bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuclear Translocation of UDCA by the Glucocorticoid Receptor Is Required to Reduce TGF-β1–Induced Apoptosis in Rat Hepatocytes *
Authors: Solá Susana , Amaral Joana D. , Castro Rui E. , Ramalho Rita M. , Borralho Pedro M. , Kren Betsy T. , Tanaka Hirotoshi , Steer Cifford J. , Rodrigues Cecília M. P. 
Published: September 2005

Abstract

Ursodeoxycholic acid (UDCA) inhibits classical mitochondrial pathways of apoptosis by either directly stabilizing mitochondrial membranes or modulating specific upstream targets. Furthermore, UDCA regulates apoptosis-related genes from transforming growth factor β1 (TGF-β1)–induced hepatocyte apoptosis by a nuclear steroid receptor (NSR)–dependent mechanism. In this study, we further investigated the potential role of the glucocorticoid receptor (GR) in the antiapoptotic function of UDCA. Our results with short interference RNA (siRNA) technology confirmed that UDCA significantly reduces TGF-β1–induced apoptosis of primary rat hepatocytes through a GR-dependent effect. Immunoprecipitation assays and confocal microscopy showed that UDCA enhanced free GR levels with subsequent GR nuclear translocation. Interestingly, when a carboxy-terminus deleted form of GR was used, UDCA no longer increased free GR and/or GR translocation, nor did it protect against TGF-β1–induced apoptosis. In co-transfection experiments with GR response element reporter and overexpression constructs, UDCA did not enhance the transactivation of GR with TGF-β1. Finally, using a flourescently labeled UDCA molecule, the bile acid appeared diffuse in the cytosol but was aggregated in the nucleus of hepatocytes. Both siRNA assays and transfection experiments with either wild-type or mutant forms of GR showed that nuclear trafficking occurs through a GR-dependent mechanism.
In conclusion
, these results further clarify the antiapoptotic mechanism(s) of UDCA and suggest that GR is crucial for the nuclear translocation of this bile acid for reducing apoptosis. (Hepatology 2005;42:925–934.)
CTLA-4Ig Suppresses Liver Injury by Inhibiting Acquired Immune Responses in a Mouse Model of Fulminant Hepatitis *
Authors: Nakayama Yasuhiro , Shimizu Yukihiro , Hirano Katsuharu , Ebata Kazumi , Minemura Masami , Watanabe Akiharu , Sugiyama Toshiro 
Published: September 2005

Abstract

Expression of costimulatory molecules is significantly upregulated in various organs in an animal model of severe hepatitis induced by injection of

Propionibacterium acnes

(

P. acnes

) and lipopolysaccharide (LPS). In the present study, we examined whether blockade of costimulatory signals by CTLA-4Ig can suppress the liver injury in this model. We injected an adenovirus encoding CTLA-4Ig (AdCTLA-4Ig) into mice 7 days before, on the same day, or 3 days after

P. acnes

priming. The virus was found to infect the liver preferentially, and CTLA-4Ig was detected in the serum as early as 2 days after viral injection. After injection of LPS, liver injury and survival rates were examined. Most of the mice not injected with AdCTLA-4Ig died within 12 hours after injection of LPS. In contrast, all the AdCTLA-4Ig–injected mice survived when the virus was injected 7 days before or on the same day as

P. acnes

priming. Importantly, hemorrhagic liver injury and serum alanine aminotransferase levels were significantly reduced after LPS injection even when AdCTLA-4Ig was injected 3 days after

P. acnes

priming. Immunological analyses showed that CTLA-4Ig inhibited the activation and expansion of

P. acnes

–specific CD4+ T cells in the hepatic lymph nodes, leading to a reduction in the recruitment of the cells to the liver. The total amounts of interferon-γ, interleukin-12, and various chemokines in the liver were then decreased, resulting in inhibition of the secondary recruitment of not only T cells but also macrophages.
In conclusion
, CTLA-4Ig could be useful for treatment of severe liver injury.

Supplementary material for this article can be found on the Hepatology website (

http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html

).

(Hepatology 2005;42:915–924.)
Molecular Changes From Dysplastic Nodule to Hepatocellular Carcinoma Through Gene Expression Profiling *
Authors: Nam Suk Woo , Park Jik Young , Ramasamy Adaikalavan , Shevade Shirish , Islam Amirul , Long Philip M. , Park Cheol Keun , Park Soo Eun , Kim Su Young , Lee Sug Hyung , Park Won Sang , Yoo Nam Jin , Liu Edison T. , Miller Lance D. , Lee Jung Young 
Published: September 2005

Abstract

Progression of hepatocellular carcinoma (HCC) is a stepwise process that proceeds from pre-neoplastic lesions—including low-grade dysplastic nodules (LGDNs) and high-grade dysplastic nodules (HGDNs)—to advanced HCC. The molecular changes associated with this progression are unclear, however, and the morphological cues thought to distinguish pre-neoplastic lesions from well-differentiated HCC are not universally accepted. To understand the multistep process of hepato-carcinogenesis at the molecular level, we used oligo-nucleotide microarrays to investigate the transcription profiles of 50 hepatocellular nodular lesions ranging from LGDNs to primary HCC (Edmondson grades 1-3). We demonstrated that gene expression profiles can discriminate not only between dysplastic nodules and overt carcinoma but also between different histological grades of HCC via unsupervised hierarchical clustering with 10,376 genes. We identified 3,084 grade-associated genes, correlated with tumor progression, using one-way ANOVA and a one-versus-all unpooled

t

test. Functional assignment of these genes revealed discrete expression clusters representing grade-dependent biological properties of HCC. Using both diagonal linear discriminant analysis and support vector machines, we identified 240 genes that could accurately classify tumors according to histological grade, especially when attempting to discriminate LGDNs, HGDNs, and grade 1 HCC.
In conclusion
, a clear molecular demarcation between dysplastic nodules and overt HCC exists. The progression from grade 1 through grade 3 HCC is associated with changes in gene expression consistent with plausible functional consequences.

Supplementary material for this article can be found on the Hepatology website (

http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html

).

(Hepatology 2005;42:809–818.)
New Kinetic Models for the Hepatitis C Virus *
Authors: Perelson Alan S. , Herrmann Eva , Micol Florence , Zeuzem Stefan 
Published: September 2005

Abstract

Viral kinetic modeling has played an important role in the analysis of HCV RNA decay after the initiation of antiviral therapy. Models have provided a means of evaluating the antiviral effectiveness of therapy, of estimating parameters such as the rate of virion clearance and the rate of clearance of hepatitis C virus (HCV)–infected cells, and they have suggested mechanisms of action for both interferon and ribavirin. Nevertheless, the models that were originally formulated were unable to explain all of the observed HCV RNA profiles. We provide an update on the state of HCV kinetic modeling and discuss new models that have taken into consideration the different pharmacokinetics of standard and pegylated forms of interferon, allow for changes in drug effectiveness as drug concentrations fall between dosing intervals, and that have incorporated alanine aminotransferase kinetics and aspects of immune responses to provide a more comprehensive picture of the biology underlying changes in HCV RNA during therapy. (Hepatology 2005;42:749–754.)
Endocannabinoids Promote Hepatic Lipogenesis and Steatosis Through CB1 Receptors
Authors: Schwabe Robert F. 
Published: September 2005

Abstract

Endogenous cannabinoids acting at CB1 receptors stimulate appetite, and CB1 antagonists show promise in the treatment of obesity. CB1−/− mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism. Here, we investigated the possible role of endocannabinoids in the regulation of hepatic lipogenesis. Activation of CB1 in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS). Treatment with a CB1 agonist also increases de novo fatty acid synthesis in the liver or in isolated hepatocytes, which express CB1. High-fat diet increases hepatic levels of the endocannabinoid anandamide (arachidonoyl ethanolamide), CB1 density, and basal rates of fatty acid synthesis, and the latter is reduced by CB1 blockade. In the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression are similarly affected by CB1 ligands. We conclude that anandamide acting at hepatic CB1 contributes to diet-induced obesity and that the FAS pathway may be a common molecular target for central appetitive and peripheral metabolic regulation.
NADPH Oxidase-Dependent Reactive Oxygen Species are Important to the Early Stage of CD95 Engagement in Hepatocytes *
Authors: Yin Xiao-Ming 
Published: September 2005

Abstract

CD95 ligand (CD95L) triggers a rapid formation of reactive oxygen species (ROS) as an upstream event of CD95 activation and apoptosis induction in rat hepatocytes. This ROS response was sensitive to inhibition by diphenyleneiodonium, apocynin, and neopterin, suggestive of an involvement of NADPH oxidases. In line with this, hepatocytes expressed mRNAs not only of the phagocyte gp91

phox

(Nox 2), but also of the homologs Nox 1 and 4 and Duox 1 and 2, as well as the regulatory subunit p47

phox

. gp91

phox

(Nox 2) and p47

phox

were also identified at the protein level in rat hepatocytes. CD95L induced within 1 min ceramide formation and serine phosphorylation of p47

phox

, which was sensitive to inhibitors of sphingomyelinase and protein kinase Cζ (PKCζ). These inhibitors and p47

phox

protein knockdown inhibited the early CD95L-induced ROS response, suggesting that ceramide and PKCζ are upstream events of the CD95Linduced Nox/Duox activation. CD95L also induced rapid activation of the Src family kinase Yes, being followed by activation of c-Src, Fyn, and c-Jun-N-terminal kinases (JNK). Only Yes and JNK activation were sensitive to

N

-acetylcysteine, inhibitors of NADPH oxidase, PKCζ, or sphingomyelinase, indicating that the CD95L-induced ROS response is upstream of Yes and JNK but not of Fyn and c-Src activation. Activated Yes rapidly associated with the epidermal growth factor receptor (EGFR), which became phosphorylated at Tyr845 and Tyr1173 but not at Tyr1045. Activated EGFR then triggered an AG1478-sensitive CD95-tyrosine phosphorylation, which was a signal for membrane targeting of the EGFR/CD95 complex, subsequent recruitment of Fas-associated death domain and caspase 8, and apoptosis induction. All of these events were significantly blunted by inhibitors of sphingomyelinase, PKCζ, NADPH oxidases, Yes, or EGFR-tyrosine kinase activity and after protein knockdown of either p47

phox

, Yes, or EGFR. The data suggest that CD95L-induced apoptosis involves a sphingomyelinase- and PKCζ-dependent activation of NADPH oxidase isoforms, which is required for Yes/EGFR/CD95 interactions as upstream events of CD95 activation. (Hepatology 2005;42:956–958.)
Comment on “Using quaternions to calculate RMSD” [J. Comp. Chem. 25, 1849 (2004)]
Authors: Kneller G. R. 
Published: September 2005

AbstractCoutsias et al. have recently published a method to find the optimal rotational superposition of two molecular structures, which is based on a representation of rotations by quaternions (J. Comp. Chem. 25(15), 1849 (2004)). The method, which has been suggested by other authors before, is compared to the one by Kabsch, where the elements of the rotation matrix are directly used as variables of the optimization problem. The statement that the two methods are equivalent is misleading in the sense that the Kabsch method may yield an improper optimal rotation, which must be explicitly checked for, whereas the quaternion method does not mix proper and improper rotations. Nevertheless, both types of solutions can be considered by solving the same eigenvector problem. The relation between the two types of solutions is briefly discussed and bounds for the eigenvalues are given. © 2005 Wiley Periodicals, Inc. J Comput Chem 26: 1660–1662, 2005
Effects of axotomy on telomere length, telomerase activity, and protein in activated microglia
Authors: Flanary Barry E. , Streit Wolfgang J. 
Published: September 2005

AbstractThe adult central nervous system (CNS) is generally thought of as a postmitotic organ. However, DNA labeling studies have shown that one major population of nonneuronal cells, called microglia, retain significant mitotic potential. Microglial cell division is prominent during acute CNS injury involving neuronal damage or death. Prior work from this laboratory has shown that purified microglia maintained in vitro with continual mitogenic stimulation exhibit telomere shortening before entering senescence. In the current study, we sought to investigate whether telomere shortening occurs in dividing microglia in vivo. For this purpose, we used a nerve injury model that is known to trigger localized microglial proliferation in a well‐defined CNS region, the facial motor nucleus. Adult Sprague‐Dawley rats underwent facial nerve axotomy, and facial motor nuclei were microdissected after 1, 4, 7, and 10 days. Whole tissue samples were subjected to measurements of telomere length, telomerase activity, and telomerase protein. Results revealed a tendency for all of these parameters to be increased in lesioned samples. In addition, microglial cells isolated directly from axotomized facial nuclei with fluorescence‐activated cell sorting (FACS) showed increased telomerase activity relative to unoperated controls, suggesting that microglia are the primary cell type responsible for the increases observed in whole tissue samples. Overall, the results show that microglia activated by injury are capable of maintaining telomere length via telomerase during periods of high proliferation in vivo. We conclude that molecular mechanisms pertaining to telomere maintenance are active in the injured CNS. © 2005 Wiley‐Liss, Inc.
Developmental change and function of chondroitin sulfate deposited around cerebellar Purkinje cells
Authors: Shimazaki Yumiko , Nagata Isao , Ishii Maki , Tanaka Masahiko , Marunouchi Tohru , Hata Toshihiro , Maeda Nobuaki 
Published: September 2005

AbstractChondroitin sulfate is a long sulfated polysaccharide with enormous structural heterogeneity that binds with various proteins, such as growth factors, in a structure‐dependent manner. In this study, we analyzed the expression of chondroitin sulfate in the postnatally developing cerebellar cortex by using three monoclonal antibodies against chondroitin sulfate, MO‐225, 2H6, and CS‐56, which recognize different structural domains in this polysaccharide. During the first postnatal week, the patterns of immunohistochemical staining made by these antibodies were quite similar, and the molecular layer, the granule cell layer, and Bergmann glial fibers in the external granular layer were densely stained. After postnatal day 12 (P12), the expression of 2H6 epitopes was down‐regulated in the molecular layer, and the expression of CS‐56 epitopes in this layer was also reduced after P16. On the other hand, the strong expression of MO‐225 epitopes, GlcA(2S)β1–3GalNAc(6S) (D unit)‐containing structures, remained until adulthood. These chondroitin sulfate epitopes were observed around Purkinje cells, including cell soma and dendrites. Detailed immunohistochemical analysis suggested that chondroitin sulfate was deposited between Purkinje cell surfaces and the processes of Bergmann glia. Furthermore, the amount of pleiotrophin, a heparin‐binding growth factor, in the cultured cerebellar slices was remarkably diminished after treatment with chondroitinase ABC or D unit‐rich chondroitin sulfate. With the previous findings that pleiotrophin binds to D unit‐rich chondroitin sulfate, we suggest that the D‐type structure is important for the signaling of pleiotrophin, which plays roles in Purkinje cell–Bergmann glia interaction, and that the structural changes of chondroitin sulfate regulate this signaling pathway. © 2005 Wiley‐Liss, Inc.
Notch 1 interacts with the amyloid precursor protein in a Numb‐independent manner
Authors: Fassa Angeliki , Mehta Pankaj , Efthimiopoulos Spiros 
Published: September 2005

AbstractWe hypothesized that the physical interaction between the amyloid precursor protein (APP) and Notch 1 (N1) may be mediating the reported cross‐talk between the respective signaling pathways. Immunoprecipitation of mouse N1 (mN1) or extracellular domain truncated mN1 (mN1‐TM, mimics TACE‐produced membrane‐bound C‐terminal fragment) specifically coprecipitated APP751. Conversely, immunoprecipitation of APP751 specifically coprecipitated mN1, furin‐generated membrane‐bound mN1 C‐terminal fragment (f.mN1‐TM), or mN1‐TM. The London mutation of APP did not affect the APP751/mN1 interaction. Coexpression of APP751 and mN1 did not affect APP processing or production of mN1 intracellular domain (mNICD). The APP751/mN1 interaction was Numb‐independent, insofar as it was observed in HEK293 cells that lack detectable levels of Numb and was unaffected by the expression of exogenous Numb or deletion of the APP cytoplasmic domain, including the Numb‐binding YENPTY sequence. This interaction was unaffected even when the N‐terminal 647 amino acids of APP were replaced by a sequence of secreted alkaline phosphatase. These data combined with data showing interaction between mN1‐TM and APP751 suggest that their transmebrane domains and short sequences around them are sufficient for the interaction and that APP751 and mN1 interact in cis. Our results imply novel functions of APP and/or N1 that derive from their interaction. © 2005 Wiley‐Liss, Inc.
Functional significance of HCN2/3‐mediated Ih in striatal cells at early developmental stages
Authors: Bajorat Rika , Bräuer Anja U. , Wasner Ulrike , Rolfs Arndt , Strauss Ulf 
Published: September 2005

AbstractHyperpolarization‐activated cAMP‐gated cation currents (Ih) were recently linked to pre‐ and postnatal developmental processes in several brain regions, including the ventral telencephalon. To evaluate the role of Ih in striatal development, we used short‐term cultured cells from the lateral ganglionic eminence at embryonic day 14 (E14) and postnatal days 1–3 (P1–3) as well as the embryonic striatal progenitor cell line ST14A. Western blot analysis of the Ih underlying subunit proteins HCN1–4 revealed strong HCN2 expression in proliferating ST14A cells and weak expression in postmitotic ST14A cells and in cells from the developing brain. We also found HCN3 expression only in ST14A cells at both proliferative and nonproliferative stages but not in short‐term cultured striatal cells. In all cases, HCN1 and HCN4 transcripts were below the detection level. Despite the selective protein expression, RT‐PCR analysis showed stable expression of HCN2–4 but not HCN1 mRNA in all short‐term‐cultured striatal cells and in the ST14A cell line. Consistent with the strong protein expression, an Ih was recorded with features of an HCN2‐mediated current in ST14A cells at the proliferative stage and in short‐term‐cultured E14 cells. Of particular importance is that we detected no currents upon hyperpolarization in the ST14A cells at the nonproliferative stage when only HCN3 protein was present. These results suggest the potential importance of ST14A cells in defining the molecular mechanisms regulating Ih expression and function. © 2005 Wiley‐Liss, Inc.
Differential effects of ethanol on glial signal transduction initiated by lipopolysaccharide and interferon‐γ
Authors: Choi Dong‐Kug , Lee Heasuk , Jeong Jaeyoon , Lim Beongou , Suk Kyoungho 
Published: September 2005

AbstractAlthough the pathogenic effects of alcohol abuse on brain are well established, its specific effects on the intracellular signal transduction pathways of glial cells in the central nervous system (CNS) are poorly understood. In this study, we evaluated how ethanol affects the glial signal transduction associated with inflammatory activation. Lipopolysaccharide (LPS), gangliosides, and interferon (IFN)‐γ induced the inflammatory activation of glia, which was differentially influenced by ethanol: 1) ethanol inhibited LPS‐ or gangliosides‐induced, but not IFNγ‐induced, glial activation as demonstrated by the production of nitric oxide and the expression of inflammatory genes such as interleukin‐1β, tumor necrosis factor‐α, IP‐10, and CD86; 2) nuclear factor (NF)‐κB or JAK/STAT1 pathway was necessary for LPS‐ or IFNγ‐induced glial activation, respectively; 3) ethanol inhibited LPS‐induced NF‐κB activation; and 4) ethanol did not significantly affect IFNγ‐induced STAT1/IRF‐1 activation. Based on these results, ethanol seems to inhibit selectively some parts of the glial signal transduction pathways that are associated with inflammatory activation, which may lead to the deregulation of CNS inflammatory responses. © 2005 Wiley‐Liss, Inc.
“I still like Google”: University student perceptions of searching OPACs and the web
Authors: Fast Karl V. , Campbell D. Grant 
Published: September 2005

AbstractThis paper reports on an exploratory study of how university students perceive and interact with Web search engines compared to Web‐based OPACs. A qualitative study was conducted involving sixteen students, eight of whom were first‐year undergraduates and eight of whom were graduate students in Library and Information Science. The participants performed searches on Google and on a university OPAC. The interviews and think‐afters revealed that while students were aware of the problems inherent in Web searching and of the many ways in which OPACS are more organized, they generally preferred Web searching. The coding of the data suggests that the reason for this preference lies in psychological factors associated with the comparative ease with which search engines can be used, and system and interface factors which made searching the Web much easier and less confusing. As a result of these factors, students were able to approach even the drawbacks of the Web—its clutter of irrelevant pages and the dubious authority of the results—in an enthusiastic and proactive manner, very different from the passive and ineffectual admiration they expressed for the OPAC. The findings suggest that requirements of good OPAC interface design must be aggressively redefined in the face of new, Web‐based standards of usability.
Evaluation of periodic leg movements and associated transcranial magnetic stimulation parameters in restless legs syndrome
Authors: Kutukcu Yasar , Dogruer Erhan , Yetki̇n Si̇nan , Ozgen Fuat , Vural Okay , Aydi̇n Hamdullah 
Published: September 2005

AbstractRestless legs syndrome (RLS), a sensorimotor disorder characterized by unpleasant sensations commonly localized in the legs, is frequently associated with periodic limb movements (PLMs) during sleep. We investigated the role of transcranial magnetic stimulation (TMS) and cortical silent period (CSP) duration as diagnostic and monitoring tools in 20 patients with primary RLS before and after 1 month of treatment and also studied 15 normal age‐ and gender‐matched subjects. Polysomnographic assessment was undertaken and the PLM index determined in 17 of the 20 patients. We also studied the correlation between sleep efficiency index and CSP duration because of the increasing severity of the sleep disturbance and PLMs in patients with RLS. Our results demonstrate that the duration of the CSP was reduced in patients with RLS, and that dopaminergic treatment normalized this duration. There was no correlation between the PLM index and CSP duration. It may be speculated that PLMs and the CSP are due to different inhibitory mechanisms and they may be used separately as diagnostic and monitoring tools in patients with primary RLS. Muscle Nerve, 2005