Medicine and Health Sciences Commons^™

Altered Protease And Antiprotease Balance During A Copd Exacerbation Contributes To Mucus Obstruction, Shashi Chillappagari, Jenni Preuss, Sebastian Licht, Christian Müller, Poornima Mahavadi, Gaurav Sarode, Claus Vogelmeier, Andreas Guenther, Lutz Narlich, Bruce K. Rubin, Markus O. Henke

Pediatrics Publications

Background

Proteases have been shown to degrade airway mucin proteins and to damage the epithelium impairing mucociliary clearance. There are increased proteases in the COPD airway but changes in protease-antiprotease balance and mucin degradation have not been investigated during the course of a COPD exacerbation. We hypothesized that increased protease levels would lead to mucin degradation in acute COPD exacerbations.

Methods

We measured neutrophil elastase (NE) and alpha 1 protease inhibitor (A1-PI) levels using immunoblotting, and conducted protease inhibitor studies, zymograms, elastin substrate assays and cigarette smoke condensate experiments to evaluate the stability of the gel-forming mucins, MUC5AC and MUC5B, …

Variability In Splanchnic Tissue Oxygenation During Preterm Red Blood Cell Transfusion Given For Symptomatic Anaemia May Reveal A Potential Mechanism Of Transfusion-Related Acute Gut Injury, Sean M. Bailey, Karen D. Hendricks-Muñoz, Pradeep V. Mally

Pediatrics Publications

Background

There is increasing evidence indicating an association between red blood cell (RBC) transfusions and necrotising enterocolitis (NEC) in preterm infants, especially late-onset NEC. This phenomenon is referred to as transfusion-related acute gut injury (TRAGI). One theory as to a pathophysiological mechanism is that transfusion may result in an ischemia-reperfusion injury to intestinal tissue. We tested the hypothesis that there is significantly greater variability during transfusion in splanchnic tissue oxygen saturation (SrSO2) than in cerebral tissue oxygen saturation (CrSO2).

Materials and methods

This was a prospective, observational study using near-infrared spectroscopy to monitor SrSO2 and CrSO2in preterm neonates undergoing RBC …

Stress Reactivity To An Electronic Version Of The Trier Social Stress Test: A Pilot Study, Sage E. Hawn, Lisa Paul, Suzanne Thomas, Stephanie Miller, Ananda B. Amstadter

Psychiatry Publications

Social stressors that rely on the inclusion of confederates (i.e., Trier Social Stress Test, TSST) are often used in clinical laboratory research paradigms to elicit a measurable stress response in participants. Although effective, the TSST is labor intensive and may introduce error variance as a function of confederate race, gender, and/or response characteristics. The present study aimed to develop and validate an electronic version of the TSST (e-TSST). The primary aim was to compare the e-TSST to an e-neutral control condition; the exploratory aim was to compare the magnitude of stress response elicited by the e-TSST to that elicited by …

Distmix: Direct Imputation Of Summary Statistics For Unmeasured Snps From Mixed Ethnicity Cohorts, Donghyun Lee, T. Bernard Bigdeli, Vernell S. Williamson, Vladimir I. Vladimirov, Brien P. Riley, Ayman H. Fanous, Silviu-Alin Bacanu

Psychiatry Publications

Motivation: To increase the signal resolution for large-scale meta-analyses of genome-wide association studies, genotypes at unmeasured single nucleotide polymorphisms (SNPs) are commonly imputed using large multi-ethnic reference panels. However, the ever increasing size and ethnic diversity of both reference panels and cohorts makes genotype imputation computationally challenging for moderately sized computer clusters. Moreover, genotype imputation requires subject-level genetic data, which unlike summary statistics provided by virtually all studies, is not publicly available. While there are much less demanding methods which avoid the genotype imputation step by directly imputing SNP statistics, e.g. Directly Imputing summary STatistics (DIST) proposed …

Stress Reactivity To An Electronic Version Of The Trier Social Stress Test: A Pilot Study, Sage E. Hawn, Lisa Paul, Suzanne Thomas, Stephanie Miller, Ananda B. Amstadler

Psychiatry Publications

Social stressors that rely on the inclusion of confederates (i.e., Trier Social Stress Test, TSST) are often used in clinical laboratory research paradigms to elicit a measurable stress response in participants. Although effective, the TSST is labor intensive and may introduce error variance as a function of confederate race, gender, and/or response characteristics. The present study aimed to develop and validate an electronic version of the TSST (e-TSST). The primary aim was to compare the e-TSST to an e-neutral control condition; the exploratory aim was to compare the magnitude of stress response elicited by the e-TSST to that elicited by …

Genetic Network Properties Of The Human Cortex Based On Regional Thickness And Surface Area Measures, Anna R. Docherty, Chelsea K. Sawyers, Matthew S. Panizzon, Michael C. Neale, Lisa T. Eyler, Christine Fennema-Notestine, Carol E. Franz, Chi-Hua Chen, Linda K. Mcevoy, Brad Verhulst, Ming T. Tsuang, William S. Kremen

Psychiatry Publications

We examined network properties of genetic covariance between average cortical thickness (CT) and surface area (SA) within genetically-identified cortical parcellations that we previously derived from human cortical genetic maps using vertex-wise fuzzy clustering analysis with high spatial resolution. There were 24 hierarchical parcellations based on vertex-wise CT and 24 based on vertex-wise SA expansion/contraction; in both cases the 12 parcellations per hemisphere were largely symmetrical. We utilized three techniques—biometrical genetic modeling, cluster analysis, and graph theory—to examine genetic relationships and network properties within and between the 48 parcellation measures. Biometrical modeling indicated significant shared genetic covariance between size of several …

Soft, Curved Electrode Systems Capable Of Integration On The Auricle As A Persistent Brain–Computer Interface, James J. S. Norton, Dong Sup Lee, Jung Woo Lee, Woosik Lee, Ohjin Kwon, Philip Won, Sung-Young Jung, Huanyu Cheng, Jae-Woong Jeong, Abdullah Akce, Stephen Umunna, Ilyoun Na, Yong Ho Kwon, Xiao-Qi Wang, Zhuangjian Liu, Ungyu Paik, Yonggang Huang, Timothy Bretl, Woon-Hong Yeo, John A. Rogers

Mechanical and Nuclear Engineering Publications

Recent advances in electrodes for noninvasive recording of electroencephalograms expand opportunities collecting such data for diagnosis of neurological disorders and brain–computer interfaces. Existing technologies, however, cannot be used effectively in continuous, uninterrupted modes for more than a few days due to irritation and irreversible degradation in the electrical and mechanical properties of the skin interface. Here we introduce a soft, foldable collection of electrodes in open, fractal mesh geometries that can mount directly and chronically on the complex surface topology of the auricle and the mastoid, to provide high-fidelity and long-term capture of electroencephalograms in ways that avoid any significant …

Metabolic Interplay Between Astrocytes And Neurons Regulates Endocannabinoid Action, Andreu Viader, Jacqueline L. Blankman, Peng Zhong, Xiaojie Liu, Joel E. Scholsburg, Christopher M. Joslyn, Qing-Song Liu, Aaron J. Tomarchio, Aron H. Lichtman, Dana E. Selley, Laura J. Sim-Selley, Benjamin F. Cravatt

Pharmacology and Toxicology Publications

The endocannabinoid 2-arachidonoylglycerol (2-AG) is a retrograde lipid messenger that modulates synaptic function, neurophysiology, and behavior. 2-AG signaling is terminated by enzymatic hydrolysis—a reaction that is principally performed by monoacylglycerol lipase (MAGL). MAGL is broadly expressed throughout the nervous system, and the contributions of different brain cell types to the regulation of 2-AG activityin vivo remain poorly understood. Here, we genetically dissect the cellular anatomy of MAGL-mediated 2-AG metabolism in the brain and show that neurons and astrocytescoordinately regulate 2-AG content and endocannabinoid-dependent forms of synaptic plasticity and behavior. We also find that astrocytic MAGL is mainly responsible …

Differing Roles Of Autophagy In Hiv-Associated Neurocognitive Impairment And Encephalitis With Implications For Morphine Co-Exposure, Seth M. Dever, Myosotys Rodriguez, Jessica Lapierre, Blair N. Costin, Nazira El-Hage

Pharmacology and Toxicology Publications

We investigated the role of autophagy in HIV-infected subjects with neurocognitive impairment (NCI) ± HIV encephalitis (HIVE), many of which had a history of polysubstance abuse/dependence, using post-mortem brain tissues to determine whether differences in autophagy related factors may be more associated with NCI or NCI-encephalitis. Using qRT-PCR, we detected significant differences in gene expression levels with SQSTM1, LAMP1 higher in HIV-infected subjects without NCI while ATG5, SQSTM1 were then lower in HIV infection/NCI and ATG7, SQSTM1 being higher in NCI-HIVE. Immunohistochemical labeling of these autophagy associated proteins (also including Beclin 1 and LC3B) in Iba1-positive microglial cells showed generally …

Male And Female Runners Demonstrate Different Sagittal Plane Mechanics As A Function Of Static Hamstring Flexibility, D. S. Blaise Williams Iii, Lee M. Welch

Physical Therapy Publications

Background:

Injuries to runners are common. However, there are many potential contributing factors to injury. While lack of flexibility alone is commonly related to injury, there are clear differences in hamstring flexibility between males and females.

Objective:

To compare the effect of static hamstring length on sagittal plane mechanics between male and female runners.

Method:

Forty subjects (30.0±6.4 years) participated and were placed in one of 4 groups: flexible males (n=10), inflexible males (n=10), flexible females (n=10), and inflexible females (n=10). All subjects were free of injury at the time of data collection. Three-dimensional kinematics and kinetics were collected while …

Anticancer Activity Of A Thymidine Quinoxaline Conjugate Is Modulated By Cytosolic Thymidine Pathways, Qiong Wei, Haijuan Liu, Honghao Zhou, Dejun Zhang, Zhiwei Zhang, Qibing Zhou

Medicinal Chemistry Publications

Background

High levels of thymidine kinase 1 (TK1) and thymidine phosphorylase (TYMP) are key molecular targets by thymidine therapeutics in cancer treatment. The dual roles of TYMP as a tumor growth factor and a key activation enzyme of anticancer metabolites resulted in a mixed outcome in cancer patients. In this study, we investigated the roles of TK1 and TYMP on a thymidine quinoxaline conjugate to evaluate an alternative to circumvent the contradictive role of TYMP.

Methods

TK1 and TYMP levels in multiple liver cell lines were assessed along with the cytotoxicity of the thymidine conjugate. Cellular accumulation of the thymidine …

6-Hydroxyflavone And Derivatives Exhibit Potent Anti-Inflammatory Activity Among Mono-, Di- And Polyhydroxylated Flavones In Kidney Mesangial Cells, Xing Wang, Zhiwei Wang, Preetpal Singh Sidhu, Umesh R. Desai, Qibing Zhou

Medicinal Chemistry Publications

Inflammatory responses by kidney mesangial cells play a critical role in the glomerulonephritis. The anti-inflammatory potential of nineteen mono-, di- and polyhydroxylated flavones including fisetin, quercetin, morin, tricetin, gossypetin, apigenin and myricetin were investigated on rat mesangial cells with lipopolysaccharide (LPS) as the inflammatory stimuli. 6-Hydroxyflavone and 4′,6-dihydroxyflavone exhibited high activity with IC50 in the range of 2.0 μM, a much better inhibition potential in comparison to the well-studied polyhydroxylated flavones. Interestingly, the anti-inflammatory activity was not due to direct quenching of NO radicals. Investigation on derivatives with methylation, acetylation or sulfation of 6-hydroxyl group revealed that 6-methoxyflavone was the …

Inhibitory Behavioral Control: A Stochastic Dynamic Causal Modeling Study Comparing Cocaine Dependent Subjects And Controls, Liangsuo Ma, Joel L. Steinberg, Kathryn A. Cunningham, Scott D. Lane, James M. Bjork, Harshini Neelakantan, Amanda E. Price, Ponnada A. Narayana, Thomas R. Kosten, Antoine Bechara, F. Gerard Moeller

Radiology Publications

Cocaine dependence is associated with increased impulsivity in humans. Both cocaine dependence and impulsive behavior are under the regulatory control of cortico-striatal networks. One behavioral laboratory measure of impulsivity is response inhibition (ability to withhold a prepotent response) in which altered patterns of regional brain activation during executive tasks in service of normal performance are frequently found in cocaine dependent (CD) subjects studied with functional magnetic resonance imaging (fMRI). However, little is known about aberrations in specific directional neuronal connectivity in CD subjects. The present study employed fMRI-based dynamic causal modeling (DCM) to study the effective (directional) neuronal connectivity associated …

Evaluation Of Methyl-Binding Domain Based Enrichment Approaches Revisited, Karolina A. Aberg, Linying Xie, Robin F. Chan, Min Zhao, Ashutosh K. Pandey, Gaurav Kumar, Shaunna L. Clark, Edwin Jcg Van Den Oord

Biomarker Research and Personalized Medicine Publications

Methyl-binding domain (MBD) enrichment followed by deep sequencing (MBD-seq), is a robust and cost efficient approach for methylome-wide association studies (MWAS). MBD-seq has been demonstrated to be capable of identifying differentially methylated regions, detecting previously reported robust associations and producing findings that replicate with other technologies such as targeted pyrosequencing of bisulfite converted DNA. There are several kits commercially available that can be used for MBD enrichment. Our previous work has involved MethylMiner (Life Technologies, Foster City, CA, USA) that we chose after careful investigation of its properties. However, in a recent evaluation of five commercially available MBD-enrichment kits the …

Successful Management Of Barth Syndrome: A Systematic Review Highlighting The Importance Of A Flexible And Multidisciplinary Approach, Stacey E. Reynolds

Occupational Therapy Publications

This review describes and summarizes the available evidence related to the treatment and management of Barth syndrome. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were used to identify articles published between December 2004 and January 2015. The Cochrane Population, Intervention, Control, Outcome, Study Design (PICOS) approach was used to guide the article selection and evaluation process. Of the 128 articles screened, 28 articles matched the systematic review inclusion criteria. The results of this review indicate the need for a flexible and multidisciplinary approach to manage the symptoms most commonly associated with Barth syndrome. It is recommended …

Medical Literary Messenger (Vol. 2, No. 2, Spring 2015)

Medical Literary Messenger

Briars / Laura Apol -- Something’s Missing Here / John M. Trumbo -- Diagnosis / Tzivia Gover -- Distance / Priscilla Frake -- Body and Blood / Peter Schmitt -- Anything But Superior Medicine / Julia Hones -- Trading Qintars for Qiviuts in Qatar / Peter Schmitt -- What We Tell Ourselves / Jennifer Campbell -- Did I Register? / Ann Silverthorn -- The Color of Voice / Carol J. Jennings -- Death Wish / Carol LaChapelle -- Dementia Unit Visit / Theresa Wyatt -- what they talk about before their meds kick in / Laurence Carr -- On Learning …

Integrating Mrna And Mirna Weighted Gene Co-Expression Networks With Eqtls In The Nucleus Accumbens Of Subjects With Alcohol Dependence, Mohammed Mamdani, Vernell Williamson, Gowon O. Mcmichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D. Van Der Vaart, Bradley Todd Webb, Silviu-Alin Bacanu, Gursharan Kalsi, Coga Consortium, Kenneth S. Kendler, Michael F. Miles, Danielle Dick, Brien P. Riley, Catherine Dumur, Vladimir I. Vladimirov

Psychiatry Publications

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and …

Integrating Mrna And Mirna Weighted Gene Co-Expression Networks With Eqtls In The Nucleus Accumbens Of Subjects With Alcohol Dependence, Mohammed Mamdani, Vernell Williamson, Gowon O. Mcmichael, Tana Blevins, Fazil Aliev, Amy Adkins, Laura Hack, Tim Bigdeli, Andrew D. Van Der Vaart, Bradley Todd Web, Silviu-Alin Bacanu, Gursharan Kalsi, Coga Consortium, Kenneth S. Kendler, Michael F. Miles, Danielle Dick, Brien P. Riley, Catherine Dumur, Vladimir I. Vladimirov

Psychiatry Publications

Alcohol consumption is known to lead to gene expression changes in the brain. After performing weighted gene co-expression network analyses (WGCNA) on genome-wide mRNA and microRNA (miRNA) expression in Nucleus Accumbens (NAc) of subjects with alcohol dependence (AD; N = 18) and of matched controls (N = 18), six mRNA and three miRNA modules significantly correlated with AD were identified (Bonferoni-adj. p≤ 0.05). Cell-type-specific transcriptome analyses revealed two of the mRNA modules to be enriched for neuronal specific marker genes and downregulated in AD, whereas the remaining four mRNA modules were enriched for astrocyte and microglial specific marker genes and …

Developmental Remodeling Of Relay Cells In The Dorsal Lateral Geniculate Nucleus In The Absence Of Retinal Input, Rana N. El-Danaf, Thomas E. Krahe, Emily K. Dilger, Martha E. Bickford, Michael A. Fox, William Guido

Anatomy and Neurobiology Publications

Background

The dorsal lateral geniculate nucleus (dLGN) of the mouse has been an important experimental model for understanding thalamic circuit development. The developmental remodeling of retinal projections has been the primary focus, however much less is known about the maturation of their synaptic targets, the relay cells of the dLGN. Here we examined the growth and maturation of relay cells during the first few weeks of life and addressed whether early retinal innervation affects their development. To accomplish this we utilized themath5 null (math5−/−) mouse, a mutant lacking retinal ganglion cells and central projections.

Results

The …

Microglia Processes Associate With Diffusely Injured Axons Following Mild Traumatic Brain Injury In The Micro Pig, Audrey D. Lafrenaye, Masak Todani, Susan A. Walker, John T. Povlishock

Anatomy and Neurobiology Publications

Background

Mild traumatic brain injury (mTBI) is an all too common occurrence that exacts significant personal and societal costs. The pathophysiology of mTBI is complex, with reports routinely correlating diffuse axonal injury (DAI) with prolonged morbidity. Progressive chronic neuroinflammation has also recently been correlated to morbidity, however, the potential association between neuroinflammatory microglia and DAI is not well understood. The majority of studies exploring neuroinflammatory responses to TBI have focused on more chronic phases of injury involving phagocytosis associated with Wallerian change. Little, however, is known regarding the neuroinflammatory response seen acutely following diffuse mTBI and its potential relationship to …

Acetylcholine Release In Mouse Hippocampal Ca1 Preferentially Activates Inhibitory-Selective Interneurons Via Α4Β2* Nicotinic Receptor Activation, L. Andrew Bell, Karen A. Bell, A. Rory Mcquiston

Anatomy and Neurobiology Publications

Acetylcholine (ACh) release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were …

Proteomics: In Pursuit Of Effective Traumatic Brain Injury Therapeutics, Pavel N. Lizhnyak, Andrew K. Ottens

Anatomy and Neurobiology Publications

Effective traumatic brain injury (TBI) therapeutics remain stubbornly elusive. Efforts in the field have been challenged by the heterogeneity of clinical TBI, with greater complexity among underlying molecular phenotypes than initially conceived. Future research must confront the multitude of factors comprising this heterogeneity, representing a big data challenge befitting the coming informatics age. Proteomics is poised to serve a central role in prescriptive therapeutic development, as it offers an efficient endpoint within which to assess post-TBI biochemistry. We examine rationale for multifactor TBI proteomic studies and the particular importance of temporal profiling in defining biochemical sequences and guiding therapeutic development. …

Acetylcholine Release In Mouse Hippocampal Ca1 Preferentially Activates Inhibitory-Selective Interneurons Via Α4Β2* Nicotinic Receptor Activation, L. Andrew Bell, Karen A. Bell, A. Rory Mcquiston

Anatomy and Neurobiology Publications

Acetylcholine (ACh) release onto nicotinic receptors directly activates subsets of inhibitory interneurons in hippocampal CA1. However, the specific interneurons activated and their effect on the hippocampal network is not completely understood. Therefore, we investigated subsets of hippocampal CA1 interneurons that respond to ACh release through the activation of nicotinic receptors and the potential downstream effects this may have on hippocampal CA1 network function. ACh was optogenetically released in mouse hippocampal slices by expressing the excitatory optogenetic protein oChIEF-tdTomato in medial septum/diagonal band of Broca cholinergic neurons using Cre recombinase-dependent adeno-associated viral mediated transfection. The actions of optogenetically released ACh were …

Gabaergic Regulation Of Cerebellar Ng2-Cell Development Is Altered In Perinatal White Matter Injury, Marzieh Zonouzi, Joseph Scafidi, Peijun Li, Brian Mcellin, Jorge Edwards, Jeffrey L. Dupree, Lloyd Harvey, Dandan Sun, Christian A. Hübner, Stuart G. Cull-Candy, Mark Farrant, Vittorio Gallo

Anatomy and Neurobiology Publications

Diffuse white matter injury (DWMI), a leading cause of neurodevelopmental disabilities in preterm infants, is characterized by reduced oligodendrocyte formation. Oligodendrocyte precursor cells (NG2-cells) are exposed to various extrinsic regulatory signals, including the neurotransmitter GABA. We investigated GABAergic signaling to cerebellar white matter NG2-cells in a mouse model of DWMI (chronic neonatal hypoxia). We found that hypoxia caused a loss of GABAA receptor-mediated synaptic input to NG2-cells, extensive proliferation of these cells and delayed oligodendrocyte maturation, leading to dysmyelination. Treatment of control mice with a GABAA receptor antagonist or deletion of the chloride-accumulating transporter NKCC1 mimicked the effects of hypoxia. …

Identification Of Small-Molecule Inhibitors Against Meso-2, 6-Diaminopimelate Dehydrogenase From Porphyromonas Gingivalis, Victoria N. Stone, Hardik I. Parikh, Fadi El-Rami, Xiuchun Ge, Weihau Chen, Yan Zhang, Glen E. Kellogg, Ping Xu

Philips Institute for Oral Health Research Publications

Species-specific antimicrobial therapy has the potential to combat the increasing threat of antibiotic resistance and alteration of the human microbiome. We therefore set out to demonstrate the beginning of a pathogen-selective drug discovery method using the periodontal pathogen Porphyromonas gingivalis as a model. Through our knowledge of metabolic networks and essential genes we identified a “druggable” essential target, meso-diaminopimelate dehydrogenase, which is found in a limited number of species. We adopted a high-throughput virtual screen method on the ZINC chemical library to select a group of potential small-molecule inhibitors. Meso-diaminopimelate dehydrogenase from P. gingivaliswas first expressed …

Lysophosphatidic Acid Up-Regulates Hexokinase Ii And Glycolysis To Promote Proliferation Of Ovarian Cancer Cells, Abir Mukherjee, Yibao Ma, Fang Yuan, Yongling Gong, Zhenyu Fang, Esraa M. Mohamed, Erika Berrios, Huanjie Shao, Xianjun Fang

Biochemistry and Molecular Biology Publications

Lysophosphatidic acid (LPA), a blood-borne lipid mediator, is present in elevated concentrations in ascites of ovarian cancer patients and other malignant effusions. LPA is a potent mitogen in cancer cells. The mechanism linking LPA signal to cancer cell proliferation is not well understood. Little is known about whether LPA affects glucose metabolism to accommodate rapid proliferation of cancer cells. Here we describe that in ovarian cancer cells, LPA enhances glycolytic rate and lactate efflux. A real time PCR-based miniarray showed that hexokinase II (HK2) was the most dramatically induced glycolytic gene to promote glycolysis in LPA-treated cells. Analysis of the …

Dual Action Of Mir-125b As A Tumor Suppressor And Oncomir-22 Promotes Prostate Cancer Tumorigenesis, William T. Budd, Sarah J. Seashols-Williams, Gene C. Clark, Danielle Weaver, Valerie Calvert, Emanuel Petricoin, Ema A. Dragoescu, Katherine O'Hanlon, Zendra E. Zehner

Biochemistry and Molecular Biology Publications

MicroRNAs (miRs) are a novel class of small RNA molecules, the dysregulation of which can contribute to cancer. A combinatorial approach was used to identify miRs that promote prostate cancer progression in a unique set of prostate cancer cell lines, which originate from the parental p69 cell line and extend to a highly tumorigenic/metastatic M12 subline. Together, these cell lines are thought to mimic prostate cancer progression in vivo. Previous network analysis and miR arrays suggested that the loss of hsa-miR-125b together with the overexpression of hsa-miR-22 could contribute to prostate tumorigenesis. The dysregulation of these two miRs was …

Dpy-17 And Mua-3 Interact For Connective Tissue-Like Tissue Integrity In Caenorhabditis Elegans: A Model For Marfan Syndrome, Pauline Fotopoulos, Jeongho Kim, Moonjung Hyun, Waiss Qamari, Inhwan Lee, Young-Jai You

Biochemistry and Molecular Biology Publications

mua-3 is a Caenorhabditis elegans homolog of the mammalian fibrillin1, a monogenic cause of Marfan syndrome. We identified a new mutation of mua-3 that carries an in-frame deletion of 131 amino acids in the extracellular domain, which allows the mutants to survive in a temperature-dependent manner; at the permissive temperature, the mutants grow normally without obvious phenotypes, but at the nonpermissive temperature, more than 90% die during the L4 molt due to internal organ detachment. Using the temperature-sensitive lethality, we performed unbiased genetic screens to isolate suppressors to find genetic interactors of MUA-3. From two independent screens, we isolated …

Dissection Of C. Elegans Behavioral Genetics In 3-D Environments, Namseop Kwon, Ara B. Hwang, Young-Jai You, Seung-Jae V. Lee, Jung Ho Je

Biochemistry and Molecular Biology Publications

The nematode Caenorhabditis elegans is a widely used model for genetic dissection of animal behaviors. Despite extensive technical advances in imaging methods, it remains challenging to visualize and quantify C. elegans behaviors in three-dimensional (3-D) natural environments. Here we developed an innovative 3-D imaging method that enables quantification of C. elegans behavior in 3-D environments. Furthermore, for the first time, we characterized 3-D-specific behavioral phenotypes of mutant worms that have defects in head movement or mechanosensation. This approach allowed us to reveal previously unknown functions of genes in behavioral regulation. We expect that our 3-D imaging method will facilitate new …

Network Modelling Reveals The Mechanism Underlying Colitis-Associated Colon Cancer And Identifies Novel Combinatorial Anti-Cancer Targets, Junyan Lu, Hanlin Zeng, Zhongjie Liang, Limin Chen, Liyi Zhang, Hao Zhang, Hong Liu, Hualiang Jiang, Bairong Shen, Ming Huang, Meiyu Geng, Sarah Spiegel, Cheng Luo

Biochemistry and Molecular Biology Publications

The connection between inflammation and tumourigenesis has been well established. However, the detailed molecular mechanism underlying inflammation-associated tumourigenesis remains unknown because this process involves a complex interplay between immune microenvironments and epithelial cells. To obtain a more systematic understanding of inflammation-associated tumourigenesis as well as to identify novel therapeutic approaches, we constructed a knowledge-based network describing the development of colitis-associated colon cancer (CAC) by integrating the extracellular microenvironment and intracellular signalling pathways. Dynamic simulations of the CAC network revealed a core network module, including P53, MDM2, and AKT, that may govern the malignant transformation of colon epithelial cells in a …