bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of genes and molecular pathways involved in a C. elegans model of neuroborreliosis
Authors: Prado Ruben , Bessing Gai-Linn , Snyder Nathaniel , Singh Gurpalik , Yang Frank , Nass Richard 
Published: January 2019

Background and Hypothesis: Lyme disease is caused by the spirochaete bacteria from the Borrelia species. Recent studies suggest that Lyme disease may be associated with dementia, brain atrophy, and protein aggregates that may be associated with the development of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimers disease (AD). The molecular basis of the Borrelia-associated innate immune response and associated neuropathology is poorly defined. A significant hindrance in dissecting these molecular components is the lack of facile in vivo genetic models to explore the mechanisms involved in the neuropathology. Here we hypothesize that the nematode C. elegans will be a useful model for Borrelia-associated innate immunity and neuropathology.
Project Methods: We utilized transcriptional reporters, transgenic animals, neuronal morphology analysis, RNAi, host defense pathways, AD- and PD-associated pathologies, and behavior assays to determine the effect that Borrelia has on C. elegans viability.
Results: C. elegans can be infected and survive using Borrelia as a food source, and the bacteria can induce highly conserved innate immune response pathways, and exacerbate PD-associated dopamine neuronal death in human A53T -synuclein-expressing animals. C. elegans models expressing AD-associated human A 1-42 also show significant movement defects and increased protein aggregates when exposed to Borrelia.
Conclusions and Potential Impact: This study further characterizes a novel genetic model for Borrelia-associated innate immunity and neuropathology. Incorporating C. elegans genetic screens, this model should allow us to identify mediators of the Borrelia-associated pathologies that should facilitate the identification of molecular pathways and potential therapeutic targets.
Paradoxical rapid normalization of serum proteins in severely sarcopenic pediatric patients following liver transplant
Authors: Schmidt II Christian M. , Mangus Richard S. 
Published: January 2019

Background and Hypothesis:
Pediatric liver disease patients develop frailty which risks adverse outcomes. This novel study aims to quantify differential rates of sarcopenia in pediatric liver failure pre/post-transplant as a function of nutritional parameters and dynamic changes in muscle mass.
Project Methods:
A retrospective review of a prospectively collected transplant database (2001-2018) at a single center was performed. Weekly serum protein values (albumin and total protein) and monthly body weights (BWs) and BMIs were collected. A select group with CT imaging pre/post-transplant underwent scaled scoring (cross sectional area at L2/L3 intervertebral space divided by height2 for core muscle mass). The post-transplant rates of change were compared to pre-transplant baseline nutrition status.
Results:
There were 114 subjects, 82 underwent CT analysis. Pre-transplant, 45% had severe sarcopenia. Post-transplant, median serum protein levels normalized, but slowest in patients infants. BMI and BW were unchanged except in adolescents it significantly decreased in the first 30 days. Paradoxically, median serum protein levels normalized at week 3 for patients with severe sarcopenia, faster than mild/moderate sarcopenia groups.
Conclusion and Potential Impact:
Liver transplant normalizes serum proteins at differential rates according to age, pre-transplant BMI and level of sarcopenia. Despite normalization liver transplant does not change BW and BMI. Paradoxically, severe sarcopenia patients normalize their serum protein levels at the fastest rate. We speculate an increased level of a novel “protein-stimulating factor” may exist in the severely sarcopenic group. Understanding post-liver transplant outcomes in patients as a function of their pre-transplant sarcopenic index is a novel method to optimize these patients care.
Effect of Tyrosine Phosphorylation of HPV31 E2 on Replication
Authors: Sharifi Mitra , Gilsonq Timra , Androphy Elliot 
Published: January 2019

Background
The HPV early E2 protein is an essential regulatory protein involved in HPV replication and transcription that is encoded by all papillomaviruses. Phosphorylation of E2 at Y102 inhibits viral replication, and an additional phosphorylation site at Y87 was recently identified through mass spectrometry. This project aimed to characterize E2 proteins encoding mutations at Y87 that abrogate phosphorylation. In parallel, we aimed to identify the kinase responsible for E2 phosphorylation at Y87. The Androphy lab previously has published that FGFR tyrosine kinases effect HPV replication, but there may be other kinases which act upon E2. Tyk2 is a tyrosine kinase regulated by the viral protein E6 and highly expressed in keratinocytes. We want to determine if Tyk2 is involved in regulation of E2 through phosphorylation.
Experimental Design
We will co-express Tyk2 and E2 in 293TT cells and through immunoprecipitations determine if Tyk2 binds E2. Using an in-vitro replication assay, viral proteins E2 and E1 will be overexpressed along with Tyk2 to determine if Tyk2 effects replication. We will make HPV genomes with Y87E/Y87F mutations through site-directed mutagenesis. Expression of mutant E2 will be examined through transfection of cells and western blot analysis.
Results
E2 harboring 87 to glutamic acid (Y87E) or phenylalanine (Y87F) mutations produces soluble protein, but 87E inhibits replication. Tyk2 expression stabilizes E2 suggesting it binds E2.
Potential impact
It is important to understanding the mechanisms underlying a virus’ replication cycle for future targeted treatments against infection.
Modulation of Myocardial Oxygen Delivery in Response to Isovolemic Hemodilution
Authors: Simon Blake R. , Baker Hana E. , Earl Conner C. , Goodwill Adam G. , Luebbe Sam , Tune Johnathan D. 
Published: January 2019

Background and Hypothesis: Prior studies have established that progressive increases in coronary blood flow are sufficient to maintain myocardial oxygen delivery in response to reductions in arterial oxygenation. However, the precise mechanisms responsible for anemic coronary vasodilation remain poorly understood. This investigation tested the hypothesis that autonomic neural pathways contribute to the maintenance of myocardial oxygen delivery in response to graded reductions in arterial hematocrit.
Experimental Design: Experiments were conducted in open-chest anesthetized swine while assessing coronary blood flow and coronary arterial and venous blood gases in response to progressive hemodilution. Isovolemic hemodilution was achieved via simultaneous removal of 250mL of arterial blood and addition of 250mL of a synthetic plasma expander (Hespan) in swine that received either vehicle or a combination of atropine (0.5mg/kg) and propranolol (1mg/kg) (Atro/Pro).
Results: Relative to vehicle control swine, treatment with Atro/Pro increased heart rate by ~50±4 beats/min and arterial pressure by ~10±1 mmHg. However, Atro/Pro did not significantly alter increases in coronary blood flow in response to isovolemic hemodilution (hematocrits ranging from ~35±1% to ~15±1%). Coronary venous PO2, an index of myocardial oxygenation, was also unchanged by hemodilution in both vehicle and Atro/Pro treated swine.
Conclusion and Potential Impact: These data suggest that autonomic neural pathways do not play a significant role in the maintenance of myocardial oxygen delivery in response to graded reduction in arterial oxygen content. Understanding of how myocardial oxygen supply is ultimately sensed and regulated in response to reductions in tissue oxygenation remains elusive.
Enhancing cytotoxic chemotherapy response through targeted BET bromodomain inhibition in preclinical pancreatic cancer models
Authors: Singh Sandeep , McCauley Ross , Schwarz Johann R. , Schwarz Roderich , Awasthi Niranjan 
Published: January 2019

Background and Hypothesis:
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and the standard of care regimen, nab-paclitaxel (NPT) plus gemcitabine (Gem), leads to a dismal 8.5 months median survival. Targeted inhibition of Bromodomain and Extra-Terminal (BET) protein is currently under investigation for several cancers. We hypothesize that BET protein pathway inhibition by iBet-762 will enhance cytotoxic chemotherapy response in PDAC.
Experimental Design:
In vitro cell proliferation assays were performed using WST-1 reagent. Protein expressions were determined by Western Blot analysis. In vivo animal survival and tumor growth experiments were performed in NOD-SCID mice.
Results:
Inhibition in cell proliferation in human PDAC cells at 1 µM concentration in NPT+Gem, iBET-762, and NPT+Gem+iBet762 was 64%, 27%, 76% in AsPC-1; 43%, 13%, 69% in Panc-1; and 42%, 51%, 75% in MIA PaCa cells. iBET-762 decreased oncogenic proteins c-Myc, [Symbol]-catenin, Vimentin, and P-AKT while apoptosis related proteins such as cleaved PARP-1 and cleaved caspase-3 and cell cycle inhibitors proteins P21 & P27 were increased. In a peritoneal dissemination model, median animal survival compared to control (21 days) was increased after therapy with NPT+Gem (33 days, a 57% increase), iBet-762 (30 days, a 43% increase) and NPT+Gem+iBET-762 (44 days, a 110% increase). Effect of iBET-762 in combination with chemotherapy on local tumor growth is currently underway.
Conclusion and Potential Impact:
These findings suggest that the effects of standard chemotherapy can be enhanced through specific inhibition of BET proteins activity, and supports the clinical application of iBET-762 in combination with standard chemotherapy in PDAC patients.
Control of Chemotherapy-Induced Peripheral Neuropathy and HMGB1 Cytosolic Translocation in Dorsal Root Ganglion Sensory Neurons Using Olaparib
Authors: Thielmeyer Hannah , Smith Jared , White Fletcher 
Published: January 2019

Background and Hypothesis: Oxaliplatin (OXL)-associated Chemotherapy-induced Peripheral Neuropathy (CIPN) is a frequent, potentially severe, and dose-limiting toxicity of colorectal cancer treatment. CIPN can persist for years beyond chemotherapy completion, causing significant challenges for cancer survivors due to its negative influence on quality of life. This work builds upon preliminary observations that platinum drugs lead to the release of a damage-associated protein, high mobility group box-1 (HMGB1). Drug-induced release of this protein from the nucleus into the cytosol and eventually into the extracellular compartment can sensitize primary afferent sensory neurons for prolonged periods of time, eliciting CIPN pain behavior in rodents. Inhibition of HMGB1 nuclear translocation through administration of olaparib may serve to diminish CIPN pain in a rodent model.
Experimental Design or Project Methods: Sprague-Dawley rats were given intraperitoneal injections of oxaliplatin and oliparib and measured using Von Frey Filaments for mechanical sensitivity and Plantar’s Test for thermal behavior. Lumbar dorsal root ganglions were collected for immunofluorescence to label tissues with anti-HMGB1 antibodies and analyzed.
Results: Oliparib transiently reverses the OXL-induced tactile allodynia one hour after drug administration. Oliparib-treated rats also exhibit diminished cytosolic HMGB1, indicating a lack of nuclear translocation in medium and large diameter sensory neurons.
Conclusion and Potential Impact: The reduced CIPN behavior after oliparib administration correlates with diminished cytosolic HMGB1. This identifies HMGB1 as an important co-regulator of neurotoxicity due to oxaliplatin, which may have important relevance for future techniques to reduce CIPN and increase efficacy of colorectal cancer treatment.
SOX-2 Mediated Conversion of Astrocyte to Neuron
Authors: Tucker Brady , Wu Wei , Xu Xiao-Ming 
Published: January 2019

Background: Axonal regeneration following SCI is crucial if individuals are to avoid permanent neurological damage. A plausible solution to circumvent neuronal death/ axonal degeneration may be in the conversion of ubiquitously distributed astrocytes into neurons. Previous research has shown that the neuronal transcription factor SOX-2 has the potential to convert mature glial cells into neuroblasts (iANBs). Furthermore, iANBs possess the capability to differentiate into functional neurons. Our study employs an in vivo mouse model to demonstrate the functional recovery that SOX-2 mediated conversion of astrocytes to neurons may pose following SCI.
Methods: Our study utilized two populations of mice. The first population received thoracic T10 contusion injuries while the second population received cervical C5 dorsal hemi-sections. Mice were subsequently blindly categorized into groups A, B, and C (treatment groups) depending on which injection they would be receiving: LV-hNG2-GFP, LV-hNG2-SOX2, or LV-p75-2. Following injection, behavioral studies including Hargreaves, roto-rod, grid walk, BMS (contusion mice) and pellet retrieval (DH mice) were performed to assess functional recovery at 2 week intervals.
Results: The astrocyte conversion to neuron project spans more than 16 weeks. Here we present data obtained in the first eight weeks which includes behavioral analyses of contusion injury mice. Currently grid walk, BMS, and Hargreaves testing show similar trends in spontaneous recovery however no significant difference is observed between the independent injection groups. On the contrary roto-rod analyses showed injection group C had a significantly lower latency to fall time in comparison to groups A and B six weeks post injection (wpi).
Conclusion: The treatments are hypothesized to not take effect until approximately 8 wpi thus we expect subsequent behavioral testing to reveal significant differences between treatment groups, ultimately taking one step closer towards therapeutic intervention following traumatic SCI.
Molecular characteristics of serum hepatitis B virus (HBV) RNA: a novel biomarker for chronic HBV infection
Authors: Valdés, BS Juan D. , Xie, MD Zhanglian , Guo, PhD Haitao 
Published: January 2019

Background and Hypothesis: HBV is a major etiological agent for viral hepatitis and hepatocellular carcinoma. HBV is a DNA virus per se but viral pregenomic RNA (pgRNA) has been recently found in patient blood. The serum pgRNA is hypothesized to function as a novel biomarker for the activity of HBV covalently- closed-circular DNA (cccDNA), which is the intracellular persistent form of HBV DNA and the template for producing viral proteins responsible for the chronic virulence of HBV. However, the molecular characteristics of serum HBV RNA remains elusive.
Experimental Design and Project Methods: HBV RNA were extracted from patient’s sera. RT-PCR and 3’ RACE were utilized to amplify the internal sequence and 3’ terminus of HBV pgRNA, respectively. The PCR products were gel purified and cloned into T vector for sequencing.
Results: After comparing the sequencing data to the reference HBV sequence, we found that the serum HBV RNA are spliced fragments of the original intracellular full-length pgRNA. The prevalence of the fragmented serum pgRNA was found in greater concentrations in untreated patients, and the ratios of different spliced forms of serum HBV RNA vary during the course of antiviral treatment.
Conclusion and Potential Impact: Our study demonstrated that the serum HBV RNA are spliced/truncated forms of pgRNA, indicating that the RNA-containing virion is noninfectious. The characterization of serum HBV RNA sequence provides important insights into the assay design for serum HBV RNA detection. Future study will focus on the mechanism underlying the selective egress of spliced pgRNA-containing virus particles.
Enhanced survival of lethally irradiated mice given pegylated G-CSF, GM-CSF, and IL-11 with lisinopril via modulation of the hematopoietic cytokines TGF[Symbol]-1 and RANTES
Authors: Walker Brett , Wu Tong , Plett Paul A. , Chua Hui L. , Feng Hailin , Orschell Christie 
Published: January 2019

Background and Hypothesis:
We have previously shown increased survival in mice given pegylated growth factors, G-CSF, GM-CSF, and IL-11 (triple combo, TC), with lisinopril compared to TC alone in the hematopoietic acute radiation syndrome (H-ARS). This experiment investigated the mechanism behind the survival benefit. We hypothesized lisinopril regulates inflammatory cytokines hence increasing quiescence of primitive bone marrow cells.
Experimental Design or Project Methods:
C57BL/6 mice were exposed to LD90/30 total body irradiation (TBI). The irradiated mice were given a TC injection on day 1, and lisinopril was administered in drinking water beginning on day 7. Mice were euthanized on day 10. Flow cytometry was used to analyze bone marrow cell cycle and Bioplex was used to analyze cytokines in bone marrow supernatant.
Results:
Treatment with TC+lisinopril significantly decreased the level of the pro-inflammatory cytokine RANTES compared with vehicle mice (Veh) and TC alone (TC+Liso vs. Veh: 3.6 vs. 7.8 pg/mL, p<0.01; TC+Liso vs. TC: 3.6 vs. 5.2 pg/ml, p<0.01). TC+lisinopril increases levels of the pro-quiescence cytokine TGF-[Symbol]1, compared with Veh and TC alone (TC+Liso vs. Veh: 92.8 vs. 45.6 pg/mL, p<0.05; TC+Liso vs. TC: 92.8 vs. 44.7 pg/ml, p<0.01). TC alone had lower percentages of quiescent Lin- primitive bone marrow cells (G0+G1) than non-irradiated (NI) mice (75.7 vs. 85.2%, p<0.05), whereas there is no difference between TC+Liso and NI mice (83.0 vs. 85.2%, p=0.44).
Conclusion and Potential Impact:
The increased survival of H-ARS mice given lisinopril might be due to the regulation of TGF-[Symbol]1 and RANTES levels in the bone marrow leading to quiescence of primitive bone marrow cells.
A Case-Based Tropical Medicine Curriculum for Interdisciplinary Global Health Track Residents
Authors: Webb Damon E. , Northquist Will , Baenziger, MD Jenny 
Published: January 2019

Global health education is essential for equipping physicians to improve population health both at home and abroad. Global health is a multidisciplinary specialty with physicians who come from many backgrounds, making it important to reinforce concepts in its education that might not have been the focus of their previous training. Tropical medicine, and its focus on infectious disease, is one area of global health that many physicians may not have focused on extensively. We developed a curriculum for tropical medicine for residents in the Indiana University Interdepartmental Global Health Track, a 2-3 year co-curricular focus on global health with residents from Family Medicine, Internal Medicine, Med-Peds, Pediatrics, OBGYN, EM, and others. Research has shown that case-based learning (CBL) is effective in engaging students and faculty compared to other educational methods. It is believed that utilizing CBL in delivering a tropical medicine curriculum to these residents will develop proficiency in the subject over the 8 sessions developed. Residents will learn about a variety of infectious diseases in each session by working through a case, engaging in critical thinking in small groups, then taking a quiz. Following completion of all sessions, they will be complete a summative test and a survey subjectively assessing the curriculum. We hope this novel curriculum will prove effective in teaching the essentials of tropical medicine to Global Health Track residents and will serve as an example for the development of other tropical medicine curricula.
Gabapentin Targeting and Bone Mineralization Defects: Proposed mechanism for increased fracture risk in patients taking GBP-class anti-epileptic drugs
Authors: Wheeler Jonathan A. , Noonan Megan L. , Thompson William R. , White Kenneth E. 
Published: January 2019

Background and Hypothesis:
Gabapentin (GBP) is an anti-epileptic drug and first-line therapy for neuropathic pain prescribed to 43 million patients in the US. Unfortunately, GBP use is associated with metabolic bone disease, leading to a 2 to 6-fold increased fracture incidence. Until now, the pathophysiology of this drug-induced bone loss was unknown. We hypothesize that the impaired bone mineralization and skeletal defects is a result of downstream effects of GBP targeting of the[Symbol]2[Symbol]1 subunit, the only known GBP receptor.
Project Methods:
In vitro: Murine mesenchymal progenitor cells (MPC-2) were treated with GBP doses varying from 0.5mM to 50mM while undergoing osteoblast differentiation for 1 or 2 weeks. Mineralization was assessed by Alizarin red stain. Gene expression was measured by RT-qPCR.
In vivo: The bone phenotype of mice lacking the [Symbol]2[Symbol]1 subunit was analyzed by longitudinal DXA analyses and examined histologically.
Results:
In vitro: MPC-2 cells treated with 50mM GBP while differentiating for 1 and 2 weeks had decreased osteoblast mineralization and a 7-fold reduction and 4 fold reduction, respectively, in DMP1.
In vivo: Male and female [Symbol]2[Symbol]1 knockout mice showed a significant decrease in whole body longitudinal (6 wk – 18 wk) bone mineral density (BMD) in males (p<0.001) and females (p=0.014), along with severe osteomalacia, displaying unmineralized osteoid in the trabecular compartment of the distal femoral metaphyses.
Conclusion and Potential Impact:
The impaired mineralization observed following [Symbol]2[Symbol]1 deletion, coupled with reduced differentiation of MPC-2 cells treated with GBP suggests that GBP regulates bone quality through a novel mechanism influencing phosphate wasting or 1,25 vitamin D deficiency leading to fracture. With this awareness physicians can monitor these patients for bone mass loss and prescribe drugs to prevent AED-mediated fracture.
Blood Loss in Primary and Aseptic Revision Total Knee Arthroplasty: A Retrospective Matched Cohort Analysis
Authors: Xiao, BS Honglin , Deckard, BSE Evan R. , Ziemba-Davis, BA Mary , Meneghini, MD Michael R. 
Published: January 2019

Background and Hypothesis: While blood loss in primary TKA is well-characterized, there is a paucity of data on blood loss in aseptic revision TKA. In this study, we hypothesized that revision TKAs would have increased blood loss compared to matched primary TKAs.
Project Methods: Two-hundred-ninety consecutive revision TKAs performed between 2010 and 2017 were retrospectively reviewed and matched to primary TKAs on surgeon, age, sex, BMI, and ASA Score. Seventy-four revision TKAs were excluded for factors affecting blood loss. Potential covariates affecting blood loss were compiled from the medical record. Outcomes including total blood loss, drain output rate, and change in hemoglobin levels from preoperative to postoperative day one were assessed.
Results: Two-hundred-sixteen revision TKAs matched to 216 primary TKAs were analyzed. Multivariate analysis showed no difference in blood loss metrics comparing primary and revision TKAs. However, increased tourniquet time (p=0.001), elevated BMI (p=0.002), male sex (p<0.001), and lack of topical TXA (p=0.005) significantly increased total blood loss. Similar results were found for increased drain output rate in addition to lack of intravenous TXA (p<0.001) and a trend for lower age (p=0.073). Increased tourniquet time (p=0.004) and lack of topical TXA (p=0.002) correlated with a greater drop in hemoglobin postoperatively.
Conclusion and Potential Impact: Primary and revision TKAs showed no difference in blood loss. However, increased tourniquet time and withholding topical TXA significantly increased total blood loss, drain output rate, and change in hemoglobin levels. This data continues to support emphasizing procedural efficiency and TXA use in revision TKA.