher Abraham, Clifford G. Robinson, Yi Huang, Joshua S. Shimony, Keith M. Rich, Tammie Benzinger

Open Access Publications

BACKGROUND: To explore if early perfusion-weighted magnetic resonance imaging (PWI) may be a promising imaging biomarker to predict local recurrence (LR) of brain metastases after stereotactic radiosurgery (SRS).

METHODS: This is a prospective pilot study of adult brain metastasis patients who were treated with SRS and imaged with PWI before and 1 week later. Relative cerebral blood volume (rCBV) parameter maps were calculated by normalizing to the mean value of the contralateral white matter on PWI. Cox regression was conducted to explore factors associated with time to LR, with Bonferroni adjusted p<0.0006 for multiple testing correction. LR rates were estimated with the Kaplan-Meier method and compared using the log-rank test.

RESULTS: Twenty-three patients were enrolled from 2013 through …

Structural Basis Of Chikungunya Virus Inhibition By Monoclonal Antibodies, Qun Fei Zhou, Julie M. Fox, James T. Earnest, Thiam-Seng Ng, Arthur S. Kim, Guntur Fibriansah, Victor A. Kostyuchenko, Jian Shi, Bo Shu, Michael S. Diamond, Shee-Mei Lok

Open Access Publications

No abstract provided.

Cathepsin S And Protease-Activated Receptor-2 Drive Alloimmunity And Immune Regulation In Kidney Allograft Rejection, Yutian Lei, Benjamin Ehle, Santhosh V Kumar, Susanne Müller, Solange Moll, Andrew F Malone, Benjamin D Humphreys, Joachim Andrassy, Hans-Joachim Anders

Open Access Publications

Alloantigen presentation is an essential process in acute allorejection. In this context, we speculated on a pathogenic role of cathepsin S (Cat-S), a cysteine protease known to promote antigenic peptide loading into MHC class II and to activate protease-activated receptor (PAR)-2 on intrarenal microvascular endothelial and tubular epithelial cells. Single-cell RNA sequencing and immunostaining of human kidney allografts confirmed Cat-S expression in intrarenal mononuclear phagocytes.

Formation Of Lung Inducible Bronchus Associated Lymphoid Tissue Is Regulated By Mycobacterium Tuberculosis Expressed Determinants, Micah D Dunlap, Oliver A Prince, Javier Rangel-Moreno, Kimberly A Thomas, Julia M Scordo, Jordi B Torrelles, Jeffery Cox, Adrie J C Steyn, Joaquín Zúñiga, Deepak Kaushal, Shabaana A Khader

Open Access Publications

No abstract provided.

Effects Of Early Life Exposure To Traffic-Related Air Pollution On Brain Development In Juvenile Sprague-Dawley Rats, Kelley T. Patten, Eduardo A. González, Anthony Valenzuela, Elizabeth Berg, Christopher Wallis, Joel R. Garbow, Jill L. Silverman, Keith J. Bein, Anthony S. Wexler, Pamela J. Lein

Open Access Publications

No abstract provided.

Policies And Practices Of Shea Research Network Hospitals During The Covid-19 Pandemic, Michael S Calderwood, Valerie M Deloney, Deverick J Anderson, Vincent Chi-Chung Cheng, Shruti Gohil, Jennie H Kwon, Lona Mody, Elizabeth Monsees, Valerie M Vaughn, Timothy L Wiemken, Matthew J Ziegler, Eric Lofgren

Open Access Publications

To understand hospital policies and practices as the COVID-19 pandemic accelerated, the Society for Healthcare Epidemiology of America (SHEA) conducted a survey through the SHEA Research Network (SRN). The survey assessed policies and practices around the optimization of personal protection equipment (PPE), testing, healthcare personnel policies, visitors of COVID-19 patients in relation to procedures, and types of patients. Overall, 69 individual healthcare facilities responded in the United States and internationally, for a 73% response rate.

Alpha-Crystallin Mutations Alter Lens Metabolites In Mouse Models Of Human Cataracts, Cheryl Frankfater, Stephanie L. Bozeman, Fong-Fu Hsu, Usha P. Andley

Open Access Publications

Cataracts are a major cause of blindness worldwide and commonly occur in individuals over 70 years old. Cataracts can also appear earlier in life due to genetic mutations. The lens proteins, αA- and αB-crystallins, are chaperone proteins that have important roles maintaining protein solubility to prevent cataract formation. Mutations in the CRYAA and CRYAB crystallin genes are associated with autosomal dominant early onset human cataracts. Although studies about the proteomic and genomic changes that occur in cataracts have been reported, metabolomics studies are very limited. Here, we directly investigated cataract metabolism using gas-chromatography-mass spectrometry (GC-MS) to analyze the metabolites in …

Experience-Dependent Resonance In Amygdalocortical Circuits Supports Fear Memory Retrieval Following Extinction, Minagi Ozawa, Patrick Davis, Jianguang Ni, Jamie Maquire, Thomas Papouin, Leon Reijmers

Open Access Publications

No abstract provided.

Comprehensive Identification Of Mrna Isoforms Reveals The Diversity Of Neural Cell-Surface Molecules With Roles In Retinal Development And Disease, Thomas A. Ray, Martha A. Cady, William J. Spencer, Philip A. Ruzycki, Brian S. Clark, Et Al.

Open Access Publications

No abstract provided.

Bioinspired Thermosensitive Hydrogel As A Vitreous Substitute: Synthesis, Properties, And Progress Of Animal Studies, Amine Laradji, Ying-Bo Shui, Bedia Begum Karakocak, Lynn Evans, Paul Hamilton, Nathan Ravi

Open Access Publications

In many vitreal diseases, the surgeon removes the natural vitreous and replaces it with silicone oils, gases, or balanced salt solutions to fill the eyeball and hold the retina in position. However, these materials are often associated with complications and have properties that differ from natural vitreous. Herein, we report an extension of our previous work on the synthesis of a biomimetic hydrogel that is composed of thiolated gellan as an analogue of type II collagen and poly(methacrylamide-co-methacrylate-co-bis(methacryloyl)cystamine), a polyelectrolyte, as an analogue of hyaluronic acid. This thermosensitive hydrogel can be injected into the eye as a viscous solution at …

Krabbe Disease Successfully Treated Via Monotherapy Of Intrathecal Gene Therapy, Allison M Bradbury, Xuntian Jiang, Mark S Sands, Daniel S Ory, Et Al

Open Access Publications

Globoid cell leukodystrophy (GLD; Krabbe disease) is a progressive, incurable neurodegenerative disease caused by deficient activity of the hydrolytic enzyme galactosylceramidase (GALC). The ensuing cytotoxic accumulation of psychosine results in diffuse central and peripheral nervous system (CNS, PNS) demyelination. Presymptomatic hematopoietic stem cell transplantation (HSCT) is the only treatment for infantile-onset GLD; however, clinical outcomes of HSCT recipients often remain poor, and procedure-related morbidity is high. There are no effective therapies for symptomatic patients. Herein, we demonstrate in the naturally occurring canine model of GLD that presymptomatic monotherapy with intrathecal AAV9 encoding canine GALC administered into the cisterna magna increased …

Focused Ultrasound For Safe And Effective Release Of Brain Tumor Biomarkers Into The Peripheral Circulation, Lifei Zhu, Arash Nazeri, Christopher Pham Pacia, Yimei Yue, Hong Chen

Open Access Publications

The development of noninvasive approaches for brain tumor diagnosis and monitoring continues to be a major medical challenge. Although blood-based liquid biopsy has received considerable attention in various cancers, limited progress has been made for brain tumors, at least partly due to the hindrance of tumor biomarker release into the peripheral circulation by the blood-brain barrier. Focused ultrasound (FUS) combined with microbubbles induced BBB disruption has been established as a promising technique for noninvasive and localized brain drug delivery. Building on this established technique, we propose to develop FUS-enabled liquid biopsy technique (FUS-LBx) to enhance the release of brain tumor …

Spatial Mapping Of The Collagen Distribution In Human And Mouse Tissues By Force Volume Atomic Force Microscopy, Annalisa Calò, Yevgeniy Romin, Rami Srouji, Constantinos P. Zambirinis, Ning Fan, Anthony Santella, Elvin Feng, Sho Fujisawa, Mesruh Turkekul, Sharon Huang, Amber L. Simpson, Michael D'Angelica, William R. Jarnagin, Katia Manova-Todorova

Open Access Publications

No abstract provided.

Deeph&M: Estimating Single-Cpg Hydroxymethylation And Methylation Levels From Enrichment And Restriction Enzyme Sequencing Methods, Yu He, Hyo Sik Jang, Xiaoyun Xing, Daofeng Li, Michael J Vasek, Joseph D Dougherty, Ting Wang

Open Access Publications

Increased appreciation of 5-hydroxymethylcytosine (5hmC) as a stable epigenetic mark, which defines cell identity and disease progress, has engendered a need for cost-effective, but high-resolution, 5hmC mapping technology. Current enrichment-based technologies provide cheap but low-resolution and relative enrichment of 5hmC levels, while single-base resolution methods can be prohibitively expensive to scale up to large experiments. To address this problem, we developed a deep learning-based method, "DeepH&M," which integrates enrichment and restriction enzyme sequencing methods to simultaneously estimate absolute hydroxymethylation and methylation levels at single-CpG resolution. Using 7-week-old mouse cerebellum data for training the DeepH&M model, we demonstrated that the 5hmC …

Targeting Cxcr4 In Aml And All, Daniel Cancilla, Michael P Rettig, John F Dipersio

Open Access Publications

The interaction of acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) blasts with the bone marrow microenvironment regulates self-renewal, growth signaling, as well as chemotherapy resistance. The chemokine receptor, CXC receptor 4 (CXCR4), with its ligand chemokine ligand 12 (CXCL12), plays a key role in the survival and migration of normal and malignant stem cells to the bone marrow. High expression of CXCR4 on AML and ALL blasts has been shown to be a predictor of poor prognosis for these diseases. Several small molecule inhibitors, short peptides, antibodies, and antibody drug conjugates have been developed for the purposes of …