Digital Commons Network^™

Biochemical And Biophysical Methods For Analysis Of Poly(Adp-Ribose) Polymerase 1 And Its Interactions With Chromatin., Maggie H. Chassé, Uma M. Muthurajan, Nicholas J. Clark, Michael A. Kramer, Srinivas Chakravarthy, Thomas Irving, Karolin Luger

Manuscripts, Articles, Book Chapters and Other Papers

Poly (ADP-Ribose) Polymerase I (PARP-1) is a first responder to DNA damage and participates in the regulation of gene expression. The interaction of PARP-1 with chromatin and DNA is complex and involves at least two different modes of interaction. In its enzymatically inactive state, PARP-1 binds native chromatin with similar affinity as it binds free DNA ends. Automodification of PARP-1 affects interaction with chromatin and DNA to different extents. Here we describe a series of biochemical and biophysical techniques to quantify and dissect the different binding modes of PARP-1 with its various substrates. The techniques listed here allow for high …

Ambulatory Blood Pressure, Left Ventricular Hypertrophy, And Allograft Function In Children And Young Adults After Kidney Transplantation., Gilad Hamdani, Edward J. Nehus, Coral D. Hanevold, Judith Sebestyen Van Sickle, Robert Woroniecki, Scott E. Wenderfer, David K. Hooper, Douglas Blowey, Amy Wilson, Bradley A. Warady, Mark M. Mitsnefes

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Hypertension is a common complication and is an important risk factor for graft loss and adverse cardiovascular outcomes in pediatric kidney transplantation. Ambulatory blood pressure monitoring (ABPM) is the preferred method to characterize blood pressure status.

METHODS: We conducted a retrospective review of a large cohort of children and young adults with kidney transplant to estimate the prevalence of abnormal ambulatory blood pressure (ABP), assess factors associated with abnormal ABP, and examine whether ambulatory hypertension is associated with worse allograft function and left ventricular hypertrophy (LVH).

RESULTS: Two hundred twenty-one patients had ABPM, and 142 patients had echocardiographic results …

Animal And Human Emotion: Concepts And Methodologies, Cátia Correia Caeiro

Animal Sentience

The human-dog relationship is particularly interesting for the study of emotions. The underlying concepts need to be made explicit and methods need to be adapted to the characteristics of the species studied as well as the shortcomings of the human experimenter’s perception.

Orthogonal Decomposition Of Left Ventricular Remodeling In Myocardial Infarction, Xingyu Zhang, Pau Medrano-Gracia, Bharath Ambale-Venkatesh, David A. Bluemke, Brett R. Cowan, J. Paul Finn, Alan H. Kadish

Office of the President Publications and Research

BACKGROUND: Left ventricular size and shape are important for quantifying cardiac remodeling in response to cardiovascular disease. Geometric remodeling indices have been shown to have prognostic value in predicting adverse events in the clinical literature, but these often describe interrelated shape changes. We developed a novel method for deriving orthogonal remodeling components directly from any (moderately independent) set of clinical remodeling indices.

RESULTS: Six clinical remodeling indices (end-diastolic volume index, sphericity, relative wall thickness, ejection fraction, apical conicity, and longitudinal shortening) were evaluated using cardiac magnetic resonance images of 300 patients with myocardial infarction, and 1991 asymptomatic subjects, obtained from …

New Horizons In Spine Research: Intervertebral Disc Repair And Regeneration., James C Iatridis, James Kang, Rita Kandel, Makarand V. Risbud

Department of Orthopaedic Surgery Faculty Papers

No abstract provided.

Mc-Ppea As A New And More Potent Inhibitor Of Clp-Induced Sepsis And Pulmonary Inflammation Than Fk866., Peixin Huang, Mark W Lee, Keivan Sadrerafi, Daniel P. Heruth, Li Q. Zhang, Dev Maulik, Shui Qing Ye

Manuscripts, Articles, Book Chapters and Other Papers

Our previous study indicated that overexpression of nicotinamide phosphoribosyltransferase (NAMPT) aggravated acute lung injury, while knockdown of NAMPT expression attenuated ventilator-induced lung injury. Recently, we found that meta-carborane-butyl-3-(3-pyridinyl)-2E-propenamide (MC-PPEA, MC4), in which the benzoylpiperidine moiety of FK866 has been replaced by a carborane, displayed a 100-fold increase in NAMPT inhibition over FK866. Here, we determined the effects of MC4 and FK866 on cecal ligation and puncture (CLP) surgery-induced sepsis in C57BL/6J mice. MC4 showed stronger inhibitory effects than FK866 on CLP-induced mortality, serum tumor necrosis factor α (TNFα) levels, pulmonary myeloperoxidase activity, alveolar injury, and interleukin 6 and interleukin1β messenger …

Decellularized Wharton's Jelly From Human Umbilical Cord As A Novel 3d Scaffolding Material For Tissue Engineering Applications., Sushma Jadalannagari, Gabriel Converse, Eric Buse, Michael Filla, Maria T. Villar, Antonio Artigues, Adam J. Mellot, Jinxi Wang, Michael S. Detamore, Richard A. Hopkins, Omar S. Aljitawi, C Mcfall

Manuscripts, Articles, Book Chapters and Other Papers

In tissue engineering, an ideal scaffold attracts and supports cells thus providing them with the necessary mechanical support and architecture as they reconstruct new tissue in vitro and in vivo. This manuscript details a novel matrix derived from decellularized Wharton's jelly (WJ) obtained from human umbilical cord for use as a scaffold for tissue engineering application. This decellularized Wharton's jelly matrix (DWJM) contained 0.66 ± 0.12 μg/mg sulfated glycosaminoglycans (GAGs), and was abundant in hyaluronic acid, and completely devoid of cells. Mass spectroscopy revealed the presence of collagen types II, VI and XII, fibronectin-I, and lumican I. When seeded onto …

Proteoglycan Neofunctions: Regulation Of Inflammation And Autophagy In Cancer Biology., Liliana Schaefer, Claudia Tredup, Maria A. Gubbiotti, Renato V. Iozzo

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Inflammation and autophagy have emerged as prominent issues in the context of proteoglycan signaling. In particular, two small, leucine-rich proteoglycans, biglycan and decorin, play pivotal roles in the regulation of these vital cellular pathways and, as such, are intrinsically involved in cancer initiation and progression. In this minireview, we will address novel functions of biglycan and decorin in inflammation and autophagy, and analyze new emerging signaling events triggered by these proteoglycans, which directly or indirectly modulate these processes. We will critically discuss the dual role of proteoglycan-driven inflammation and autophagy in tumor biology, and delineate the potential mechanisms through which …

Randomized Trial Of Two Doses Of Vitamin D3 In Preterm Infants <32 Weeks: Dose Impact On Achieving Desired Serum 25(Oh)D3 In A Nicu Population., Ann Anderson-Berry, Melissa Thoene, Julie Wagner, Elizabeth Lyden, Glenville Jones, Martin Kaufmann, Matthew Van Ormer, Corrine K. Hanson

Journal Articles: Pediatrics

BACKGROUND: Recommendations for vitamin D supplementation for preterm infants span a wide range of doses. Response to vitamin D supplementation and impact on outcomes in preterm infants is not well understood.

OBJECTIVE: Evaluate serum 25(OH)D3 concentration changes after 4 weeks in response to two different doses of vitamin D3 supplementation in a population of premature infants and quantify the impact on NICU outcomes.

DESIGN: 32 infants born at 24-32 weeks gestation were prospectively randomized to receive 400 or 800 IU/day vitamin D3 supplementation. Serum 25(OH)D3 levels were measured every 4 weeks. The Wilcoxon signed rank test was used to compare …

Targeted Calcium Influx Boosts Cytotoxic T Lymphocyte Function In The Tumour Microenvironment, Kyun-Do Kim, Seyeon Bae, Tara Capece, Hristina Nedelkovska, Rafael G. De Rubio, Alan V. Smrcka, Jun Chang-Duk, Jung Woojin, Byeonghak Park, Minsoo Kim, Tae-Il Kim, Minsoo Kim

Biology

Adoptive cell transfer utilizing tumour-targeting cytotoxic T lymphocytes (CTLs) is one of the most effective immunotherapies against haematological malignancies, but significant clinical success has not yet been achieved in solid tumours due in part to the strong immunosuppressive tumour microenvironment. Here, we show that suppression of CTL killing by CD4+CD25+Foxp+ regulatory T cell (Treg) is in part mediated by TGFβ-induced inhibition of inositol trisphosphate (IP3) production, leading to a decrease in T cell receptor (TCR)-dependent intracellular Ca2+ response. Highly selective optical control of Ca2+ signalling in adoptively transferred CTLs enhances T cell activation and IFN-γ production in vitro, leading to …

The Influence Of Recollection And Familiarity In The Formation And Updating Of Associative Representations, Jason D. Ozubko, Morris Moscovitch, Gordon Winocur

Psychology

Prior representations affect future learning. Little is known, however, about the effects of recollective or familiarity-based representations on such learning. We investigate the ability to reuse or reassociate elements from recollection- and familiarity-based associations to form new associations. Past neuropsychological research suggests that hippocampal, and presumably recollective, representations are more flexible than extra-hippocampal, presumably familiarity-based, representations. We therefore hypothesize that the elements of recollective associations, as opposed to familiarity-based representations, may be more easily manipulated and decoupled from each other, and facilitate the formation of new associations. To investigate this hypothesis we used the AB/AC learning paradigm. Across two recall …

Recollection-Dependent Memory For Event Duration In Large-Scale Spatial Navigation, Iva K.W. Brunec, Jason D. Ozubko, Morgan D. Barense, Morris Moscovitch

Psychology

Time and space represent two key aspects of episodic memories, forming the spatiotemporal context of events in a sequence. Little is known, however, about how temporal information, such as the duration and the order of particular events, are encoded into memory, and if it matters whether the memory representation is based on recollection or familiarity. To investigate this issue, we used a real world virtual reality navigation paradigm where periods of navigation were interspersed with pauses of different durations. Crucially, participants were able to reliably distinguish the durations of events that were subjectively "reexperienced" (i.e., recollected), but not of those …

Harnessing The Power Of Cell Transplantation To Target Respiratory Dysfunction Following Spinal Cord Injury., Brittany A. Charsar, Mark W. Urban, Angelo C. Lepore

Department of Neuroscience Faculty Papers

The therapeutic benefit of cell transplantation has been assessed in a host of central nervous system (CNS) diseases, including disorders of the spinal cord such as traumatic spinal cord injury (SCI). The promise of cell transplantation to preserve and/or restore normal function can be aimed at a variety of therapeutic mechanisms, including replacement of lost or damaged CNS cell types, promotion of axonal regeneration or sprouting, neuroprotection, immune response modulation, and delivery of gene products such as neurotrophic factors, amongst other possibilities. Despite significant work in the field of transplantation in models of SCI, limited attention has been directed at …

Sialylation Of Porphyromonas Gingivalis Lps And Its Effect On Bacterial-Host Interactions., Ss Zaric, Mj Lappin, Cr Fulton, Ft Lundy, Wa Coulter, Cr Irwin

Peninsula Dental School

Porphyromonas gingivalis produces different LPS isoforms with significant structural variations of their lipid A and O-antigen moieties that can affect its pro-inflammatory and bone-resorbing potential. We show here, for the first time, that P. gingivalis LPS isolated from W83 strain is highly sialylated and possesses significantly reduced inflammatory potential compared with less sialylated ATCC 33277 strain LPS. Nevertheless, the reduction in the endotoxin activity is not mediated by the presence of sialic acid LPS moieties as the sialic acid-free LPS produced by the mutant W83 strain exhibits a similar inflammatory potential to the wild type strain. Furthermore, our findings suggest …

Fibroblast Growth Requires Ct10 Regulator Of Kinase (Crk) And Crk-Like (Crkl)., Taeju Park, Mateusz Koptyra, Tom Curran

Manuscripts, Articles, Book Chapters and Other Papers

CT10 regulator of kinase (Crk) and Crk-like (CrkL) are the cellular counterparts of the viral oncogene v-Crk Elevated levels of Crk and CrkL have been observed in many human cancers; inhibition of Crk and CrkL expression reduced the tumor-forming potential of cancer cell lines. Despite a close relationship between the Crk family proteins and tumorigenesis, how Crk and CrkL contribute to cell growth is unclear. We ablated endogenous Crk and CrkL from cultured fibroblasts carrying floxed alleles of Crk and CrkL by transfection with synthetic Cre mRNA (synCre). Loss of Crk and CrkL induced by synCre transfection blocked cell proliferation …

Calcium-Mediated Actin Reset (Caar) Mediates Acute Cell Adaptations, Pauline Wales, Christian Schuberth, Roland Aufschnaiter, Johannes Fels, Ireth Garcia-Aguilar, Annette Janning, Christopher D. Dlugos, Marco Schaefer-Herte, Christoph Klingner, Mike Waelte, Julian Kuhlmann, Ekaterina Menis, Hockaday Kang Hockaday Kang, Kerstin C. Maier, Wenya Hou, Antonella Russo, Henry N. Higgs

Dartmouth Scholarship

Actin has well established functions in cellular morphogenesis. However, it is not well understood how the various actin assemblies in a cell are kept in a dynamic equilibrium, in particular when cells have to respond to acute signals. Here, we characterize a rapid and transient actin reset in response to increased intracellular calcium levels. Within seconds of calcium influx, the formin INF2 stimulates filament polymerization at the endoplasmic reticulum (ER), while cortical actin is disassembled. The reaction is then reversed within a few minutes. This Calcium-mediated actin reset (CaAR) occurs in a wide range of mammalian cell types and in …

Farm Work Injuries Among A Cohort Of Children In Kentucky, Usa, Steven R. Browning, Susan C. Westneat, Deborah B. Reed

Epidemiology and Environmental Health Faculty Publications

Children residing on farms with livestock may be at an increased risk for work-related injuries, compared to children who work on other commodity farms. This study characterizes children's work tasks on Kentucky farms and assesses whether children who work on beef cattle farms are at an increased risk for farm work injuries. The results of a cohort study of children aged 5-18 years (N=999 at baseline) working on family farms in Kentucky, followed for two consecutive years after an initial enumeration five years previously, found that 70% of the children were involved in animal-related chores. Across all age groups, children …

Self-Reported Sleep Apnea And Dementia Risk: Findings From The Prevention Of Alzheimer's Disease With Vitamin E And Selenium Trial, Xiuhua Ding, Richard J. Kryscio, Joshua Turner, Gregory A. Jicha, Gregory E. Cooper, Allison M. Caban-Holt, Frederick A. Schmitt, Erin L. Abner

Sanders-Brown Center on Aging Faculty Publications

OBJECTIVES: To investigate the association between baseline sleep apnea and risk of incident dementia in the Prevention of Alzheimer's Disease with Vitamin E and Selenium (PREADViSE) study and to explore whether the association depends on apolipoprotein E (APOE) ɛ4 allele status.

DESIGN: Secondary analysis based on data collected during PREADViSE.

SETTING: Participants were assessed at 128 local clinical study sites during the clinical trial phase and later were followed by telephone from a centralized location.

PARTICIPANTS: Men enrolled in PREADViSE (without dementia or other active neurological conditions that affect cognition such as major psychiatric disorders, including depression; N = …

Interpreting Measurements Of Cardiac Function Using Vendor-Independent Speckle Tracking Echocardiography In Children: A Prospective, Blinded Comparison With Catheter-Derived Measurements., Suma Goudar, G Hamilton Baker, Shahryar M. Chowdhury, Kimberly J. Reid, Girish S. Shirali, Mark A. Scheurer

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Adult studies demonstrate that echocardiographic measurements of cardiac function using speckle tracking correlate with invasive measurements, but such data in the pediatric population are sparse. Our aim was to compare speckle-derived measures of cardiac function to measurements routinely obtained by cardiac catheterization in children.

METHODS: Echocardiograms were performed on the day of cardiac catheterization. Using Tomtec 2D Cardiac Performance Analysis, longitudinal strain (LS), longitudinal strain rate (LSR), early diastolic LSR, and ejection fraction (EF) for the right and left ventricle (RV and LV) were calculated via speckle tracking. Global LS and LSR were calculated for the LV. These results …

Indoor Tobacco Legislation Is Associated With Fewer Emergency Department Visits For Asthma Exacerbation In Children., Christina E. Ciaccio, Tami Gurley-Calvez, Theresa I. Shireman

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: During the past 3 decades, numerous cities and states have adopted laws that ban smoking in public indoor spaces. The rationale for these policies has been to protect nonsmokers from the adverse health effects of secondhand smoke.

OBJECTIVE: To determine whether the implementation of indoor smoking legislation is associated with a decrease in emergency department visits for asthma in children.

METHODS: This retrospective analysis used a natural experiment to estimate the impact of clean indoor air legislation on the rate of emergency department admissions for asthma exacerbation in children. Data were obtained from the Pediatric Health Information System. A …

Human And Asinine Postures In Apuleius’ Golden Ass, Timothy M. O'Sullivan

Classical Studies Faculty Research

This article examines the ways in which Apuleius’ Metamorphoses thematizes the contrast between the prone posture of the ass and the upright posture of the human. A long philosophical tradition, starting with Plato and Xenophon, argued that the human body was especially constructed for celestial contemplation, while the quadruped body was more suited for baser activities such as eating and sex. Physical posture thus becomes another way for Apuleius to emphasize the “unphilosophical” nature of Lucius-as-ass. Moreover, in Book 11, numerous references to celestial contemplation give the theme an ironic climax. Apuleius uses these celestial allusions, I argue, as further …

The Nuts And Bolts Of The Platelet Release Reaction, Smita Joshi, Sidney W. Whiteheart

Molecular and Cellular Biochemistry Faculty Publications

Secretion is essential to many of the roles that platelets play in the vasculature, e.g., thrombosis, angiogenesis, and inflammation, enabling platelets to modulate the microenvironment at sites of vascular lesions with a myriad of bioactive molecules stored in their granules. Past studies demonstrate that granule cargo release is mediated by Soluble NSF Attachment Protein Receptor (SNARE) proteins, which are required for granule-plasma membrane fusion. Several SNARE regulators, which control when, where, and how the SNAREs interact, have been identified in platelets. Additionally, platelet SNAREs are controlled by post-translational modifications, e.g., phosphorylation and acylation. Although there have been many …

V-Src Oncogene Induces Trop2 Proteolytic Activation Via Cyclin D1., Xiaoming Ju, Xuanmao Jiao, Adam Ertel, Mathew C. Casimiro, Gabriele Disante, Shengqiong Deng, Zhiping Li, Agnese Di Rocco, Tingting Zhan, Adam Hawkins, Tanya Stoyanova, Sebastiano Andò, Alessandro Fatatis, Michael P. Lisanti, Leonard G. Gomella, Lucia R. Languino, Richard G. Pestell

Department of Cancer Biology Faculty Papers

Proteomic analysis of castration-resistant prostate cancer demonstrated the enrichment of Src tyrosine kinase activity in approximately 90% of patients. Src is known to induce cyclin D1, and a cyclin D1-regulated gene expression module predicts poor outcome in human prostate cancer. The tumor-associated calcium signal transducer 2 (TACSTD2/Trop2/M1S1) is enriched in the prostate, promoting prostate stem cell self-renewal upon proteolytic activation via a γ-secretase cleavage complex (PS1, PS2) and TACE (ADAM17), which releases the Trop2 intracellular domain (Trop2 ICD). Herein, v-Src transformation of primary murine prostate epithelial cells increased the proportion of prostate cancer stem cells as characterized by gene expression, …

One Isn't The Loneliest Of Numbers: N-Of-1 Trials, Jerry Yee

Nephrology Articles

No abstract provided.

Human-Associated Bacteroides Spp. And Human Polyomaviruses As Microbial Source Tracking Markers In Hawaii, Marek Kirs, Roberto A Caffaro-Filho, Mayee Wong, Valerie J. Harwood, Philip Moravcik, Roger S Fujioka

Integrative Biology Faculty and Staff Publications

Identification of sources of fecal contaminants is needed to (i) determine the health risk associated with recreational water use and (ii) implement appropriate management practices to mitigate this risk and protect the environment. This study evaluated human-associated Bacteroides spp. (HF183TaqMan) and human polyomavirus (HPyV) markers for host sensitivity and specificity using human and animal fecal samples collected in Hawaii. The decay rates of those markers and indicator bacteria were identified in marine and freshwater microcosms exposed and not exposed to sunlight, followed by field testing of the usability of the molecular markers. Both markers were strongly associated with sewage, although …

Evidence Supporting Idarucizumab For The Reversal Of Dabigatran., Charles V. Pollack

Department of Emergency Medicine Faculty Papers

Idarucizumab is a monoclonal antibody fragment specifically targeted to dabigatran. It has demonstrated prompt and durable reversal of the anticoagulant effects of dabigatran in animal studies and phase 1 studies of young, elderly, and renally impaired volunteers. Although elective invasive procedures and most bleeding complications in dabigatran-treated patients can be managed by temporarily stopping dabigatran therapy and using supportive measures, there are rare clinical situations that require urgent reversal of the anticoagulant effect of dabigatran. The effectiveness and safety of 5 g of intravenous idarucizumab is being investigated in a prospective, open-label, single-cohort study in patients with serious bleeding or …

Toxic Environmental Exposures And Kidney Health In Children., Darcy K. Weidemann, Virginia M. Weaver, Jeffrey J. Fadrowski

Manuscripts, Articles, Book Chapters and Other Papers

High-level exposures to a number of agents are known to have direct nephrotoxic effects in children. A growing body of literature supports the hypothesis that chronic, relatively low-level exposure to various nephrotoxicants may also increase the risk for chronic kidney disease (CKD) or accelerate its progression. In this review we highlight several environmental nephrotoxicants and their association with CKD in children and adolescents. We also discuss unique epidemiological challenges in the use of kidney biomarkers in environmental nephrotoxicology.

Bleeding With Direct Oral Anticoagulants Vs Warfarin: Clinical Experience., John Eikelboom, Geno J. Merli

Department of Surgery Faculty Papers

The risk of bleeding in the setting of anticoagulant therapy continues to be re-evaluated following the introduction of a new generation of direct oral anticoagulants (DOACs). Interruption of DOAC therapy and supportive care may be sufficient for the management of patients who present with mild or moderate bleeding, but in those with life-threatening bleeding, a specific reversal agent is desirable. We review the phase 3 clinical studies of dabigatran, rivaroxaban, apixaban, and edoxaban in patients with nonvalvular atrial fibrillation, in the context of bleeding risk and management.

P70s6k1 (S6k1)-Mediated Phosphorylation Regulates Phosphatidylinositol 4-Phosphate 5-Kinase Type I Γ Degradation And Cell Invasion, Naser Jafari, Qiaodan Zheng, Liqing Li, Wei Li, Lei Qi, Jianyong Xiao, Tianyan Gao, Cai Huang

Markey Cancer Center Faculty Publications

Phosphatidylinositol 4-phosphate 5-kinase type I γ (PIPKIγ90) ubiquitination and subsequent degradation regulate focal adhesion assembly, cell migration, and invasion. However, it is unknown how upstream signals control PIPKIγ90 ubiquitination or degradation. Here we show that p70S6K1 (S6K1), a downstream target of mechanistic target of rapamycin (mTOR), phosphorylates PIPKIγ90 at Thr-553 and Ser-555 and that S6K1-mediated PIPKIγ90 phosphorylation is essential for cell migration and invasion. Moreover, PIPKIγ90 phosphorylation is required for the development of focal adhesions and invadopodia, key machineries for cell migration and invasion. Surprisingly, substitution of Thr-553 and Ser-555 …

The Skp1 Homologs Skr-1/2 Are Required For The Caenorhabditis Elegans Skn-1 Antioxidant/Detoxification Response Independently Of P38 Mapk., Cheng-Wei Wu, Andrew Deonarine, Aaron Przybysz, Kevin Strange, Keith P. Chloe

Molecular Biosciences Faculty Publications

SKN-1/Nrf are the primary antioxidant/detoxification response transcription factors in animals and they promote health and longevity in many contexts. SKN-1/Nrf are activated by a remarkably broad-range of natural and synthetic compounds and physiological conditions. Defining the signaling mechanisms that regulate SKN-1/Nrf activation provides insights into how cells coordinate responses to stress. Nrf2 in mammals is regulated in part by the redox sensor repressor protein named Keap1. In C. elegans, the p38 MAPK cascade in the intestine activates SKN-1 during oxidative stress by promoting its nuclear accumulation. Interestingly, we find variation in the kinetics of p38 MAPK activation and tissues with …