tbuckley/cabot-search huggingface dataset:
Molecular Evolution of Adeno-associated Virus for Enhanced Glial Gene Delivery
Authors: James T Koerber, Ryan Klimczak, Jae-Hyung Jang, Deniz Dalkara, John G Flannery, David V Schaffer
Journal: Molecular Therapy (2009)

The natural tropism of most viral vectors, including adeno-associated viral (AAV) vectors, leads to predominant transduction of neurons and epithelia within the central nervous system (CNS) and retina. Despite the clinical relevance of glia for homeostasis in neural tissue, and as causal contributors in genetic disorders such as Alzheimer's and amyotrophic lateral sclerosis, efforts to develop more efficient gene delivery vectors for glia have met with limited success. Recently, viral vector engineering involving high-throughput random diversification and selection has enabled the rapid creation of AAV vectors with valuable new gene delivery properties. We have engineered novel AAV variants capable of efficient glia transduction by employing directed evolution with a panel of four distinct AAV libraries, including a new semi-random peptide replacement strategy. These variants transduced both human and rat astrocytes in vitro up to 15-fold higher than their parent serotypes, and injection into the rat striatum yielded astrocyte transduction levels up to 16% of the total transduced cell population, despite the human astrocyte selection platform. Furthermore, one variant exhibited a substantial shift in tropism toward Müller glia within the retina, further highlighting the general utility of these variants for efficient glia transduction in multiple species within the CNS and retina.
Mutations in PCBD1 Cause Hypomagnesemia and Renal Magnesium Wasting
Authors: Silvia Ferrè, Jeroen H.F. de Baaij, Patrick Ferreira, Roger Germann, Johannis B.C. de Klerk, Marla Lavrijsen, Femke van Zeeland, Hanka Venselaar, Leo A.J. Kluijtmans, Joost G.J. Hoenderop, René J.M. Bindels
Journal: Journal of the American Society of Nephrology (2013)

Mutations in PCBD1 are causative for transient neonatal hyperphenylalaninemia and primapterinuria (HPABH4D). Until now, HPABH4D has been regarded as a transient and benign neonatal syndrome without complications in adulthood. In our study of three adult patients with homozygous mutations in the PCBD1 gene, two patients were diagnosed with hypomagnesemia and renal Mg(2+) loss, and two patients developed diabetes with characteristics of maturity onset diabetes of the young (MODY), regardless of serum Mg(2+) levels. Our results suggest that these clinical findings are related to the function of PCBD1 as a dimerization cofactor for the transcription factor HNF1B. Mutations in the HNF1B gene have been shown to cause renal malformations, hypomagnesemia, and MODY. Gene expression studies combined with immunohistochemical analysis in the kidney showed that Pcbd1 is expressed in the distal convoluted tubule (DCT), where Pcbd1 transcript levels are upregulated by a low Mg(2+)-containing diet. Overexpression in a human kidney cell line showed that wild-type PCBD1 binds HNF1B to costimulate the FXYD2 promoter, the activity of which is instrumental in Mg(2+) reabsorption in the DCT. Of seven PCBD1 mutations previously reported in HPABH4D patients, five mutations caused proteolytic instability, leading to reduced FXYD2 promoter activity. Furthermore, cytosolic localization of PCBD1 increased when coexpressed with HNF1B mutants. Overall, our findings establish PCBD1 as a coactivator of the HNF1B-mediated transcription necessary for fine tuning FXYD2 transcription in the DCT and suggest that patients with HPABH4D should be monitored for previously unrecognized late complications, such as hypomagnesemia and MODY diabetes.
The role of the insulin-like growth factor-1 system in breast cancer
Authors: Panagiotis F Christopoulos, Pavlos Msaouel, Michael Koutsilieris
Journal: Molecular Cancer (2015)

IGF-1 is a potent mitogen of major importance in the mammary gland. IGF-1 binding to the cognate receptor, IGF-1R, triggers a signaling cascade leading to proliferative and anti-apoptotic events. Although many of the relevant molecular pathways and intracellular cascades remain to be elucidated, a growing body of evidence points to the important role of the IGF-1 system in breast cancer development, progression and metastasis. IGF-1 is a point of convergence for major signaling pathways implicated in breast cancer growth. In this review, we provide an overview and concise update on the function and regulation of IGF-1 as well as the role it plays in breast malignancies.
Diminished Sensitivity of Chronic Lymphocytic Leukemia Cells to ABT-737 and ABT-263 Due to Albumin Binding in Blood
Authors: Meike Vogler, Silviya D. Furdas, Manfred Jung, Tomomi Kuwana, Martin J.S. Dyer, Gerald M. Cohen
Journal: Clinical Cancer Research (2010)

Inhibition of the antiapoptotic BCL2 family is one of the most promising areas of anticancer drug development. However, ABT-737, a specific BCL2 inhibitor, is neither orally bioavailable nor metabolically stable. To overcome these problems, the structurally related molecule ABT-263 was synthesized and recently entered clinical trials in hematologic malignancies, including chronic lymphocytic leukemia (CLL). Almost all laboratory studies have been carried out with ABT-737 rather than ABT-263, the drug being used in clinical trials. Currently there are no published data on the comparative effects of these inhibitors. To gain insight into the potential value or limitations of ABT-263 in the clinic, we assessed its ability to induce apoptosis in clinically relevant cellular models of CLL.The susceptibility of freshly isolated primary CLL cells to these inhibitors was compared in standard culture conditions and in conditions that more closely mimic in vivo conditions in a whole blood assay system.ABT-737 was more potent than ABT-263 at inducing apoptosis in CLL cells. In whole blood, approximately 100-fold higher concentrations of both drugs were required to induce apoptosis. We found that ABT-263 was highly bound by albumin and that an increased albumin binding of ABT-263 as compared with ABT-737 accounted for the differential sensitivity of CLL cells.Our data indicate that the exquisite in vitro sensitivity of CLL cells to BCL2 inhibitors may be lost in vivo due to high cell densities and the albumin binding of ABT-263. Modification of ABT-263 may yield a BCL2 inhibitor with greater bioavailability and more favorable pharmacokinetics.
Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents coronary artery reocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs.
Authors: T Yasuda, H K Gold, J T Fallon, R C Leinbach, J L Guerrero, L E Scudder, M Kanke, D Shealy, M J Ross, D Collen
Journal: Journal of Clinical Investigation (1988)

Localized thrombosis was produced in the left anterior descending (LAD) coronary artery of open chest dogs by constricting a segment so as to produce greater than 90% stenosis (reducing blood flow to 40 +/- 10% of baseline), and placing a thrombus in the segment immediately proximal to the stenosis by inducing endothelial cell injury and instilling a mixture of blood and thrombin. Intravenous infusion of recombinant tissue-type plasminogen activator (rt-PA) at a rate of 15-30 micrograms/kg per min for 30 or 60 min in eight dogs induced coronary artery reperfusion within 23 +/- 7 min (mean +/- SD), but reocclusion occurred despite heparin anticoagulation in all but one of these dogs within 7 +/- 5 min. Intravenous injection of 0.8 mg/kg of the F(ab')2 fragment of a monoclonal antibody (7E3) directed against the platelet GPIIb/IIIa receptor, prevented reocclusion in 10/10 dogs during an observation period of 2 h (P less than 0.001 vs. rt-PA alone). The antibody abolished ADP-induced platelet aggregation and markedly prolonged the bleeding time. Intravenous aspirin or dipyridamole prevented reocclusion for 1 h or more in only 2/7 and 1/6 dogs, respectively. We conclude that the monoclonal antibody is very effective in preventing reocclusion after successful thrombolysis of occluded coronary arteries with rt-PA.
Low glucose level and low pH alter the electrochemical function of human parietal pleura
Authors: V. K. Kouritas, C. Hatzoglou, C. N. Foroulis, A. Hevas, K. I. Gourgoulianis, P. A. Molyvdas
Journal: European Respiratory Journal (2007)

The aim of the present study was to investigate whether low glucose and pH level, which are usually measured in complicated pleural effusions, alter the electrochemical function of healthy human parietal pleura. Parietal pleural pieces were stripped from 66 patients during thoracic surgery and were mounted in Ussing chambers. Krebs' solutions containing different glucose levels (0, 40 and 100 mg) and balanced at different pH levels (7.4, 7.3 and 7.2) were added to the pleural cavity surface of the pieces. Transmesothelial potential difference was measured at various time-points as an electrophysiological variable and transmesothelial resistance (R(TM)) was calculated using Ohm's law. When normal-glucose Krebs at pH 7.45 was used, R(TM) remained unchanged over time, but when low-glucose Krebs was used, R(TM) decreased. Krebs without glucose caused the greatest decrease in R(TM). Use of low-pH Krebs decreased R(TM). The lower the pH of the Krebs, the faster the decrease in R(TM) and the greater the effect. The decrease in R(TM) was greater with low-pH than with low-glucose Krebs. Low glucose and low pH caused an additive decrease in R(TM). Low glucose concentration and low pH cause alteration of the electrochemical function of human parietal pleura and could act as agents that lead to further exudate progression.
Human Endothelial Cells Regulate Survival and Proliferation of Human Mast Cells
Authors: Claudia T. Mierke, Matthias Ballmaier, Uwe Werner, Michael P. Manns, Karl Welte, Stephan C. Bischoff
Journal: The Journal of Experimental Medicine (2000)

Mast cells (MCs) are immunoregulatory and inflammatory tissue cells preferentially located around blood vessels. Since endothelial cells have been suggested to regulate MC functions, we analyzed MC–endothelial cell interactions in vitro by performing coculture experiments with purified human intestinal MCs and human umbilical vein endothelial cells (HUVECs). We found that HUVECs provide signals allowing MCs to survive for at least 3 wk and to proliferate without addition of cytokines; otherwise all MCs died. HUVEC-dependent MC proliferation was more pronounced than that induced by stem cell factor (SCF), known to act as an MC growth factor both in vitro and in vivo. After coculture with HUVECs, most MCs were of the tryptase and chymase double-positive phenotype (MCTC). Transwell experiments suggested that the HUVECs' effects on MCs are not mediated by soluble factors. HUVEC-dependent MC adhesion and proliferation were inhibited by neutralizing antibodies directed against SCF and vascular cell adhesion molecule (VCAM)-1 expressed on HUVECs, and c-kit and very late antigen 4 (VLA-4) on MCs. The data suggest that two mechanisms (membrane-bound SCF/c-kit and VCAM-1/VLA-4) are involved in human MC–endothelial cell interactions. In conclusion, our study provides evidence that endothelial cells regulate MC survival and preferentially support human MCTC development.
Dermal piercings: unregulated high street surgery?
Authors: G. Parkins, M. Porter
Journal: British Journal of Dermatology (2014)

Journal Article Dermal piercings: unregulated high street surgery? Get access G. Parkins, G. Parkins Alan Lyell Centre for Dermatology Southern General Hospital, 1345 Govan Road Glasgow G51 4TF U.K E‐mail: parkins38@hotmail.co.uk Search for other works by this author on: Oxford Academic Google Scholar M. Porter M. Porter Alan Lyle Centre for Dermatology Western Infirmary Glasgow U.K Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 171, Issue 5, 1 November 2014, Pages 1273–1274, https://doi.org/10.1111/bjd.12968 Published: 01 November 2014
Possible role of nuclear receptor nr4a1 in hypoxia-induced cisplatin resistance
Authors: Christoph Wohlkoenig, Katharina Leithner, Andelko Hrzenjak, Andrea Olschewski, Horst Olschewski
Journal: European Respiratory Journal (2013)

Background:  Many apoptosis-inducing agents induce cell-death by activating the orphan nuclear receptor nr4a1. Upon this activation nr4a1 is shifted from nucleus to mitochondria, where it is changing the conformation of the anti-apoptotic protein bcl-2 to a pro-apoptotic protein. However, in solid tumours  in vivo  hypoxic conditions prevail and these conditions add to chemotherapy resistance. It is still unknown whether apoptosis induction through nr4a1-mediated functional changes of bcl-2 is relevant under hypoxic conditions.  Methods:  A549 cells were treated with cisplatin under normoxia and hypoxia for predefined time periods. Cell proteins were harvested and separated into nuclear, cytoplasmic and mitochondrial fraction using commercial kits. Thereafter western blots were performed to assess the expression of nr4a1.  Results:  We found a down regulation of nr4a1 in the cytoplasmic fraction and an up regulation in the mitochondrial fraction following cisplatin treatment under normoxia. However, the same treatment under hypoxic conditions (1% O2) did not lead to an up regulation of mitochondrial nr4a1 (Fig.). Interestingly, under both conditions nuclear content did not change.  Conclusion:  We conclude that mitochondrial induction of apoptosis through nr4a1 may be suppressed by hypoxia and might represent an additional mechanism of hypoxia-induced cisplatin resistance.
Primary Retinal Detachment
Authors: Donald J. D'Amico
Journal: New England Journal of Medicine (2008)

A 57-year-old man noted flashing lights in his right eye, followed 2 days later by a cluster of dark floaters that mildly interfered with his vision. Over the course of the next week, he noted a progressive loss of the nasal visual field in that eye, with an eventual striking loss of central acuity that prompted him to seek ophthalmologic evaluation. Examination of the fundus with the pupil dilated showed a retinal detachment involving the temporal retina, including the macula. How should his case be managed?
Vacuolar H+-ATPase d2 Subunit
Authors: Annabel N. Smith, Franc[COMBINING CEDILLA]ois Jouret, Sharyn Bord, Katherine J. Borthwick, Rafia S. Al-Lamki, Carsten A. Wagner, Deborah C. Ireland, Valerie Cormier-Daire, Annalisa Frattini, Anna Villa, Uwe Kornak, Olivier Devuyst, Fiona E. Karet
Journal: Journal of the American Society of Nephrology (2005)

The ubiquitous multisubunit vacuolar-type proton pump (H<sup>+</sup>- or V-ATPase) is essential for acidification of diverse intracellular compartments. It is also present in specialized forms at the plasma membrane of intercalated cells in the distal nephron, where it is required for urine acidification, and in osteoclasts, playing an important role in bone resorption by acid secretion across the ruffled border membrane. It was reported previously that, in human, several of the renal pump's constituent subunits are encoded by genes that are different from those that are ubiquitously expressed. These paralogous proteins may be important in differential functions, targeting or regulation of H<sup>+</sup>-ATPases. They include the d subunit, where d1 is ubiquitous whereas d2 has a limited tissue expression. This article reports on an investigation of d2. It was first confirmed that in mouse, as in human, kidney and bone are two of the main sites of d2 mRNA expression. d2 mRNA and protein appear later during nephrogenesis than does the ubiquitously expressed E1 subunit. Mouse nephron-segment reverse transcription–PCR revealed detectable mRNA in all segments except thin limb of Henle's loop and distal convoluted tubule. However, with the use of a novel d2-specific antibody, high-intensity d2 staining was observed only in intercalated cells of the collecting duct in fresh-frozen human kidney, where it co-localized with the a4 subunit in the characteristic plasma membrane-enhanced pattern. In human bone, d2 co-localized with the a3 subunit in osteoclasts. This different subunit association in different tissues emphasizes the possibility of the H<sup>+</sup>-ATPase as a future therapeutic target.
Telomeres revisited: <i>RTEL1</i> variants in pulmonary fibrosis
Authors: Caroline Kannengiesser, Borie Raphael, Christelle Ménard, Marion Réocreux, Patrick Nitschké, Steven Gazal, Hervé Mal, Camille Taillé, Jacques Cadranel, Hilario Nunes, Dominique Valeyre, Jean François Cordier, Isabelle Callebaut, Catherine Boileau, Vincent Cottin, Bernard Grandchamp, Patrick Revy, Bruno Crestani
Journal: European Respiratory Journal (2015)

For decades, it has been recognised that cases of pulmonary fibrosis cluster in families. While previous studies have implicated mutations in several surfactant-related proteins [1–3] and telomere-related genes [4–12], in most families the genetic basis of their disease has remained uncertain [13]. In this issue of the European Respiratory Journal , Kannengiesser et al. [14] report that rare genetic variants in regulator of telomere elongation helicase 1 ( RTEL1 ) are associated with familial pulmonary fibrosis (FPF). Coupled with two other recent reports [7, 10], this work suggests that mutations in RTEL1 represent an important genetic cause of pulmonary fibrosis, responsible for disease in approximately 6% of families. Mutations in the telomere pathway gene RTEL1 represent an important cause of familial pulmonary fibrosis <http://ow.ly/OahXy>
Widespread promoter-mediated coordination of transcription and mRNA degradation
Authors: Mally Dori-Bachash, Ophir Shalem, Yair S Manor, Yitzhak Pilpel, Itay Tirosh
Journal: Genome biology (2012)

Previous work showed that mRNA degradation is coordinated with transcription in yeast, and in several genes the control of mRNA degradation was linked to promoter elements through two different mechanisms. Here we show at the genomic scale that the coordination of transcription and mRNA degradation is promoter-dependent in yeast and is also observed in humans.We first demonstrate that swapping upstream cis-regulatory sequences between two yeast species affects both transcription and mRNA degradation and suggest that while some cis-regulatory elements control either transcription or degradation, multiple other elements enhance both processes. Second, we show that adjacent yeast genes that share a promoter (through divergent orientation) have increased similarity in their patterns of mRNA degradation, providing independent evidence for the promoter-mediated coupling of transcription to mRNA degradation. Finally, analysis of the differences in mRNA degradation rates between mammalian cell types or mammalian species suggests a similar coordination between transcription and mRNA degradation in humans.Our results extend previous studies and suggest a pervasive promoter-mediated coordination between transcription and mRNA degradation in yeast. The diverse genes and regulatory elements associated with this coordination suggest that it is generated by a global mechanism of gene regulation and modulated by gene-specific mechanisms. The observation of a similar coupling in mammals raises the possibility that coupling of transcription and mRNA degradation may reflect an evolutionarily conserved phenomenon in gene regulation.
Respiratory and neurological outcomes in children born preterm study (RANOPs): Early Term outcomes
Authors: Martin Edwards, Sarah Kotecha, John Lowe, W. John Watkins, A. John Henderson, Sailesh Kotecha
Journal: European Respiratory Journal (2014)

Introduction 

Early term deliveries, which are common in mothers who have elective Caesarean section, are at increased risk of respiratory and other health related problems in the neonatal period compared to full term born children.

Aims 

To assess if early term (37-38 weeks) born infants had greater respiratory symptoms in childhood compared to term (≥39 weeks) born children.

Methods 

A cross sectional survey of preterm-born children in Wales with matched term-control (N=13361) children was undertaken. Children aged 1-10 years old were sent questionnaires (based on ISAAC) to assess respiratory and general health outcomes with additional data gathered from national health database. Data was analysed for the term controls (early term vs full term) and children <5 or ≥ 5 years of age.

Results 

548 early term born children and 2313 term born children were included. Early term-born children had higher rates of admission on the neonatal unit and admission during their first year of life (OR 1.6, p<0.001). 41% of early term born children report 'ever wheezing' vs 33% term born children (OR 1.4, p<0.001) and 15% vs 9.5% report having been diagnosed with a breathing problem such as asthma or recurrent wheeze (OR 1.7, p<0.001). Children <5 years old, born early term reported more wheezing during the day time over the last 3 months than term controls (OR 1.7, p=0.001). Early term-born children aged 5-10 years reported more wheezing episodes over the last 12 months than term controls (OR 1.5, p=0.034).

Conclusion 

Early term born children had significantly increased respiratory symptoms when compared to term-born children at both time periods of <5 & ≥5 years of age.
Three-dimensional morphology and gene expression in the Drosophila blastoderm at cellular resolution II: dynamics.
Authors: Soile VE Keränen, Charless C Fowlkes, Cris L Luengo Hendriks, Damir Sudar, David W Knowles, Jitendra Malik, Mark D Biggin
Journal: Genome biology (2006)

Abstract Background To accurately describe gene expression and computationally model animal transcriptional networks, it is essential to determine the changing locations of cells in developing embryos. Results Using automated image analysis methods, we provide the first quantitative description of temporal changes in morphology and gene expression at cellular resolution in whole embryos, using the Drosophila blastoderm as a model. Analyses based on both fixed and live embryos reveal complex, previously undetected three-dimensional changes in nuclear density patterns caused by nuclear movements prior to gastrulation. Gene expression patterns move, in part, with these changes in morphology, but additional spatial shifts in expression patterns are also seen, supporting a previously proposed model of pattern dynamics based on the induction and inhibition of gene expression. We show that mutations that disrupt either the anterior/posterior (a/p) or the dorsal/ventral (d/v) transcriptional cascades alter morphology and gene expression along both the a/p and d/v axes in a way suggesting that these two patterning systems interact via both transcriptional and morphological mechanisms. Conclusion Our work establishes a new strategy for measuring temporal changes in the locations of cells and gene expression patterns that uses fixed cell material and computational modeling. It also provides a coordinate framework for the blastoderm embryo that will allow increasingly accurate spatio-temporal modeling of both the transcriptional control network and morphogenesis.
Post-prandial hypoglycemia results from a non-glucose-dependent inappropriate insulin secretion in Roux-en-Y gastric bypassed patients
Authors: Charlotte Vaurs, Jean-Frederic Brun, Monelle Bertrand, Rémy Burcelin, Mael Chalret du Rieu, Yves Anduze, Hélène Hanaire, Patrick Ritz
Journal: Metabolism (2015)