bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases
Authors: Haston Kelly M. , Finkbeiner Steven
Published: October 2015

Neurodegenerative diseases are a leading cause of death. No disease-modifying therapies are available, and preclinical animal model data have routinely failed to translate into success for therapeutics. Induced pluripotent stem cell (iPSC) biology holds great promise for human in vitro disease modeling because these cells can give rise to any cell in the human brain and display phenotypes specific to neurodegenerative diseases previously identified in postmortem and clinical samples. Here, we explore the potential and caveats of iPSC technology as a platform for drug development and screening, and the future potential to use large cohorts of disease-bearing iPSCs to perform clinical trials in a dish.
Approaches to Validate and Manipulate RNA Targets with Small Molecules in Cells
Authors: Childs-Disney Jessica L. , Disney Matthew D.
Published: October 2015

RNA has become an increasingly important target for therapeutic interventions and for chemical probes that dissect and manipulate its cellular function. Emerging targets include human RNAs that have been shown to directly cause cancer, metabolic disorders, and genetic disease. In this review, we describe various routes to obtain bioactive compounds that target RNA, with a particular emphasis on the development of small molecules. We use these cases to describe approaches that are being developed for target validation, which include target-directed cleavage, classic pull-down experiments, and covalent cross-linking. Thus, tools are available to design small molecules to target RNA and to identify the cellular RNAs that are their targets.
MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective
Authors: Liu Jiabei , Clough Shannon J. , Hutchinson Anthony J. , Adamah-Biassi Ekue B. , Popovska-Gorevski Marina , Dubocovich Margarita L.
Published: October 2015

Melatonin, or 5-methoxy-N-acetyltryptamine, is synthesized and released by the pineal gland and locally in the retina following a circadian rhythm, with low levels during the day and elevated levels at night. Melatonin activates two high-affinity G protein–coupled receptors, termed MT1 and MT2, to exert beneficial actions in sleep and circadian abnormality, mood disorders, learning and memory, neuroprotection, drug abuse, and cancer. Progress in understanding the role of melatonin receptors in the modulation of sleep and circadian rhythms has led to the discovery of a novel class of melatonin agonists for treating insomnia, circadian rhythms, mood disorders, and cancer. This review describes the pharmacological properties of a slow-release melatonin preparation (i.e., Circadin®) and synthetic ligands (i.e., agomelatine, ramelteon, tasimelteon), with emphasis on identifying specific therapeutic effects mediated through MT1 and MT2 receptor activation. Discovery of selective ligands targeting the MT1 or the MT2 melatonin receptors may promote the development of novel and more efficacious therapeutic agents.
Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis
Authors: Nighot Prashant , Al-Sadi Rana , Rawat Manmeet , Guo Shuhong , Watterson D. Martin , Ma Thomas
Published: October 2015

Recent studies have implicated a pathogenic role for matrix metalloproteinases 9 (MMP-9) in inflammatory bowel disease. Although loss of epithelial barrier function has been shown to be a key pathogenic factor for the development of intestinal inflammation, the role of MMP-9 in intestinal barrier function remains unclear. The aim of this study was to investigate the role of MMP-9 in intestinal barrier function and intestinal inflammation. Wild-type (WT) and MMP-9−/−mice were subjected to experimental dextran sodium sulfate (DSS) colitis by administration of 3% DSS in drinking water for 7 days. The mouse colonic permeability was measured in vivo by recycling perfusion of the entire colon using fluorescently labeled dextran. The DSS-induced increase in the colonic permeability was accompanied by an increase in intestinal epithelial cell MMP-9 expression in WT mice. The DSS-induced increase in intestinal permeability and the severity of DSS colitis was found to be attenuated in MMP-9−/−mice. The colonic protein expression of myosin light chain kinase (MLCK) and phospho-MLC was found to be significantly increased after DSS administration in WT mice but not in MMP-9−/−mice. The DSS-induced increase in colonic permeability and colonic inflammation was attenuated in MLCK−/−mice and MLCK inhibitor ML-7-treated WT mice. The DSS-induced increase in colonic surface epithelial cell MLCK mRNA was abolished in MMP-9−/−mice. Lastly, increased MMP-9 protein expression was detected within the colonic surface epithelial cells in ulcerative colitis cases. These data suggest a role of MMP-9 in modulation of colonic epithelial permeability and inflammation via MLCK.
Elevated IL-33 expression is associated with pediatric eosinophilic esophagitis, and exogenous IL-33 promotes eosinophilic esophagitis development in mice
Authors: Judd L. M. , Heine R. G. , Menheniott T. R. , Buzzelli J. , O'Brien-Simpson N. , Pavlic D. , O'Connor L. , Al Gazali K. , Hamilton O. , Scurr M. , Collison A. M. , Mattes J. , Allen K. J. , Giraud A. S.
Published: October 2015

We tested whether the T helper (Th) type 2 (Th2) cell agonist and allergenic ligand IL-33 was associated with eosinophilic esophagitis (EoE) development in a pediatric cohort and whether IL-33 protein could induce disease symptoms in mice. Biopsies from EoE patients or controls were used to measure IL-33 mRNA and protein expression. Increased expression of IL-33 mRNA was found in the esophageal mucosa in EoE. IL-33 protein was detected in cells negative for CD45, mast cells, and epithelial cell markers near blood vessels. Circulating levels of IL-33 were not increased. The time course for IL-33 gene expression was quantified in an established Aspergillus fumigatus allergen mouse model of EoE. Because IL-33 induction was transient in this model and chronicity of IL-33 expression has been demonstrated in humans, naive mice were treated with recombinant IL-33 for 1 wk and esophageal pathology was evaluated. IL-33 application produced changes consistent with phenotypically early EoE, including transmural eosinophilia, mucosal hyperproliferation, and upregulation of eosinophilic genes and chemokines. Th2 cytokines, including IL-13, along with innate lymphoid cell group 2, Th1/17, and M2 macrophage marker genes, were increased after IL-33 application. IL-33-induced eosinophilia was ablated in IL-13 null mice. In addition, IL-33 induced a profound inhibition of the regulatory T cell gene signature. We conclude that IL-33 gene expression is associated with pediatric EoE development and that application of recombinant protein in mice phenocopies the early clinical phase of the human disease in an IL-13-dependent manner. IL-33 inhibition of esophageal regulatory T cell function may induce loss of antigenic tolerance, thereby providing a mechanistic rationale for EoE development.
Endogenous angiotensin-(1-7)/Mas receptor/NO pathway mediates the cardioprotective effects of pacing postconditioning
Authors: Abwainy Ala'a , Babiker Fawzi , Akhtar Saghir , Benter Ibrahim F.
Published: October 2015

The aim of the present study was to investigate the role of the ANG-(1–7) receptor (Mas) and nitric oxide (NO) in pacing postconditiong (PPC)-mediated cardioprotection against ischemia-reperfusion injury. Cardiac contractility and hemodynamics were assessed using a modified Langendorff system, cardiac damage was assessed by measuring infarct size and creatinine kinase levels, and levels of phosphorylated and total endothelial NO synthase (eNOS) were determined by Western blot analysis. Isolated hearts were subjected to 30 min of regional ischemia, produced by fixed position ligation of the left anterior descending coronary artery, followed by 30 min of reperfusion ( n = 6). Hearts were also subjected to PPC (three cycles of 30 s of left ventricular pacing alternated with 30 s of right atrial pacing) and/or treated during reperfusion with ANG-(1–7), NG-nitro-l-arginine methyl ester, or the Mas antagonist (d-Ala7)-ANG I/II (1–7). The PPC-mediated improvement in cardiac contractility and hemodyanamics, cardiac damage, and eNOS phosphorylation were significantly attenuated upon treatment with (d-Ala7)-ANG I/II (1–7) or NG-nitro-l-arginine methyl ester. Treatment with ANG-(1–7) improved cardiac function and reduced infarct size and creatinine kinase levels; however, the effects of ANG-(1–7) were not additive with PPC. In conclusion, these data provide novel insights into the cardioprotective mechanisms of PPC in that they involve the Mas receptor and eNOS and further suggest a potential therapeutic role for ANG-(1–7) in cardiac ischemic injury.
Heterozygous deletion of sarcolipin maintains normal cardiac function
Authors: Shimura Daisuke , Kusakari Yoichiro , Sasano Tetsuo , Nakashima Yasuhiro , Nakai Gaku , Jiao Qibin , Jin Meihua , Yokota Tomohiro , Ishikawa Yoshihiro , Nakano Atsushi , Goda Nobuhito , Minamisawa Susumu
Published: October 2015

Sarcolipin (SLN) is a small proteolipid and a regulator of sarco(endo)plasmic reticulum Ca2+-ATPase. In heart tissue, SLN is exclusively expressed in the atrium. Previously, we inserted Cre recombinase into the endogenous SLN locus by homologous recombination and succeeded in generating SLN-Cre knockin (SlnCre/+) mice. This SlnCre/+ mouse can be used to generate an atrium-specific gene-targeting mutant, and it is based on the Cre-loxP system. In the present study, we used adult SlnCre/+ mice atria and analyzed the effects of heterozygous SLN deletion by Cre knockin before use as the gene targeting mouse. Both SLN mRNA and protein levels were decreased in SlnCre/+ mouse atria, but there were no morphological, physiological, or molecular biological abnormalities. The properties of contractility and Ca2+ handling were similar to wild-type (WT) mice, and expression levels of several stress markers and sarcoplasmic reticulum-related protein levels were not different between SlnCre/+ and WT mice. Moreover, there was no significant difference in sarco(endo)plasmic reticulum Ca2+-ATPase activity between the two groups. We showed that SlnCre/+ mice were not significantly different from WT mice in all aspects that were examined. The present study provides basic characteristics of SlnCre/+ mice and possibly information on the usefulness of SlnCre/+ mice as an atrium-specific gene-targeting model.
MPST but not CSE is the primary regulator of hydrogen sulfide production and function in the coronary artery
Authors: Kuo Maggie M. , Kim Dae Hee , Jandu Sandeep , Bergman Yehudit , Tan Siqi , Wang Huilei , Pandey Deepesh R. , Abraham Theodore P. , Shoukas Artin A. , Berkowitz Dan E. , Santhanam Lakshmi
Published: October 2015

Hydrogen sulfide (H2S) has emerged as an important gasotransmitter in the vasculature. In this study, we tested the hypothesis that H2S contributes to coronary vasoregulation and evaluated the physiological relevance of two sources of H2S, namely, cystathionine-γ-lyase (CSE) and 3-mercaptypyruvate sulfertransferase (MPST). MPST was detected in human coronary artery endothelial cells as well as rat and mouse coronary artery; CSE was not detected in the coronary vasculature. Rat coronary artery homogenates produced H2S through the MPST pathway but not the CSE pathway in vitro. In vivo coronary vasorelaxation response was similar in CSE knockout mice, wild-type mice (WT), and WT mice treated with the CSE inhibitor propargylglycine, suggesting that CSE-produced H2S does not have a significant role in coronary vasoregulation in vivo. Ex vivo, the MPST substrate 3-mercaptopyruvate (3-MP) and H2S donor sodium hydrosulfide (NaHS) elicited similar coronary vasoreactivity responses. Pyruvate did not have any effects on vasoreactivity. The vasoactive effect of H2S appeared to be nitric oxide (NO) dependent: H2S induced coronary vasoconstriction in the presence of NO and vasorelaxation in its absence. Maximal endothelial-dependent relaxation was intact after 3-MP and NaHS induced an increase in preconstriction tone, suggesting that endothelial NO synthase activity was not significantly inhibited. In vitro, H2S reacted with NO, which may, in part explain the vasoconstrictive effects of 3-MP and NaHS. Taken together, these data show that MPST rather than CSE generates H2S in coronary artery, mediating its effects through direct modulation of NO. This has important implications for H2S-based therapy in healthy and diseased coronary arteries.
Lymph flow pattern in pleural diaphragmatic lymphatics during intrinsic and extrinsic isotonic contraction
Authors: Moriondo Andrea , Solari Eleonora , Marcozzi Cristiana , Negrini Daniela
Published: October 2015

Peripheral rat diaphragmatic lymphatic vessels, endowed with intrinsic spontaneous contractility, were in vivo filled with fluorescent dextrans and microspheres and subsequently studied ex vivo in excised diaphragmatic samples. Changes in diameter and lymph velocity were detected, in a vessel segment, during spontaneous lymphatic smooth muscle contraction and upon activation, through electrical whole-field stimulation, of diaphragmatic skeletal muscle fibers. During intrinsic contraction lymph flowed both forward and backward, with a net forward propulsion of 14.1 ± 2.9 μm at an average net forward speed of 18.0 ± 3.6 μm/s. Each skeletal muscle contraction sustained a net forward-lymph displacement of 441.9 ± 159.2 μm at an average velocity of 339.9 ± 122.7 μm/s, values significantly higher than those documented during spontaneous contraction. The flow velocity profile was parabolic during both spontaneous and skeletal muscle contraction, and the shear stress calculated at the vessel wall at the highest instantaneous velocity never exceeded 0.25 dyne/cm2. Therefore, we propose that the synchronous contraction of diaphragmatic skeletal muscle fibers recruited at every inspiratory act dramatically enhances diaphragmatic lymph propulsion, whereas the spontaneous lymphatic contractility might, at least in the diaphragm, be essential in organizing the pattern of flow redistribution within the diaphragmatic lymphatic circuit. Moreover, the very low shear stress values observed in diaphragmatic lymphatics suggest that, in contrast with other contractile lymphatic networks, a likely interplay between intrinsic and extrinsic mechanisms be based on a mechanical and/or electrical connection rather than on nitric oxide release.
A Novel Bioavailable BH3 Mimetic Efficiently Inhibits Colon Cancer via Cascade Effects of Mitochondria
Authors: Wang Xuefeng , Zhang Chen , Yan Xiangming , Lan Bin , Wang Jianyong , Wei Chongyang , Cao Xingxin , Wang Renxiao , Yao Jianhua , Zhou Tao , Zhou Mi , Liu Qiaoling , Jiang Biao , Jiang Pengfei , Kesari Santosh , Lin Xinjian , Guo Fang
Published: October 2015

Purpose: Gossypol and its analogs, through their ability to bind to and inactivate BH3 domain-containing antiapoptotic proteins, have been shown to inhibit the growth of various human cancer cells in culture and xenograft models. Here, we evaluated the antitumor efficacy of a novel gossypol derivative and BH3 mimetic ch282-5 (2-aminoethanesulfonic acid sodium-gossypolone) in colon cancer models. Several innovative combination strategies were also explored and elaborated.

Experimental Design: Ch282-5 was synthesized by modifying the active aldehyde groups and R groups of gossypol according to a computer-aided drug design program. The stability of ch282-5 was examined by high-performance liquid chromatography, and cytotoxic effects of ch282-5 on colon cancer cells were assessed by MTS assay. Activation of mitochondrial apoptotic pathway by ch282-5 was evidenced with a series of molecular biology techniques. In vivo antitumor activity of ch282-5 and its combination with chloroquine, rapamycin, oxaliplatin, and ABT-263 was also evaluated in colon cancer xenograft models and experimental liver metastasis models.

Results: Ch282-5 showed antiproliferative and pro-cell death activity against colon cancer cells both in vitro and in vivo, and the response to the drug correlated with inhibition of antiapoptotic Bcl-2 proteins, induction of mitochondria-dependent apoptotic pathway, and disruption of mitophagy and mTOR pathway. Ch282-5 also suppressed liver metastasis produced by intrasplenic injection of colon cancer cells. Furthermore, ch282-5 could potentiate the effectiveness of oxaliplatin and rescue ABT-263 efficacy by downregulation of Mcl-1 and elevation of platelet number.

Conclusions: These findings provide a rational basis for clinical investigation of this highly promising BH3 mimetic in colon cancer. Clin Cancer Res; 22(6); 1445–58. ©2015 AACR.
RAS/MAPK Activation Is Associated with Reduced Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer: Therapeutic Cooperation Between MEK and PD-1/PD-L1 Immune Checkpoint Inhibitors
Authors: Loi Sherene , Dushyanthen Sathana , Beavis Paul A. , Salgado Roberto , Denkert Carsten , Savas Peter , Combs Susan , Rimm David L. , Giltnane Jennifer M. , Estrada Monica V. , Sánchez Violeta , Sanders Melinda E. , Cook Rebecca S. , Pilkinton Mark A. , Mallal Simon A. , Wang Kai , Miller Vincent A. , Stephens Phil J. , Yelensky Roman , Doimi Franco D. , Gómez Henry , Ryzhov Sergey V. , Darcy Phillip K. , Arteaga Carlos L. , Balko Justin M.
Published: October 2015

Purpose: Tumor-infiltrating lymphocytes (TIL) in the residual disease (RD) of triple-negative breast cancers (TNBC) after neoadjuvant chemotherapy (NAC) are associated with improved survival, but insight into tumor cell-autonomous molecular pathways affecting these features are lacking.

Experimental Design: We analyzed TILs in the RD of clinically and molecularly characterized TNBCs after NAC and explored therapeutic strategies targeting combinations of MEK inhibitors with PD-1/PD-L1–targeted immunotherapy in mouse models of breast cancer.

Results: Presence of TILs in the RD was significantly associated with improved prognosis. Genetic or transcriptomic alterations in Ras–MAPK signaling were significantly correlated with lower TILs. MEK inhibition upregulated cell surface MHC expression and PD-L1 in TNBC cells both in vivo and in vitro. Moreover, combined MEK and PD-L1/PD-1 inhibition enhanced antitumor immune responses in mouse models of breast cancer.

Conclusions: These data suggest the possibility that Ras–MAPK pathway activation promotes immune-evasion in TNBC, and support clinical trials combining MEK- and PD-L1–targeted therapies. Furthermore, Ras/MAPK activation and MHC expression may be predictive biomarkers of response to immune checkpoint inhibitors. Clin Cancer Res; 22(6); 1499–509. ©2015 AACR.
Severely Impaired and Dysregulated Cytochrome P450 Expression and Activities in Hepatocellular Carcinoma: Implications for Personalized Treatment in Patients
Authors: Yan Tongmeng , Lu Linlin , Xie Cong , Chen Jiamei , Peng Xiaojuan , Zhu Lijun , Wang Ying , Li Qiang , Shi Jian , Zhou Fuyuan , Hu Ming , Liu Zhongqiu
Published: October 2015

This study aims to systematically determine the activities and expressions of cytochrome P450s (CYP) in hepatocellular carcinoma (HCC) patients to support their optimal use in personalized treatment of HCC. Activities of seven major drug-metabolizing CYP enzymes (CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, and 3A4) were determined in tumors and pericarcinomatous tissues harvested from 26 patients with hepatitis B virus-positive HCC using probe substrates. Protein and mRNA levels of these CYPs were also measured using isotope label-free LC/MS-MS method and real-time PCR, respectively. Maximal metabolic velocity (Vmax) of CYP probe substrates was decreased by 2.5- to 30-fold in tumor microsomes, accompanied by a corresponding decrease in their protein and mRNA expression levels. However, Km values and turnover numbers of substrates in tumor microsomes were not changed. High correlations between activities and CYP protein levels were also observed, but the correlation between activities and mRNA levels was often poor. There was a major decrease in the degree of correlation in CYP expression in tumor tissues, suggesting that CYP expression levels are greatly disrupted by the tumorigenic process. Our unprecedented systemic study of the effects of HCC on CYPs demonstrated that activities of CYPs were seriously impaired and their expression patterns were severely altered by HCC. We proposed that determination of the CYP protein expression profile by LC/MS-MS in each patient is a promising approach that can be clinically used for individualized treatment of HCC. Mol Cancer Ther; 14(12); 2874–86. ©2015 AACR.
Laparoscopy Reveals a Diversity of Peritoneal Change in Patients with Long-Term Vintage of Peritoneal Dialysis
Authors: Sasaki Koichi , Mizuno Hitoshi , Iwamoto Noriyuki , Imakita Masami , Yasuda Keiko , Kimura Tomonori , Rakugi Hiromi , Isaka Yoshitaka , Hayashi Terumasa
Published: October 2015

Background: Although laparoscopy may provide more detailed morphological and histological information about peritoneal damage, its significance in patients with long vintage of peritoneal dialysis (PD) is not elucidated. Methods: Findings in 12 patients with PD vintage of 7.3 (5.0-8.4) years who had undergone laparoscopy between 2007 and 2011 were reviewed. Macroscopic (peritoneal change, hypervascular change, adhesion, encapsulation) and histopathological peritoneal findings (interstitial fibrosis, microvascular change, fibrin deposition, inflammatory cell infiltration) were scored and summed as Macro-total score (Macro-TS) and Micro-total score (Micro-TS), respectively. Factors associated with these scores and the relationship between these scores were investigated. Results: Neither Macro-TS nor Micro-TS were related to PD vintage (p = 0.069 and p = 0.769, respectively); moreover, Macro-TS varied from patient to patient regardless of similar PD vintage. However, Macro-TS showed a significant association with duration of acidic dialysate (p = 0.003). Conclusion: Macroscopic and microscopic findings via laparoscopy may help the assessment of peritoneal damage in patients with long PD vintage.
Developmental Characterization of Tail Movements in the Appendicularian Urochordate Oikopleura dioica
Authors: Kreneisz Orsolya , Glover Joel C.
Published: October 2015

Using high-speed video cinematography, we characterized kinematically the spontaneous tail movements made by the appendicularian urochordate Oikopleura dioica. Videos of young adult (1-day-old) animals discriminated 4 cardinal movement types: bending, nodding, swimming and filtering, each of which had a characteristic signature including cyclicity, event or cycle duration, cycle frequency, cycle frequency variation, laterality, tail muscle segment coordination and episode duration. Bending exhibited a more common, unilateral form (single bending) and a rarer, bilateral form (alternating bending). Videos of developing animals showed that bending and swimming appeared in rudimentary form starting just after hatching and exhibited developmental changes in movement excursion, duration and frequency, whereas nodding and filtering appeared in the fully mature form in young adults at the time of first house production. More complex behaviors were associated with inflating, entering and exiting the house. We also assessed the influence of descending inputs by separating the tail (which contains all muscles and most likely the neural circuits that generate most motor outputs) from the head. Isolated tails spontaneously generated either bending or swimming movements in abnormally protracted episodes. This together with other observations of interactions between bending and swimming behaviors indicates the presence of several types of descending inputs that regulate the activity of the pattern generating circuitry in the tail nervous system.
New Genetic Forms of Childhood-Onset Primary Osteoporosis
Authors: Kämpe Anders J. , Mäkitie Riikka E. , Mäkitie Outi
Published: October 2015

Recent developments in genetic technology have given us the opportunity to look at diseases in a new and more detailed way. This Mini Review discusses monogenetic forms of childhood-onset primary osteoporosis, with the main focus on osteoporosis caused by mutations in WNT1 and PLS3, two of the most recently discovered genes underlying early-onset osteoporosis. The importance of WNT1 in the accrual and maintenance of bone mass through activation of canonical WNT signaling was recognized in 2013. WNT1 was shown to be a key ligand for the WNT-signaling pathway, which is of major importance in the regulation of bone formation. More recently, mutations in PLS3, located on the X chromosome, were shown to be the cause of X-linked childhood-onset primary osteoporosis affecting mainly males. The function of PLS3 in bone metabolism is still not completely understood, but it has been speculated to have an important role in mechanosensing by osteocytes and in matrix mineralization. In this new era of genetics, our knowledge on genetic causes of childhood-onset osteoporosis expands constantly. These discoveries bring new possibilities, but also new challenges. Guidelines are needed to implement this new genetic knowledge to clinical patient care and to guide genetic investigations in affected families.
The Role of Congestion in Cardiorenal Syndrome Type 2: New Pathophysiological Insights into an Experimental Model of Heart Failure
Authors: Angelini Annalisa , Castellani Chiara , Virzì Grazia Maria , Fedrigo Marny , Thiene Gaetano , Valente Marialuisa , Ronco Claudio , Vescovo Giorgio
Published: October 2015

Background: In cardiorenal syndrome type 2 (CRS2), the role of systemic congestion in heart failure (HF) is still obscure. We studied a model of CRS2 [monocrotaline (MCT)-treated rats] secondary to pulmonary hypertension and right ventricular (RV) failure in order to evaluate the contribution of prevalent congestion to the development of kidney injury. Methods: Ten animals were treated with MCT for 4 weeks until they developed HF. Eleven animals were taken as controls. Signs of hypertrophy and dilatation of the right ventricle demonstrated the occurrence of HF. Brain natriuretic peptide (BNP), serum creatinine (sCreatinine), both kidney and heart neutrophil gelatinase-associated lipocalin (NGAL), matrix metallopeptidase 9 (MMP9), serum cytokines as well as kidney and heart cell death, as assessed by TUNEL, were studied. Results: Rats with HF showed higher BNP levels [chronic HF (CHF) 4.8 ± 0.5 ng/ml; controls 1.5 ± 0.2 ng/ml; p < 0.0001], marked RV hypertrophy and dilatation (RV mass/RV volume: CHF 1.46 ± 0.31, controls 2.41 ± 0.81; p < 0.01) as well as pleural and peritoneal effusions. A significant increase in proinflammatory cytokines and sCreatinine was observed (CHF 3.06 ± 1.3 pg/ml vs. controls 0.54 ± 0.23 pg/ml; p = 0.04). Serum (CHF 562.7 ± 93.34 ng/ml vs. controls 245.3 ± 58.19 ng/ml; p = 0.02) as well as renal and heart tissue NGAL levels [CHF 70,680 ± 4,337 arbitrary units (AU) vs. controls 32,120 ± 4,961 AU; p = 0.001] rose significantly, and they were found to be complexed with MMP9 in CHF rats. A higher number of kidney TUNEL-positive tubular cells was also detected (CHF 114.01 ± 45.93 vs. controls 16.36 ± 11.60 cells/mm2; p = 0.0004). Conclusion: In this model of CHF with prevalent congestion, kidney injury is characterized by tubular damage and systemic inflammation. The upregulated NGAL complexed with MMP9 perpetuates the vicious circle of kidney/heart damage by enhancing the enzymatic activity of MMP9 with extracellular matrix degradation, worsening heart remodeling.
Nitric Oxide Increases the Expression of Aquaporin-4 Protein in Rat Optic Nerve Astrocytes through the Cyclic Guanosine Monophosphate/Protein Kinase G Pathway
Authors: Oku Hidehiro , Morishita Seita , Horie Taeko , Kida Teruyo , Mimura Masashi , Fukumoto Masanori , Kojima Shota , Ikeda Tsunehiko
Published: October 2015

Aims: Nitric oxide (NO) is associated with neuroinflammation in the central nervous system. We determined whether NO increases the expression of aquaporin-4 (AQP4) in optic nerve astrocytes of rats. Methods: Isolated astrocytes were incubated under normoxic or hypoxic conditions with or without glucose (5.5 mM). The astrocytes were also exposed to different concentrations of S-nitroso-N-acetyl-DL-penicillamine (SNAP, 1.0-100 μM), an NO donor. The expression of AQP4 was determined by Western blot analyses, and NO formation was measured by the Griess reaction. The changes in astrocytic cellular volumes were determined by flow cytometry. Results: Hypoxia and glucose deprivation increased AQP4 expression and NO formation. Inhibition of NO synthetase (NOS) significantly suppressed these changes. SNAP caused a significant increase in AQP4 expression, and the increase was significantly suppressed by carboxy-PTIO, a scavenger of NO. Incubation with 8-Br-cyclic guanosine monophosphate (cGMP) mimicked the effects of SNAP, while the addition of either 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ; inhibitor of soluble guanylate cyclase) or KT5823 (protein kinase G inhibitor) suppressed the SNAP-induced increase in AQP4 significantly. SNAP also caused a significant increase in astrocytic cellular volume through the AQP4 channels. Conclusions: NO increased the AQP4 expression of optic nerve astrocytes through the cGMP/protein kinase G pathway and enlarged their volume.
Erythropoietin Decreases the Occurrence of Myocardial Fibrosis by Inhibiting the NADPH-ERK-NF-κB Pathway
Authors: Wang Li-Ping , Yang Xiu-Hong , Wang Xiao-Jun , Li Shu-Min , Sun Na , Zhang Tian
Published: October 2015

Objectives: The aim of this study was to investigate the protective role of erythropoietin (EPO) against myocardial fibrosis (MF). Methods: Pressure-overloaded rats were established by abdominal aortic constriction, the rats were randomly divided in a double-blind manner into 3 groups (n = 12 for each group): sham-operated rats (sham), operated rats receiving physiological saline (vehicle) and operated rats receiving 4,000 U/kg rhEPO (EPO group). The vehicle and drugs were administered to rats by intraperitoneal injection. In addition, cultured adult rat cardiac fibroblasts (CFs) were utilized to investigate the role of EPO in CF proliferation and collagen secretion. Results: After 4 weeks, besides an increase in blood pressure, myocardial hypertrophy, collagen deposition in the myocardium and decreased cardiac function were observed in the pressure-overloaded rats. The expression of NADPH oxidase (Nox2 and Nox4) and inflammatory cytokines (CD45, F4/80 and MCP-1) was also significantly increased. All these alterations were prevented by EPO. TGF-ß promoted CF proliferation, collagen secretion, ROS production and Nox2/Nox4 expression, which was inhibited by EPO. In addition, the TGF-ß-induced increase of ERK1/2 phosphorylation and NF-κB expression were attenuated by EPO. Conclusion: EPO inhibited rat MF induced by pressure overload and improved myocardial function by decreasing CF proliferation and differentiation via inhibition of the NADPH-ERK-NF-κB pathway.
Trends in Social Inequality in Tooth Brushing among Adolescents: 1991-2014
Authors: Holstein Bjørn E. , Bast Lotus Sofie , Brixval Carina Sjöberg , Damsgaard Mogens Trab
Published: October 2015

This study examines whether social inequality in tooth brushing frequency among adolescents changed from 1991 to 2014. The data material was seven comparable cross-sectional studies of nationally representative samples of 11- to 15-year-olds in Denmark with data about frequency of tooth brushing and occupation of parents. The total number of participants was 31,464, of whom 21.7% brushed their teeth less than the recommended 2 times a day. The absolute social inequality measured as prevalence difference between low and high social class increased from 7.7% in 1991 to 14.6% in 2014. The relative social inequality assessed by odds ratios for infrequent tooth brushing also increased from 1991 to 2014.
Multiple Small Supernumerary Marker Chromosomes Resulting from Maternal Meiosis I or II Errors
Authors: Hochstenbach Ron , Nowakowska Beata , Volleth Marianne , Ummels Amber , Kutkowska-Kaźmierczak Anna , Obersztyn Ewa , Ziemkiewicz Kamila , Gerloff Claudia , Schanze Denny , Zenker Martin , Muschke Petra , Schanze Ina , Poot Martin , Liehr Thomas
Published: October 2015

We present 2 cases with multiple de novo supernumerary marker chromosomes (sSMCs), each derived from a different chromosome. In a prenatal case, we found mosaicism for an sSMC(4), sSMC(6), sSMC(9), sSMC(14) and sSMC(22), while a postnatal case had an sSMC(4), sSMC(8) and an sSMC(11). SNP-marker segregation indicated that the sSMC(4) resulted from a maternal meiosis II error in the prenatal case. Segregation of short tandem repeat markers on the sSMC(8) was consistent with a maternal meiosis I error in the postnatal case. In the latter, a boy with developmental/psychomotor delay, autism, hyperactivity, speech delay, and hypotonia, the sSMC(8) was present at the highest frequency in blood. By comparison to other patients with a corresponding duplication, a minimal region of overlap for the phenotype was identified, with CHRNB3 and CHRNA6 as dosage-sensitive candidate genes. These genes encode subunits of nicotinic acetylcholine receptors (nAChRs). We propose that overproduction of these subunits leads to perturbed component stoichiometries with dominant negative effects on the function of nAChRs, as was shown by others in vitro. With the limitation that in each case only one sSMC could be studied, our findings demonstrate that different meiotic errors lead to multiple sSMCs. We relate our findings to age-related aneuploidy in female meiosis and propose that predivision sister-chromatid separation during meiosis I or II, or both, may generate multiple sSMCs.
Individual Proton Pump Inhibitors and Outcomes in Patients With Coronary Artery Disease on Dual Antiplatelet Therapy: A Systematic Review
Authors: Sherwood Matthew W. , Melloni Chiara , Jones W. Schuyler , Washam Jeffrey B. , Hasselblad Vic , Dolor Rowena J.
Published: October 2015

Background

Observational studies evaluating the possible interaction between proton pump inhibitors (
PPI
s) and clopidogrel have shown mixed results. We conducted a systematic review comparing the safety of individual
PPI
s in patients with coronary artery disease taking clopidogrel.

Methods and Results

Studies performed from January 1995 to December 2013 were screened for inclusion. Data were extracted, and study quality was graded for 34 potential studies. For those studies in which follow‐up period, outcomes, and multivariable adjustment were comparable, meta‐analysis was performed.

The adjusted odds or hazard ratios for the composite of cardiovascular or all‐cause death, myocardial infarction, and stroke at 1 year were reported in 6 observational studies with data on individual
PPI
s. Random‐effects meta‐analyses of the 6 studies revealed an increased risk for adverse cardiovascular events for those taking pantoprazole (
hazard ratio
1.38; 95%
CI
1.12–1.70), lansoprazole (
hazard ratio
1.29; 95%
CI
1.09–1.52), or esomeprazole (
hazard ratio
1.27; 95%
CI
1.02–1.58) compared with patients on no
PPI
. This association was not significant for omeprazole (
hazard ratio
1.16; 95%
CI
0.93–1.44). Sensitivity analyses for the
coronary artery disease
population (acute coronary syndrome versus mixed) and exclusion of a single study due to heterogeneity of reported results did not have significant influence on the effect estimates for any
PPI
s.

Conclusions

Several frequently used
PPI
s previously thought to be safe for concomitant use with clopidogrel were associated with greater risk of adverse cardiovascular events. Although the data are observational, they highlight the need for randomized controlled trials to evaluate the safety of concomitant
PPI
and clopidogrel use in patients with
coronary artery disease
.
Incidence of Stroke or Systemic Embolism in Paroxysmal Versus Sustained Atrial Fibrillation
Authors: Takabayashi Kensuke , Hamatani Yasuhiro , Yamashita Yugo , Takagi Daisuke , Unoki Takashi , Ishii Mitsuru , Iguchi Moritake , Masunaga Nobutoyo , Ogawa Hisashi , Esato Masahiro , Chun Yeong-Hwa , Tsuji Hikari , Wada Hiromichi , Hasegawa Koji , Abe Mitsuru , Lip Gregory Y.H. , Akao Masaharu
Published: October 2015

Background and Purpose—

There is controversy on the relationship of the type of atrial fibrillation (AF) to stroke. Although several studies show that patients with paroxysmal AF (PAF) have a stroke risk similar to those with persistent or permanent AF, recent studies suggest that PAF is associated with a lower rate of stroke. Limited data on stroke risk associated with PAF are evident in Asian populations.

Methods—

The Registry Study of Atrial Fibrillation Patients in Fushimi-ku (Fushimi AF Registry) is a community-based survey of patients with AF in Fushimi-ku, Kyoto, Japan. Patients were categorized into 2 types of AF: PAF or sustained (persistent or permanent) AF. We compared clinical events between PAF (n=1588) and sustained AF (n=1716).

Results—

Patients with PAF were younger, had less comorbidities, and received oral anticoagulants (OAC) less commonly. A lower risk of stroke/systemic embolism during follow-up period in the patients with PAF was consistently observed (non-OAC users: hazard ratio, 0.45; 95% confidence intervals, 0.27–0.75;
P
<0.01 and OAC users: hazard ratio, 0.59; 95% confidence interval, 0.35–0.93;
P
=0.03). The composite end point of stroke/systemic embolism/all-cause mortality was also lower in PAF, whether among OAC users (hazard ratio, 0.77; 95% confidence interval, 0.59–0.99;
P
=0.046) or non-OAC users (hazard ratio, 0.59; 95% confidence interval, 0.46–0.75;
P
<0.01). On multivariate analysis, PAF was an independent predictor of lower stroke/systemic embolism risk.

Conclusions—

In this large cohort of Japanese patients with AF, PAF was independently associated with lower incidence of stroke/systemic embolism than sustained AF. This may aid decision making for anticoagulation, especially in those patients with AF with few stroke risk factors.

Clinical Trial Registration—

URL:
http://www.umin.ac.jp/ctr/index.htm
. Unique identifier: UMIN000005834.
I and Animal Thou
Authors: Spannring Reingard
Published: October 2015

Nonhuman animals and human-animal relationships have so far attracted very little interest among educational scientists. However, from the perspective of human-animal studies, the strong impact of education, learning, and socialization on the continuous reproduction of culturally formed human-animal relationships suggests a rich and important research area for educational science. Educational science has neglected nonhuman beings as participants in learning environments and victims of the end result of human education. It has also failed to deconstruct the anthropocentric basis of mainstream educational theory, its understanding of learning and teaching, and the meaning of being human. Building on Martin Buber’s philosophy of dialogue, a relational approach in educational theory was developed that integrates nonhuman animals and sees the aim of education in fostering the growth of whole persons in relationships in a more than human world.
Murder on the Margins: The Paxton Massacre and the Remaking of Sovereignty in Colonial Pennsylvania
Authors: Smolenski John
Published: October 2015

On December 14 and 27, 1763, rioters in western Pennsylvania attacked and killed nearly two dozen Conestoga Indians living near Lancaster, Pennsylvania. Five weeks later, two hundred and fifty men, calling themselves the Paxton Boys, marched on Pennsylvania to kill Indians housed there for their protection. These events sparked outrage, as pro- and anti-Paxtonite authors debated the attacks. Defenders of the massacre claimed that they had not only the right but the duty as good British subjects to kill “alien” Indians within the colony’s borders. This article argues that these efforts to articulate the civic rights and duties in the aftermath of the massacre represented a subtle attempt to redefine imperial authority on the frontier. The Paxton rioters, in their actions and their post-hoc justifications, seized sovereign power of life and death and the ability to delimit the meanings of allegiance, casting themselves as sovereign subjects on the frontier.
Constructing Identities through Multilingualism and MultiscriptualismThe Linguistic Landscape in Dutch and Belgian Chinatowns多元语言文字中的认同建构——以荷兰、比利 时唐人街的语言风貌为例
Authors: Wang Xiaomei , de Velde Hans Van
Published: October 2015

This paper examines characteristics of the linguistic landscape (ll) in Chinatowns in Belgium and the Netherlands. Fieldwork was conducted in four cities in the Netherlands (Amsterdam, Utrecht, The Hague, and Rotterdam) and two in Belgium (Brussels and Antwerp). All these cities are situated in the Dutch language area, but Brussels is officially bilingual French-Dutch. In the study, the traditional approach in linguistic landscape studies was combined with an ethnographic approach, in which shopkeepers were interviewed about language and script choice in their signs. The quantitative analysis shows that Chinese shows up in more than three quarters of all signs and that in almost 60 per cent of the signs Chinese is the dominant language. Dutch (the language of the region) and English (the international language) show up in almost half the signs. French shows up almost exclusively in Brussels, where Dutch is less used in signs. The analysis also shows interesting differences in script types between the cities. The presence of different types of Chinese character and pinyin systems indexes the Chineseness of the community, the origin of the local Chinese population, the position of the different establishments in the host countries, and the tendency of these Chinese immigrants to localize. We will show how these small overseas-Chinese communities construct and express their new identity by means of multilingualism and multiscriptualism.
The Contact Diffusion of Linguistic Practices
Authors: Bohnemeyer Jürgen , Donelson Katharine T. , Moore Randi E. , Benedicto Elena , Eggleston Alyson , O’Meara Carolyn K. , Pérez Báez Gabriela , Capistrán Garza Alejandra , Hernández Green Néstor , de Jesús Selene Hernández Gómez María , Herrera Castro Samuel , Palancar Enrique , Polian Gilles , Romero Méndez Rodrigo
Published: October 2015

We examine the extent to which practices of language use may be diffused through language contact and areally shared, using data on spatial reference frame use by speakers of eight indigenous languages from in and around the Mesoamerican linguistic area and three varieties of Spanish. Regression models show that the frequency of L2-Spanish use by speakers of the indigenous languages predicts the use of relative reference frames in the L1 even when literacy and education levels are accounted for. A significant difference in frame use between the Mesoamerican and non-Mesoamerican indigenous languages further supports the contact diffusion analysis.
‘A Genuine Respect for the People’
Authors: Hoerder Dirk
Published: October 2015

I, first, discuss the ethical and scholarly bases of approaches ‘emancipated’ from mainstream societal discourses. Next, I reinsert into the genealogy of us migration history’s development several ‘early’ research clusters or schools from the 1880s with a focus on other people than white western and northern Europeans. Third, I argue that, in a subsequent phase, such approaches coalesced around Franz Boas and what I call the Columbia University/ Barnard School of interdisciplinary research from the 1890s to the 1950s. Both men and women were part of this group working in the spatial-intellectual context of New York City’s Ellis Island, Greenwich Village, and Harlem. In addition, a network of cooperative scholarly transnational relationships emerged esp. to Polish post-1918 scholarship. I will focus on the Columbia-Barnard scholars’ research on (a) European immigrants and exiles, (b) Mexican migration to and life-ways in the us, and (c) African American (more precisely: ‘African-us’) and African-Caribbean cultures. To emphasise agency and networks I will emphasize individual scholars’ contributions and connections. The question, why this scholarship was ignored or (deliberately?) forgotten, remains latent but any suggestion for an answer can be made.
Reviving a Lost Potential of the Chicago School of Sociology?
Authors: Yu Henry
Published: October 2015

This paper traces the effects of anti-Asian politics and immigration exclusion in shaping early studies of Asian migration in the Pacific region, in particular within the United States, Canada, and Australian. Yu argues that there are collaborative community research approaches that marked early 20th century studies of Asian migrants to North America that should be recovered, a lost potential of early survey research work of the Chicago school of sociology in general.
Determination of Convective Boundary Layer Entrainment Fluxes, Dissipation Rates, and the Molecular Destruction of Variances: Theoretical Description and a Strategy for Its Confirmation with a Novel Lidar System Synergy
Authors: Wulfmeyer Volker , Muppa Shravan Kumar , Behrendt Andreas , Hammann Eva , Späth Florian , Sorbjan Zbigniew , Turner David D. , Hardesty R. Michael
Published: October 2015

Atmospheric variables in the convective boundary layer (CBL), which are critical for turbulence parameterizations in weather and climate models, are assessed. These include entrainment fluxes, higher-order moments of humidity, potential temperature, and vertical wind, as well as dissipation rates. Theoretical relationships between the integral scales, gradients, and higher-order moments of atmospheric variables, fluxes, and dissipation rates are developed mainly focusing on the entrainment layer (EL) at the top of the CBL. These equations form the starting point for tests of and new approaches in CBL turbulence parameterizations. For the investigation of these relationships, an observational approach using a synergy of ground-based water vapor, temperature, and wind lidar systems is proposed. These systems measure instantaneous vertical profiles with high temporal and spatial resolution throughout the CBL including the EL. The resolution of these systems permits the simultaneous measurement of gradients and fluctuations of these atmospheric variables. For accurate analyses of the gradients and the shapes of turbulence profiles, the lidar system performances are very important. It is shown that each lidar profile can be characterized very well with respect to bias and system noise and that the constant bias has negligible effect on the measurement of turbulent fluctuations. It is demonstrated how different gradient relationships can be measured and tested with the proposed lidar synergy within operational measurements or new field campaigns. Particularly, a novel approach is introduced for measuring the rate of destruction of humidity and temperature variances, which is an important component of the variance budget equations.