Digital Commons Network^™

A New Mouse Model To Explore Therapies For Preeclampsia, Abdulwahab Ahmed, Jameel Singh, Ysodra Khan, Surya V. Seshan, Guillermina Girardi

Publications and Research

Background Pre-eclampsia, a pregnancy-specific multisystemic disorder is a leading cause of maternal and perinatal mortality and morbidity. This syndrome has been known to medical science since ancient times. However, despite considerable research, the cause/s of preeclampsia remain unclear, and there is no effective treatment. Development of an animal model that recapitulates this complex pregnancy-related disorder may help to expand our understanding and may hold great potential for the design and implementation of effective treatment. Methodology/Principal Findings Here we show that the CBA/J x DBA/2 mouse model of recurrent miscarriage is also a model of immunologically-mediated preeclampsia (PE). DBA/J mated CBA/J …

Molecular Signatures Of The Primitive Prostate Stem Cell Niche Reveal Novel Mesenchymal-Epithelial Signaling Pathways, Roy Blum, Rashmi Gupta, Patricia E. Burger, Christopher S. Ontiveros, Sarah N. Salm, Xiaozhong Xiong, Alexander Kamb, Holger Wesche, Lisa Marshall, Gene Cutler, Xiangyun Wang, Jiri Zavadil, David Moscatelli, E. Lynette Wilson

Publications and Research

Background Signals between stem cells and stroma are important in establishing the stem cell niche. However, very little is known about the regulation of any mammalian stem cell niche as pure isolates of stem cells and their adjacent mesenchyme are not readily available. The prostate offers a unique model to study signals between stem cells and their adjacent stroma as in the embryonic prostate stem cell niche, the urogenital sinus mesenchyme is easily separated from the epithelial stem cells. Here we investigate the distinctive molecular signals of these two stem cell compartments in a mammalian system. Methodology/Principal Findings We isolated …

Identification Of An Archaeal Presenilin-Like Intramembrane Protease, Celia Torres-Arancivia, Carolyn M. Ross, Jose Chavez, Zahra Assur, Georgia Dolios, Filippo Mancia, Iban Ubarretxena-Belandia

Publications and Research

Background: The GXGD-type diaspartyl intramembrane protease, presenilin, constitutes the catalytic core of the c-secretase multi-protein complex responsible for activating critical signaling cascades during development and for the production of b-amyloid peptides (Ab) implicated in Alzheimer’s disease. The only other known GXGD-type diaspartyl intramembrane proteases are the eukaryotic signal peptide peptidases (SPPs). The presence of presenilin-like enzymes outside eukaryots has not been demonstrated. Here we report the existence of presenilin-like GXGD-type diaspartyl intramembrane proteases in archaea.

Methodology and Principal Findings: We have employed in vitro activity assays to show that MCMJR1, a polytopic membrane protein from the archaeon Methanoculleus marisnigri JR1, …

Drug Off-Target Effects Predicted Using Structural Analysis In The Context Of A Metabolic Network Model, Roger L. Chang, Lei Xie, Philip E. Bourne, Bernhard O. Palsson

Publications and Research

Recent advances in structural bioinformatics have enabled the prediction of protein-drug off-targets based on their ligand binding sites. Concurrent developments in systems biology allow for prediction of the functional effects of system perturbations using large-scale network models. Integration of these two capabilities provides a framework for evaluating metabolic drug response phenotypes in silico. This combined approach was applied to investigate the hypertensive side effect of the cholesteryl ester transfer protein inhibitor torcetrapib in the context of human renal function. A metabolic kidney model was generated in which to simulate drug treatment. Causal drug off-targets were predicted that have previously been …

Dmyc Functions Downstream Of Yorkie To Promote The Supercompetitive Behavior Of Hippo Pathway Mutant Cells, Marcello Ziosi, Luis Alberto Baena-López, Daniela Grifoni, Francesca Froldi, Andrea Pession, Flavio Garoia, Vincenzo Trotta, Paola Bellosta, Sandro Cavicchi, Annalisa Pession

Publications and Research

Genetic analyses in Drosophila epithelia have suggested that the phenomenon of “cell competition” could participate in organ homeostasis. It has been speculated that competition between different cell populations within a growing organ might play a role as either tumor promoter or tumor suppressor, depending on the cellular context. The evolutionarily conserved Hippo (Hpo) signaling pathway regulates organ size and prevents hyperplastic disease from flies to humans by restricting the activity of the transcriptional cofactor Yorkie (yki). Recent data indicate also that mutations in several Hpo pathway members provide cells with a competitive advantage by unknown mechanisms. Here we provide insight …

Dipolar Cortico-Muscular Electrical Stimulation: A Novel Method That Enhances Motor Function In Both - Normal And Spinal Cord Injured Mice, Zaghloul Ahmed

Publications and Research

Background Electrical stimulation of the central and peripheral nervous systems is a common tool that is used to improve functional recovery after neuronal injury. Methods Here we described a new configuration of electrical stimulation as it was tested in anesthetized control and spinal cord injury (SCI) mice. Constant voltage output was delivered through two electrodes. While the negative voltage output (ranging from -1.8 to -2.6 V) was delivered to the muscle via transverse wire electrodes (diameter, 500 μm) located at opposite ends of the muscle, the positive output (ranging from + 2.4 to +3.2 V) was delivered to the primary …

The Terebridae And Teretoxins: Combining Phylogeny And Anatomy For Concerted Discovery Of Bioactive Compounds, Nicolas Puillandre, Mandë Holford

Publications and Research

The Conoidea superfamily, comprised of cone snails, terebrids, and turrids, is an exceptionally promising group for the discovery of natural peptide toxins. The potential of conoidean toxins has been realized with the distribution of the first Conus (cone snail) drug, Prialt (ziconotide), an analgesic used to alleviate chronic pain in HIV and cancer patients. Cone snail toxins (conotoxins) are highly variable, a consequence of a high mutation rate associated to duplication events and positive selection. As Conus and terebrids diverged in the early Paleocene, the toxins from terebrids (teretoxins) may demonstrate highly divergent and unique functionalities. Recent analyses of the …

Negative Effects Of Paternal Age On Children's Neurocognitive Outcomes Can Be Explained By Maternal Education And Number Of Siblings, Ryan D. Edwards, Jennifer Roff

Publications and Research

Background Recent findings suggest advanced paternal age may be associated with impaired child outcomes, in particular, neurocognitive skills. Such patterns are worrisome given relatively universal trends in advanced countries toward delayed nuptiality and fertility. But nature and nurture are both important for child outcomes, and it is important to control for both when drawing inferences about either pathway.

Methods and Findings We examined cross-sectional patterns in six developmental outcome measures among children in the U.S. Collaborative Perinatal Project (n=31,346). Many of these outcomes at 8 mo, 4 y, and 7 y of age (Bayley scales, Stanford Binet Intelligence Scale, Graham-Ernhart …

The Uneven Distribution Of Social Suffering: Documenting The Social Health Consequences Of Neo-Liberal Social Policy On Marginalized Youth, Michelle Fine, Brett G. Stoudt, Maddy Fox, Maybelline Santos

Publications and Research

In 2009, British epidemiologists Richard Wilkinson and Kate Pickett published "The Spirit Level: Why Greater Equality Makes Societies Strong", in which they argue that severely unequal societies produce high rates of ‘social pain”: adverse outcomes including school drop out, teen pregnancy, mental health problems, lack of social trust, high mortality rates, violence and crime, low social participation. Their volume challenges the belief that the extent of poverty in a community predicts negative outcomes. They assert instead that the size of the inequality gap defines the material and psychological contours of the chasm between the wealthiest and the most impoverished, enabling …

The Cinema Of Control: On Diabetic Excess And Illness In Film, Kevin L. Ferguson

Publications and Research

While not rare, films that do represent diabetes must work around the disease’s banal invisibility,and images of diabetics in film are thus especially susceptible to metaphor and exaggeration.This essay is the first to outline a diabetic filmography, discussing medical and cinematic strategies for visualizing the disease as well as how the illness informs family plots and heroic characters in horror films. Doing so, it participates in a larger discussion of the manner in which film images of ill or disabled groups sustain notions of “normalcy” by both representing and denying otherness.

Selective Targeting Of Neuroblastoma Tumour-Initiating Cells By Compounds Identified In Stem Cell-Based Small Molecule Screens, Kristen M. Smith, Alessandro Datti, Mayumi Fujitani, Natalie Grinshtein, Libo Zhang, Olena Morozova, Kim M. Blakely, Susan A. Rotenberg, Loen M. Hansford, Freda D. Miller, Herman Yeger, Meredith S. Irwin, Jason Moffat, Marco A. Marra, Sylvain Baruchel, Jeffrey L. Wrana, David R. Kaplan

Publications and Research

Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at …

Pharmacological Characterization Of Gabaa Receptors In Taurine-Fed Mice, William J. L’Amoreaux, Alexandra Marsillo, Abdeslem El Idrissi

Publications and Research

Background Taurine is one of the most abundant free amino acids especially in excitable tissues, with wide physiological actions. Chronic supplementation of taurine in drinking water to mice increases brain excitability mainly through alterations in the inhibitory GABAergic system. These changes include elevated expression level of glutamic acid decarboxylase (GAD) and increased levels of GABA. Additionally we reported that GABAA receptors were down regulated with chronic administration of taurine. Here, we investigated pharmacologically the functional significance of decreased / or change in subunit composition of the GABAA receptors by determining the threshold for picrotoxin-induced seizures. Picrotoxin, an antagonist of GABAA …

Taurine Regulation Of Short Term Synaptic Plasticity In Fragile X Mice, Abdeslem El Idrissi, Lorenz S. Neuwirth, William L’Amoreaux

Publications and Research

Background Fragile X Syndrome is the most common known genetic cause of autism. The Fmr1-KO mouse, lacks the fragile X mental retardation protein (FMRP), and is used as a model of the syndrome. The core behavioral deficits of autism may be conceptualized either as excessive adherence to patterns as seen in repetitive actions and aberrant language, or as insensitivity to subtle but socially important changes in patterns. The hippocampus receives information from the entorhinal cortex and plays a crucial role in the processing of patterned information. To gain more insight into the physiological function of FMRP and the neuronal mechanisms …

Neuro-Endocrine Basis For Altered Plasma Glucose Homeostasis In The Fragile X Mouse, Abdeslem El Idrissi, Xin Yan, Francoise Sidime, William L’Amoreaux

Publications and Research

Background The fragile X mouse model shows an increase in seizure susceptibility, indicating an involvement of the GABAergic system via an alteration in cellular excitability. In the brain, we have previously described a reduction in GABAA receptor expression as a likely basis for this susceptibility. In the brains of fragile X mice, this reduction in receptor expression culminates with a concomitant increase in the expression of glutamic acid decarboxylase (GAD), the enzyme responsible for GABA synthesis. Further, voltage-sensitive calcium channel expression is reduced in the pancreas of the fragile X mouse. Since there are considerable similarities in the GABAergic system …

Taurine Regulates Insulin Release From Pancreatic Beta Cell Lines, William J. L’Amoreaux, Christina Cuttitta, Allison Santora, Jonathan F. Blaize, Janto Tachjadi, Abdeslem El Idrissi

Publications and Research

Background Pancreatic β-cells release insulin via an electrogenic response triggered by an increase in plasma glucose concentrations. The critical plasma glucose concentration has been determined to be ~3 mM, at which time both insulin and GABA are released from pancreatic β-cells. Taurine, a β-sulfonic acid, may be transported into cells to balance osmotic pressure. The taurine transporter (TauT) has been described in pancreatic tissue, but the function of taurine in insulin release has not been established. Uptake of taurine by pancreatic β-cells may alter membrane potential and have an effect on ion currents. If taurine uptake does alter β-cell current, …

Shear Stress Modulation Of Smooth Muscle Cell Marker Genes In 2-D And 3-D Depends On Mechanotransduction By Heparan Sulfate Proteoglycans And Erk1/2, Zhong-Dong Shi, Giya Abraham, John M. Tarbell

Publications and Research

Background During vascular injury, vascular smooth muscle cells (SMCs) and fibroblasts/myofibroblasts (FBs/MFBs) are exposed to altered luminal blood flow or transmural interstitial flow. We investigate the effects of these two types of fluid flows on the phenotypes of SMCs and MFBs and the underlying mechanotransduction mechanisms. Methodology/Principal Findings Exposure to 8 dyn/cm2 laminar flow shear stress (2-dimensional, 2-D) for 15 h significantly reduced expression of α-smooth muscle actin (α-SMA), smooth muscle protein 22 (SM22), SM myosin heavy chain (SM-MHC), smoothelin, and calponin. Cells suspended in collagen gels were exposed to interstitial flow (1 cmH2O, ∼0.05 dyn/cm2, 3-D), and after 6 …

Delayed Onset Of A Daytime Nap Facilitates Retention Of Declarative Memory, Sara E. Alger, Hiuyan Lau, William Fishbein

Publications and Research

Background Learning followed by a period of sleep, even as little as a nap, promotes memory consolidation. It is now generally recognized that sleep facilitates the stabilization of information acquired prior to sleep. However, the temporal nature of the effect of sleep on retention of declarative memory is yet to be understood. We examined the impact of a delayed nap onset on the recognition of neutral pictorial stimuli with an added spatial component. Methodology/Principal Findings Participants completed an initial study session involving 150 neutral pictures of people, places, and objects. Immediately following the picture presentation, participants were asked to make …

Variability In Avian Eggshell Colour: A Comparative Study Of Museum Eggshells, Phillip Cassey, Steven J. Portugal, Golo Maurer, John G. Ewen, Rebecca L. Boulton, Mark E. Hauber, Tim M. Blackburn

Publications and Research

Background The exceptional diversity of coloration found in avian eggshells has long fascinated biologists and inspired a broad range of adaptive hypotheses to explain its evolution. Three main impediments to understanding the variability of eggshell appearance are: (1) the reliable quantification of the variation in eggshell colours; (2) its perception by birds themselves, and (3) its relation to avian phylogeny. Here we use an extensive museum collection to address these problems directly, and to test how diversity in eggshell coloration is distributed among different phylogenetic levels of the class Aves. Methodology and Results Spectrophotometric data on eggshell coloration were collected …

Cord Blood Versus Age 5 Mononuclear Cell Proliferation On Ige And Asthma, Carolyn Chang, Kevin Gauvey-Kern, Alina Johnson, Elizabeth A. Kelvin, Ginger L. Chew, Frederica Perera, Rachel L. Miller

Publications and Research

Background: Fetal immune responses following exposure of mothers to allergens during pregnancy may influence the subsequent risk of childhood asthma. However, the association of allergen-induced cord blood mononuclear cell (CBMC) proliferation and cytokine production with later allergic immune responses and asthma has been controversial. Our objective was to compare indoor allergen-induced CBMC with age 5 peripheral blood mononuclear cell (PBMC) proliferation and determine which may be associated with age 5 allergic immune responses and asthma in an inner city cohort.

Methods: As part of an ongoing cohort study of the Columbia Center for Children’s Environmental Health (CCCEH), CBMCs and age …

Identification And Structural Characterization Of Fyve Domain-Containing Proteins Of Arabidopsis Thaliana, Ewa Wywial, Shaneen M. Singh

Publications and Research

Background FYVE domains have emerged as membrane-targeting domains highly specific for phosphatidylinositol 3-phosphate (PtdIns(3)P). They are predominantly found in proteins involved in various trafficking pathways. Although FYVE domains may function as individual modules, dimers or in partnership with other proteins, structurally, all FYVE domains share a fold comprising two small characteristic double-stranded β-sheets, and a C-terminal α-helix, which houses eight conserved Zn2+ ion-binding cysteines. To date, the structural, biochemical, and biophysical mechanisms for subcellular targeting of FYVE domains for proteins from various model organisms have been worked out but plant FYVE domains remain noticeably under-investigated.

Results We carried out an …

Metallic Nanoparticle On Micro Ring Resonator For Bio Optical Detection And Sensing, Ali Haddadpour, Yasha Yi

Publications and Research

We have numerically investigated the unique effects of metallic nanoparticle on the ring resonator, especially multiple Au nanoparticles on the micro ring resonator with the 4-port configuration on chip. For the Au nanoparticle, because it has smaller real refractive index than air and large absorption refractive index, we found that there is a blue shift for the ring resonance wavelength, instead of red shift normally observed for dielectric nanoparticles. The drop port intensity is strongly dependent on both number and size of nanoparticles, while relatively independent on position of nanoparticles. The correlation between the penetration depth of Au and the …

Differential Toxicity Of Dna Adducts Of Mitomycin C, Jill Bargonetti, Elise Champeil, Maria Tomasz

Publications and Research

The clinically used antitumor agent mitomycin C (MC) alkylates DNA upon reductive activation, forming six covalent DNA adducts in this process. This review focuses on differential biological effects of individual adducts in various mammalian cell cultures, observed in the authors' laboratories. Evidence is reviewed that various adducts are capable of inducing different cell death pathways in cancer cells.This evidence is derived from a parallel study of MC and its derivatives 2,7-diaminomitosene (2,7-DAM) which is the main metabolite of MC and forms two mono-adducts with DNA, and decarbamoyl mitomycin C (DMC), which alkylates and cross-links DNA, predominantly with a chirality opposite …

Lim-Domain Proteins Trip6 And Lpp Associate With Shelterin To Mediate Telomere Protection, Samantha A. Sheppard, Diego Loayza

Publications and Research

POT1 is the single stranded telomeric overhang binding protein, and is part of the shelterin complex, a group of six proteins essential for proper telomere function. The reduction or abrogation of POT1 DNA binding activity in mammalian cells results in telomere elongation, or activation of the ATR DNA damage response at telomeres. Therefore, overhang binding represents the functionally relevant activity of POT1. To better understand the roles of POT1, we sought to isolate proteins that interact with the DNA binding domain of the protein. A yeast two-hybrid screen was implemented using a C-terminal truncation termed POT1ΔC, retaining the DNA binding …

Ubr1 And Ubr2 Function In A Quality Control Pathway For Degradation Of Unfolded Cytosolic Proteins, Nadinath B. Nillegoda, Maria A. Theodoraki, Atin K. Mandal, Katie J. Mayo, Hong Yu Ren, Rasheda Sultana, Kenneth Wu, Jill Johnson, Douglas M. Cyr, Avrom J. Caplan

Publications and Research

Ubr1 and Ubr2 ubiquitin ligases are shown to promote degradation of misfolded cytosolic polypeptides in vivo and in a purified system in association with Hsp70.

Autoregulation Of Sinorhizobium Meliloti Exor Gene Expression, Hai-Yang Lu, Hai-Ping Cheng

Publications and Research

The successful nitrogen-fixing symbiosis between the Gram-negative soil bacterium Sinorhizobium meliloti and its leguminous plant host alfalfa (Medicago sativa) requires the bacterial exopolysaccharide succinoglycan. Succinoglycan and flagellum production, along with the ability to metabolize more than 20 different carbon sources and control the expression of a large number of S. meliloti genes, is regulated by the ExoR–ExoS/ChvI signalling pathway. The ExoR protein interacts with and suppresses the sensing activities of ExoS, the membrane-bound sensor of the ExoS/ChvI two-component regulatory system. Here we show that exoR expression is clearly upregulated in the absence of any functional ExoR protein. This upregulation was …

Ospie1, The Rice Ortholog Of Arabidopsis Photoperiod-Independent Early Flowering1, Is Essential For Embryo Development, Yonghan Xu, Minjuan Deng, Jianfei Peng, Zhanghua Hu, Lieming Bao, Junming Wang, Zhi-Liang Zheng

Publications and Research

Background The SWR1 complex is important for the deposition of histone variant H2A.Z into chromatin necessary to robustly regulate gene expression during growth and development. In Arabidopsis thaliana, the catalytic subunit of the SWR1-like complex, encoded by PIE1 (PHOTOPERIOD-INDEPENDENT EARLY FLOWERING1), has been shown to function in multiple developmental processes including flowering time pathways and petal number regulation. However, the function of the PIE1 orthologs in monocots remains unknown. Methodology/Findings We report the identification of the rice (Oryza sativa) ortholog, OsPIE1. Although OsPIE1 does not exhibit a conserved exon/intron structure as Arabidopsis PIE1, its encoded protein is highly similar to …

Alternative Trans-Splicing Of Caenorhabditis Elegans Sma-9/Schnurri Generates A Short Transcript That Provides Tissue-Specific Function In Bmp Signaling, Jianghua Yin, Ling Yu, Cathy Savage-Dunn

Publications and Research

Background Transcription cofactors related to Drosophila Schnurri facilitate the transcriptional programs regulated by BMP signaling in C. elegans, Drosophila, Xenopus, and mouse. In different systems, Schnurri homologs have been shown to act as either agonists or antagonists of Smad function, and as either positive or negative regulators of transcription. How Schnurri proteins achieve this diversity of activities is not clear. The C. elegans sma-9/schnurri locus undergoes alternative splicing, including an unusual trans-splicing event that could generate two non-overlapping shorter transcripts.

Results We demonstrate here that the shorter transcripts are expressed in vivo. Furthermore, we find that one of the short …

Comparative Genomics Of The Family Vibrionaceae Reveals The Wide Distribution Of Genes Encoding Virulence-Associated Proteins, Timothy G. Lilburn, Jianying Gu, Hong Cai, Yufeng Wang

Publications and Research

Background Species of the family Vibrionaceae are ubiquitous in marine environments. Several of these species are important pathogens of humans and marine species. Evidence indicates that genetic exchange plays an important role in the emergence of new pathogenic strains within this family. Data from the sequenced genomes of strains in this family could show how the genes encoded by all these strains, known as the pangenome, are distributed. Information about the core, accessory and panproteome of this family can show how, for example, genes encoding virulence-associated proteins are distributed and help us understand how virulence emerges. Results We deduced the …

Dna Adducts Of Decarbamoyl Mitomycin C Efficiently Kill Cells Without Wild-Type P53 Resulting From Proteasome-Mediated Degradation Of Checkpoint Protein 1, Ernest K. Boamah, Angelika Brekman, Maria Tomasz, Natura Myeka, Maria E. Figueiredo-Pereira, Senyene Hunter, Joel Meyer, Rahul C. Bhosle, Jill Bargonetti

Publications and Research

The mitomycin derivative 10-decarbamoyl mitomycin C (DMC) more rapidly activates a p53-independent cell death pathway than mitomycin C (MC). We recently documented that an increased proportion of mitosene1-β-adduct formation occurs in human cells treated with DMC in comparison to those treated with MC. Here, we compare the cellular and molecular response of human cancer cells treated with MC and DMC. We find the increase in mitosene 1-β-adduct formation correlates with a condensed nuclear morphology and increased cytotoxicity in human cancer cells with or without p53. DMC caused more DNA damage than MC in the nuclear and mitochondrial genomes. Checkpoint 1 …

Neural Substrates Of Reliability-Weighted Visual-Tactile Multisensory Integration, Michael S. Beauchamp, Siavash Pasalar, Tony Ro

Publications and Research

As sensory systems deteriorate in aging or disease, the brain must relearn the appropriate weights to assign each modality during multisensory integration. Using blood-oxygen level dependent functional magnetic resonance imaging of human subjects, we tested a model for the neural mechanisms of sensory weighting, termed “weighted connections.” This model holds that the connection weights between early and late areas vary depending on the reliability of the modality, independent of the level of early sensory cortex activity. When subjects detected viewed and felt touches to the hand, a network of brain areas was active, including visual areas in lateral occipital cortex, …