Digital Commons Network^™

Transcutaneous Auricular Vagus Nerve Stimulation-Paired Rehabilitation For Oromotor Feeding Problems In Newborns: An Open-Label Pilot Study, Bashar W. Badran, Dorothea D. Jenkins, Daniel Cook, Sean Thompson, Morgan Darcy, William H. Devries, Georgia Mappin, Philipp Summers, Marom Bikson, Mark S. George

Publications and Research

Neonates born premature or who suffer brain injury at birth often have oral feeding dysfunction and do not meet oral intake requirements needed for discharge. Low oral intake volumes result in extended stays in the hospital (>2 months) and can lead to surgical implant and explant of a gastrostomy tube (G-tube). Prior work suggests pairing vagus nerve stimulation (VNS) with motor activity accelerates functional improvements after stroke, and transcutaneous auricular VNS (taVNS) has emerged as promising noninvasive form of VNS. Pairing taVNS with bottle-feeding rehabilitation may improve oromotor coordination and lead to improved oral intake volumes, ultimately avoiding the …

Discovery Of A Bacterial Peptide As A Modulator Of Glp-1 And Metabolic Disease, Catherine Tomaro-Duchesneau, Stephanie L Levalley, Daniel Roeth, Liang Sun, Frank T Horrigan, Markus Kalkum, Joseph M Hyser, Robert A Britton

Faculty, Staff and Students Publications

Early work in rodents highlighted the gut microbiota's importance in metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-like peptide-1 (GLP-1), an incretin secreted by L-cells lining the gastrointestinal epithelium, has important functions: promoting insulin secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and appetite. We set out to identify microbial strains with GLP-1 stimulatory activity as potential metabolic disease therapeutics. Over 1500 human-derived strains were isolated from healthy individuals and screened for GLP-1 modulation by incubating bacterial cell-free supernatants with NCI H716 L-cells. Approximately 45 strains capable of increasing GLP-1 were discovered. All GLP-1 positive …

The Sineb1 Element In The Long Non-Coding Rna Malat1 Is Necessary For Tdp-43 Proteostasis, Tuan M Nguyen, Elena B Kabotyanski, Lucas C Reineke, Jiaofang Shao, Feng Xiong, Joo-Hyung Lee, Julien Dubrulle, Hannah Johnson, Fabio Stossi, Phoebe S Tsoi, Kyoung-Jae Choi, Alexander G Ellis, Na Zhao, Jin Cao, Oluwatoyosi Adewunmi, Josephine C Ferreon, Allan Chris M Ferreon, Joel R Neilson, Michael A Mancini, Xi Chen, Jongchan Kim, Li Ma, Wenbo Li, Jeffrey M Rosen

Faculty, Staff and Students Publications

Transposable elements (TEs) comprise a large proportion of long non-coding RNAs (lncRNAs). Here, we employed CRISPR to delete a short interspersed nuclear element (SINE) in Malat1, a cancer-associated lncRNA, to investigate its significance in cellular physiology. We show that Malat1 with a SINE deletion forms diffuse nuclear speckles and is frequently translocated to the cytoplasm. SINE-deleted cells exhibit an activated unfolded protein response and PKR and markedly increased DNA damage and apoptosis caused by dysregulation of TDP-43 localization and formation of cytotoxic inclusions. TDP-43 binds stronger to Malat1 without the SINE and is likely 'hijacked' by cytoplasmic Malat1 to the …

Gut Microbial Protein Expression In Response To Dietary Patterns In A Controlled Feeding Study: A Metaproteomic Approach, Sheng Pan, Meredith A J Hullar, Lisa A Lai, Hong Peng, Damon H May, William S Noble, Daniel Raftery, Sandi L Navarro, Marian L Neuhouser, Paul D Lampe, Johanna W Lampe, Ru Chen

Faculty, Staff and Students Publications

Although the gut microbiome has been associated with dietary patterns linked to health, microbial metabolism is not well characterized. This ancillary study was a proof of principle analysis for a novel application of metaproteomics to study microbial protein expression in a controlled dietary intervention. We measured the response of the microbiome to diet in a randomized crossover dietary intervention of a whole-grain, low glycemic load diet (WG) and a refined-grain, high glycemic load diet (RG). Total proteins in stools from 9 participants at the end of each diet period (

Approaches To Overcome Flow Cytometry Limitations In The Analysis Of Cells From Veterinary Relevant Species, Julia Hunka, John T. Riley, Gudrun F. Debes

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Flow cytometry is a powerful tool for the multiparameter analysis of leukocyte subsets on the single cell level. Recent advances have greatly increased the number of fluorochrome-labeled antibodies in flow cytometry. In particular, an increase in available fluorochromes with distinct excitation and emission spectra combined with novel multicolor flow cytometers with several lasers have enhanced the generation of multidimensional expression data for leukocytes and other cell types. However, these advances have mainly benefited the analysis of human or mouse cell samples given the lack of reagents for most animal species. The flow cytometric analysis of important veterinary, agricultural, wildlife, …

Cell Type Composition And Circuit Organization Of Clonally Related Excitatory Neurons In The Juvenile Mouse Neocortex, Cathryn R Cadwell, Federico Scala, Paul G Fahey, Dmitry Kobak, Shalaka Mulherkar, Fabian H Sinz, Stelios Papadopoulos, Zheng H Tan, Per Johnsson, Leonard Hartmanis, Shuang Li, Ronald J Cotton, Kimberley F Tolias, Rickard Sandberg, Philipp Berens, Xiaolong Jiang, Andreas Savas Tolias

Faculty, Staff and Students Publications

Clones of excitatory neurons derived from a common progenitor have been proposed to serve as elementary information processing modules in the neocortex. To characterize the cell types and circuit diagram of clonally related excitatory neurons, we performed multi-cell patch clamp recordings and Patch-seq on neurons derived from Nestin-positive progenitors labeled by tamoxifen induction at embryonic day 10.5. The resulting clones are derived from two radial glia on average, span cortical layers 2–6, and are composed of a random sampling of transcriptomic cell types. We find an interaction between shared lineage and connection type: related neurons are more likely to …

Comparison Of Outcomes Following Minimally Invasive And Open Posterior Cervical Foraminotomy: Description Of Minimally Invasive Technique And Review Of Literature., Andrew Platt, Carter S Gerard, John E O'Toole

Articles, Abstracts, and Reports

Although minimally invasive posterior cervical foraminotomy (MIS-PCF) is frequently employed in the treatment of cervical radiculopathy, there are very few studies directly comparing outcomes between MIS-PCF and open posterior cervical foraminotomy and between MIS-PCF and percutaneous endoscopic (full-endoscopic) posterior cervical foraminotomy (FE-PCF). This study includes a description of technique and systematic review of literature and analysis of clinical studies comparing outcomes between MIS-PCF and open posterior cervical foraminotomy and between MIS-PCF and FE-PCF. Six comparative studies, including one randomized controlled trial were included in analysis. Average operative time ranged from 60.5 to 171 minutes in the open group and 77.65 …

Short-Term Outcome Of Onabotulinumtoxin A Injection For The Treatment Of Refractory Idiopathic Detrusor Overactivity, Amr M. Elsofy, Ayman M. Gabr, Gamal E. A. Abourjila, Khalid F. Elewa

Journal of Medicine in Scientific Research

Introduction There are many theories behind the etiology of refractory idiopathic detrusor overactivity (IDO), but it is generally accepted that it is caused by a combination of myogenic and neurogenic alterations. It is also believed that mucosal sensory systems make a significant contribution to the disorder as well. Intravesical botulinum toxin A (BoNT/A) prevents acetylcholine release at the neuromuscular junction, resulting in temporary chemodenervation and muscle relaxation. The aim of this work was to assessment of outcome of BoNT/A injection for the treatment of refractory IDO. Patients and methods The author included 37 patients who received intravesical BoNT/A for the …

Probable African Tick Bite Fever In The United States, Kami Lowery, Theodore Rosen

Faculty, Staff and Students Publications

African tick bite fever (ATBF) is a tick-borne rickettsial disease most often observed in North American and European tourists returning home from the southern portion of Africa. Ticks infected with Rickettsia africae transmit this parasitic bacterium to humans, who subsequently develop an influenza-like illness, one or more inoculation eschars, and in some cases, a cutaneous rash. Because ATBF often presents with non-specific symptoms that suggest other infectious diseases, establishing the diagnosis may be difficult. Confirmatory assays, including serology and nucleic acid amplification, may take weeks to return and cannot help with acute treatment decisions. We present a case of a …

Safety And Efficacy Profile Of Ozenoxacin 1% Cream In Pediatric Patients With Impetigo, Adelaide A Hebert, Theodore Rosen, Núria Albareda López, Ilonka Zsolt, Xavier Masramon

Faculty, Staff and Students Publications

BACKGROUND: Ozenoxacin is a topical antibiotic approved in the United States for treatment of impetigo in adults and children age ≥2 months. This analysis evaluated the efficacy and safety of ozenoxacin in specific pediatric age groups.

METHODS: Data for children aged 2 months to <18 years recruited from eight countries who had participated in phase 1 and 3 trials of ozenoxacin were extracted and analyzed by age range.

RESULTS: Across studies, 644 pediatric patients with impetigo received ozenoxacin 1% cream (n = 287) or vehicle (n = 247). One study included retapamulin 1% ointment as the internal validity control (n = 110). The clinical success rate at the end of treatment and bacterial eradication rates after 3 to 4 days of treatment and at …

Mail-Back Envelopes For Retrieval Of Opioids After Pediatric Surgery, Adam C Adler, Ammar N Yamani, Caitlin D Sutton, Danielle M Guffey, Arvind Chandrakantan

Faculty, Staff and Students Publications

BACKGROUND: Opioid overprescription has the potential to lead to harmful medications remaining in homes and to a rise in accidental or deliberate ingestion by children and adolescents. Although methods for opioid disposal are available, many are costly or require greater than minimal effort for the patient. In this study, we used a mail-back return envelope to retrieve unused opioids after ambulatory pediatric surgery.

METHODS: This feasibility study was performed to assess the rate of opioid return by using a mail-back envelope for children ages 0 to 18 prescribed opioids after outpatient surgery. Participants were provided a return envelope as well …

Temporal Trends And Geographic Variations In Mortality Rates From Prescription Opioids: Lessons From Florida And West Virginia, Sarah A Palumbo, Charles H Hennekens, Janet D Robishaw, Robert S Levine

Faculty, Staff and Students Publications

OBJECTIVES: To explore temporal trends and geographic variations in mortality from prescription opioids from 1999 to 2016.

METHODS: Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Multiple Cause of Death files were used to calculate age-adjusted rates and 95% confidence intervals (CIs) and create spatial cluster maps.

RESULTS: From 1999 to 2016, counties in West Virginia experienced the highest overall mortality rates in the United States from prescription opioids. Specifically, from 1999 to 2004, the highest rate in West Virginia of 24.87/100,000 (95% CI 17.84-33.73) was the fourth highest in the United States. From 2005 to …

The Impact Of Diabetic Foot Ulcers And Unilateral Offloading Footwear On Gait In People With Diabetes, Erica Ling, Brian Lepow, He Zhou, Ana Enriquez, Ashley Mullen, Bijan Najafi

Faculty, Staff and Students Publications

BACKGROUND: Unilateral offloading footwear prescribed to patients with diabetic foot ulcers elevates one limb relative to the other, which may lead to limp and abnormal gait. This study investigated whether the unilateral foot ulcer and offloading combination negatively impacts gait function beyond diabetic peripheral neuropathy.

METHODS: Eighty-six participants were recruited in 3 groups: 12 with diabetic peripheral neuropathy and unilateral foot ulcers wearing offloading footwear (offloading group, age = 55.6 ± 9.5 years, BMI = 30.9 ± 4.5 kg/m

FINDINGS: The offloading group exhibited deteriorated gait function compared to the non-diabetic group (p < 0.005, Cohen's effect size d = 0.90-2.61). They also had decreased gait speed (p < 0.001, d = 1.79) and stride length (p < 0.001, d = 1.76), as well as increased gait cycle time (p < 0.001, d = 1.67) and limp (p < 0.050, d = 0.72-1.49) compared to the neuropathy group. The offloading group showed increased gait unsteadiness compared to the neuropathy group, but the difference did not reach statistical significance in our samples.

INTERPRETATION: This study demonstrated that while diabetic …

The Struggling Infectious Diseases Fellow: Remediation Challenges And Opportunities, Michael T Melia, Armando Paez, Gail Reid, Lisa M Chirch, Vera P Luther, Brian G Blackburn, Federico Perez, Emily Abdoler, Daniel R Kaul, Susan Rehm, Nada Harik, Alice Barsoumian, Anna K Person, Heather Yun, J David Beckham, Susan Boruchoff, Paloma F Cariello, James B Cutrell, Christopher J Graber, Dong Heun Lee, Eileen Maziarz, Molly L Paras, Raymund R Razonable, Roseanne Ressner, Anne Chen, Brian Chow, Gerome Escota, Erica Herc, Andrew Johnson, Ryan C Maves, Obinna Nnedu, Heather Clauss, Prathit Kulkarni, Paul S Pottinger, Jose A Serpa, Tanaya Bhowmick, Marvin Bittner, Darcy Wooten, Beata Casanas, Rachel Shnekendorf, Emily A Blumberg

Faculty, Staff and Students Publications

Remediation of struggling learners is a challenge faced by all educators. In recognition of this reality, and in light of contemporary challenges facing infectious diseases (ID) fellowship program directors, the Infectious Diseases Society of America Training Program Directors' Committee focused the 2018 National Fellowship Program Directors' Meeting at IDWeek on "Remediation of the Struggling Fellow." Small group discussions addressed 7 core topics, including feedback and evaluations, performance management and remediation, knowledge deficits, fellow well-being, efficiency and time management, teaching skills, and career development. This manuscript synthesizes those discussions around a competency-based framework to provide program directors and other educators with …

Orthostatic Hypotension, Cardiovascular Outcomes, And Adverse Events: Results From Sprint, Stephen P Juraschek, Addison A Taylor, Jackson T Wright, Gregory W Evans, Edgar R Miller, Timothy B Plante, William C Cushman, Tanya R Gure, William E Haley, Imran Moinuddin, John Nord, Suzanne Oparil, Carolyn Pedley, Christianne L Roumie, Jeff Whittle, Alan Wiggers, Ciarán Finucane, Rose Anne Kenny, Lawrence J Appel, Raymond R Townsend

Faculty, Staff and Students Publications

Orthostatic hypotension (OH) is frequently observed with hypertension treatment, but its contribution to adverse outcomes is unknown. The Systolic Blood Pressure Intervention Trial (SPRINT) was a randomized trial of adults, age ≥50years at high risk for cardiovascular disease (CVD) with a seated systolic BP (SBP) of 130–180 mmHg and a standing SBP ≥110 mmHg. Participants were randomized to a SBP treatment goal of either <120 mmHg or <140 mmHg. OH was defined as a drop in SBP≥20 or diastolic BP ≥10 mmHg one minute after standing from a seated position. We used Cox models to examine the association of OH with CVD or adverse study events by randomized BP goal. During the follow-up period (median 3years), there were 1,170 (5.7%) instances of OH among those assigned a standard BP goal, and 1,057 (5.0%) among those assigned the intensive BP goal. OH was not associated with higher risk of CVD events (primary outcome: HR 1.06; 95%CI: 0.78,1.44). Moreover, OH was not associated with syncope, electrolyte abnormalities, injurious falls, or acute renal failure. OH was associated with hypotension-related hospitalizations or emergency department visits (HR 1.77; 1.11,2.82) and bradycardia (HR 1.94; 1.19,3.15), but these associations did not differ by BP treatment goal. OH was not associated with a higher risk of CVD events and BP treatment goal had no effect on OH’s association with hypotension and bradycardia. Symptomless OH during hypertension treatment should not be viewed as a reason to down-titrate therapy even in the setting of a lower BP goal.

Methyl-Sensing Nuclear Receptor Liver Receptor Homolog-1 Regulates Mitochondrial Function In Mouse Hepatocytes, Sungwoo Choi, Bingning Dong, Chih-Chun Janet Lin, Mi Jeong Heo, Kang Ho Kim, Zhen Sun, Martin Wagner, Nagireddy Putluri, Jae Myoung Suh, Meng C Wang, David D Moore

Faculty, Staff and Students Publications

Liver receptor homologue-1 (LRH-1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH-1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid via the Kennedy pathway, or trimethylation of phosphatidylethanolamine via Phosphatidylethanolamine N-methyl Transferase (PEMT). Here we report that a PEMT - LRH-1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh-1 reduces mitochondrial number, basal respiration, beta-oxidation and ATP production in hepatocytes, and decreases expression of mitochondrial …

Dissociable Posterior And Anterior Insula Activations In Processing Negative Stimulus Before And After The Application Of Cognitive Reappraisals, Ze Zhang, Tingting Guo, Jin Fan, Xiaofei Wu, Tengteng Tan, Jing Luo

Publications and Research

Although the role of the insular cortex in representing bodily and emotional feelings has been recognized, whether the mid-posterior and anterior parts of the insula act differentially in the encoding and regulation of emotional feelings is still unclear. In this functional magnetic resonance imaging (fMRI) study, we examined the effects of the creative cognitive reappraisals versus the non-creative ordinary reappraisals on the activation pattern of the mid-posterior and anterior insular cortex during the processing of unpleasant pictures by comparing the neural correlates for processing these pictures before and after the application of cognitive reappraisals. We found significant anterior insular activation …

Adjuvant Therapy In Adrenocortical Carcinoma: Reflections And Future Directions, Sara Bedrose, Marilyne Daher, Lina Altameemi, Mouhammed Amir Habra

Faculty, Staff and Students Publications

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with high risk of recurrence despite macroscopically complete surgical resection. The main predictors of ACC recurrence include advanced disease stage, incomplete surgical resection, cortisol production, certain genetic alterations, and high proliferation rate (Ki-67 proliferation index). Mitotane has been the mainstay adjuvant therapy of ACC. However, the use of mitotane is based on retrospective and occasionally conflicting evidence. As mitotane levels can take a few months before reaching therapeutic levels, there is an emerging practice of combining platinum-based chemotherapy with mitotane in the adjuvant setting. Retrospective data indicate that radiotherapy is an …

Antagonistic Regulation Of Circadian Output And Synaptic Development By Jetlag And The Dyschronic-Slowpoke Complex, Angelique Lamaze, James E.C. Jepson, Oghenerukevwe Akpoghiran, Kyunghee Koh

Department of Neuroscience Faculty Papers

Circadian output genes act downstream of the clock to promote rhythmic changes in behavior and physiology, yet their molecular and cellular functions are not well understood. Here we characterize an interaction between regulators of circadian entrainment, output, and synaptic development in Drosophila that influences clock-driven anticipatory increases in morning and evening activity. We previously showed the JETLAG (JET) E3 ubiquitin ligase resets the clock upon light exposure, whereas the PDZ protein DYSCHRONIC (DYSC) regulates circadian locomotor output and synaptic development. Surprisingly, we find that JET and DYSC antagonistically regulate synaptic development at the larval neuromuscular junction, and reduced JET activity …

Comparison Of Microneutralization And Histo-Blood Group Antigen-Blocking Assays For Functional Norovirus Antibody Detection, Robert L Atmar, Khalil Ettayebi, B Vijayalakshmi Ayyar, Frederick H Neill, Ralph P Braun, Sasirekha Ramani, Mary K Estes

Faculty, Staff and Students Publications

BACKGROUND: The development of an in vitro cultivation system for human noroviruses allows the measurement of neutralizing antibody levels.

METHODS: Serum neutralizing antibody levels were determined using a GII.4/Sydney/2012-like virus in human intestinal enteroids in samples collected before and 4 weeks after administration of an investigational norovirus vaccine and were compared with those measured in histo-blood group antigen (HBGA)-blocking assays.

RESULTS: Neutralizing antibody seroresponses were observed in 71% of 24 vaccinated adults, and antibody levels were highly correlated (r = 0.82, P < .001) with those measured by HBGA blocking.

CONCLUSIONS: HBGA-blocking antibodies are a surrogate for neutralization in human noroviruses.

Vancomycin In Peritoneal Dialysis: Clinical Pharmacology Considerations In Therapy., Edwin Lam, Yi Ting Kayla Lien, Walter K. Kraft, Beth Piraino, Valvanera Vozmediano, Stephan Schmidt, Jingjing Zhang

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Intraperitoneal vancomycin is the first-line therapy in the management of peritoneal dialysis (PD)-related peritonitis. However, due to the paucity of data, vancomycin dosing for peritonitis in patients on automated peritoneal dialysis (APD) is empiric and based on clinical experience rather than evidence. Studies in continuous ambulatory peritoneal dialysis (CAPD) patients have been used to provide guidelines for dosing and are often extrapolated for APD use, but it is unclear whether this is appropriate. This review summarizes the available pharmacokinetic data used to inform optimal dosing in patients on CAPD or APD. The determinants of vancomycin disposition and pharmacodynamic effects are …

Mathematical Model Of Atm Activation And Chromatin Relaxation By Ionizing Radiation, Yongfeng Li, Francis A. Cucinotta

Healthcare Administration and Policy Faculty Research

International Journal of Molecular Sciences

Nanocatalytic Activity Of Clean-Surfaced, Faceted Nanocrystalline Gold Enhances Remyelination In Animal Models Of Multiple Sclerosis., Andrew P. Robinson, Joanne Zhongyan Zhang, Haley E. Titus, Molly Karl, Mikhail Merzliakov, Adam R. Dorfman, Stephen Karlik, Michael G G. Stewart, Richard K. Watt, Benjin D. Facer, Jon D. Facer, Noah D. Christian, Karen S. Ho, Michael T. Hotchkin, Mark G. Mortenson, Robert H. Miller, Stephen D. Miller

Student Papers, Posters & Projects

Development of pharmacotherapies that promote remyelination is a high priority for multiple sclerosis (MS), due to their potential for neuroprotection and restoration of function through repair of demyelinated lesions. A novel preparation of clean-surfaced, faceted gold nanocrystals demonstrated robust remyelinating activity in response to demyelinating agents in both chronic cuprizone and acute lysolecithin rodent animal models. Furthermore, oral delivery of gold nanocrystals improved motor functions of cuprizone-treated mice in both open field and kinematic gait studies. Gold nanocrystal treatment of oligodendrocyte precursor cells in culture resulted in oligodendrocyte maturation and expression of myelin differentiation markers. Additional in vitro data demonstrated …

The Project Talent Twin And Sibling Study: Zygosity And New Data Collection, Carol A. Prescott, Ellen E. Walters, Thalida Em Arpawong, Catalina Zavala, Tara L. Gruenewald, Margaret Gatz

Psychology Faculty Articles and Research

The Project Talent Twin and Sibling (PTTS) study includes 4481 multiples and their 522 nontwin siblings from 2233 families. The sample was drawn from Project Talent, a U.S. national longitudinal study of 377,000 individuals born 1942–1946, first assessed in 1960 and representative of U.S. students in secondary school (Grades 9–12). In addition to the twins and triplets, the 1960 dataset includes 84,000 siblings from 40,000 other families. This design is both genetically informative and unique in facilitating separation of the ‘common’ environment into three sources of variation: shared by all siblings within a family, specific to twin-pairs, and associated with …

Expression Of Tryptophan 2,3-Dioxygenase In Metastatic Uveal Melanoma, Mizue Terai, Eric R Londin, Ankit Rochani, Emma Link, Bao Lam, Gagan Kaushal, Alok Bhushan, Marlana Orloff, Takami Sato

Kimmel Cancer Center Faculty Papers

Uveal melanoma (UM) is the most common primary eye malignancy in adults and up to 50% of patients subsequently develop systemic metastasis. Metastatic uveal melanoma (MUM) is highly resistant to immunotherapy. One of the mechanisms for resistance would be the immune-suppressive tumor microenvironment. Here, we have investigated the role of tryptophan 2,3-dioxygenase (TDO) in UM. Both TDO and indoleamine 2,3-dioxygenase (IDO) catalyze tryptophan and produce kynurenine, which could cause inhibition of T cell immune responses. We first studied the expression of TDO on tumor tissue specimens obtained from UM hepatic metastasis. High expression of TDO protein was confirmed in all …

Homogeneous And Functional Group Tolerant Ring-Closing Metathesis For Dna-Encoded Chemical Libraries, Olivier B C Monty, Pranavanand Nyshadham, Kurt M Bohren, Murugesan Palaniappan, Martin M Matzuk, Damian W Young, Nicholas Simmons

Faculty, Staff and Students Publications

Reaction heterogeneity, poor pH control, and catalyst decomposition in the ring-closing metathesis (RCM) of DNA–chemical conjugates lead to poor yields of the cyclized products. Herein we address these issues with a RCM reaction system that includes a novel aqueous solvent combination to enable reaction homogeneity, an acidic buffer system which masks traditionally problematic functional groups, and a decomposition-resistant catalyst which maximizes conversion to the cyclized product. Additionally, we provide a systematic study of the substrate scope of the on-DNA RCM reaction, a demonstration of its applicability to a single-substrate DNA-encoded chemical library that includes sequencing analysis, and the first successful …

A Broad-Spectrum Antiviral Molecule, Ql47, Selectively Inhibits Eukaryotic Translation, Mélissanne De Wispelaere, Margot Carocci, Dominique J Burri, William J Neidermyer, Calla M Olson, Imme Roggenbach, Yanke Liang, Jinhua Wang, Sean P J Whelan, Nathanael S Gray, Priscilla L Yang

Faculty, Staff and Students Publications

Small-molecule inhibitors of translation are critical tools to study the molecular mechanisms of protein synthesis. In this study, we sought to characterize how QL47, a host-targeted, small-molecule antiviral agent, inhibits steady-state viral protein expression. We demonstrate that this small molecule broadly inhibits both viral and host protein synthesis and targets a translation step specific to eukaryotic cells. We show that QL47 inhibits protein neosynthesis initiated by both canonical cap-driven and noncanonical initiation strategies, most likely by targeting an early step in translation elongation. Our findings thus establish QL47 as a new small-molecule inhibitor that can be utilized to probe the …

The Role Of Noninvasive Tests For Differentiating Nash From Nafl And Diagnosing Advanced Fibrosis Among Patients With Nafld, Maya Balakrishnan, Rohit Loomba

Faculty, Staff and Students Publications

Assessing for the presence of non-alcoholic steatohepatitis (NASH) and the presence of advanced fibrosis is vital among patients with non-alcoholic fatty liver disease (NAFLD) as each is predictive of disease outcomes. A liver biopsy is the gold standard method for doing so but is impossible to perform among all patients with NAFLD. Reliable methods for noninvasively detecting for the presence of NASH and advanced fibrosis are thus a pressing need. The search for noninvasive tests has been more successful for advanced fibrosis than for NASH. Clinical prediction models and elastography have acceptable accuracy for ruling out advanced fibrosis; when used …

Activation Of The Sonic Hedgehog Effector Smoothened Counteracts L-Dopa Induced Dyskinesia By Restoring Cholinergic Interneuron Function, Lauren Malave

Dissertations, Theses, and Capstone Projects

Many types of neurons act as multimodal signaling centers. Yet, we have only limited insight into the regulation and functional consequences of neuronal co-transmission. For example, dopamine (DA) neurons, whose degeneration causes motor deficits characteristic of Parkinson’s Diseases (PD), communicate with all their targets by DA but only a selective subset of their targets using GABA, Glutamate, and the secreted cell signaling protein Sonic Hedgehog (Shh). It is unknown whether Levo-dopamine (L-Dopa) induced dyskinesia (LIDs), a severely debilitating side effect of DA supplementation in PD, might appear because DA neuron targets are exposed to high DA- but low Shh- signaling …

Age Of Acquisition Impacts The Brain Differently Depending On Neuroanatomical Metric, Hannah Claussenius-Kalman, Kelly A Vaughn, Pilar Archila-Suerte, Arturo E Hernandez

Faculty, Staff and Student Publications

Although researchers generally agree that a certain set of brain areas underlie bilingual language processing, there is discrepancy regarding what effect timing of language acquisition has on these regions. We aimed to investigate the neuroanatomical correlates of age of acquisition (AoA), which has been examined previously, but with inconsistent results, likely influenced by methodological differences across studies. We analyzed gray matter density, volume, and thickness using whole-brain linear models in 334 bilinguals and monolinguals. Neuroanatomical correlates of AoA differed depending on gray matter metric. Relative to early bilinguals, late bilinguals had thicker cortex in language processing and cognitive control regions, …