bluuebunny/crossref_metadata_2025 huggingface dataset:
Less Smad2 is good for you! A scientific update on coffee's liver benefits #
Authors: Gressner Olav A.
Published: May 2009

Scientists at the National Institutes of Health have reported that increased coffee consumption is associated with a slower progression of fibrogenesis in patients with chronic and particularly alcoholic liver disease and a reduced incidence of heptocellular carcinoma. However, a causal mechanistic explanation was pending. New results indicate that the methylxanthine caffeine—a major component of coffee and the most widely consumed pharmacologically active substance in the world—might be responsible for this phenomenon, because it inhibits the synthesis of connective tissue growth factor (CTGF/CCN2) in liver parenchymal and nonparenchymal cells, primarily by inducing degradation of Smad2 (and to a much lesser extent Smad3) and thus impairment of transforming growth factor β (TGF-β) signaling. CTGF and TGF-β play crucial roles in the fibrotic remodeling of various organs, and, ultimately, carcinogenesis. This article summarizes the clinical-epidemiological observations as well as the pathophysiological background and provides suggestions for the therapeutic use of (methyl)xanthine derivatives in the management of fibro-/carcinogenic (liver) diseases. (Hepatology 2009.)
Susceptibility to liver fibrosis in mice expressing a connective tissue growth factor transgene in hepatocytes # †
Authors: Tong ZhenYue , Chen Ruju , Alt Daniel S. , Kemper Sherri , Perbal Bernard , Brigstock David R.
Published: May 2009

Connective tissue growth factor (CCN2) is a matricellular protein that is up-regulated in many fibrotic disorders and coexpressed with transforming growth factor β. CCN2 promotes fibrogenesis and survival in activated hepatic stellate cells, and injured or fibrotic liver contains up-regulated levels of CCN2 that are produced by a variety of different cell types, including hepatocytes. To investigate CCN2 action in vivo, transgenic FVB mice were created in which the human CCN2 gene was placed under the control of the albumin enhancer promoter to elevate hepatocyte CCN2 levels. Production of human CCN2 (hCCN2) messenger RNA and elevated CCN2 protein levels was demonstrated in transgenic livers, whereas levels of endogenous mouse CCN2 were comparable between transgenic and wild-type mice. Liver histology and liver function tests were unaffected in transgenic animals. However, after chronic administration of CCl4, α-smooth muscle actin (α-SMA)–expressing cells and collagen deposition were increased as a function of the dosage of the hCCN2 transgene (hccn2
+/+ > hccn2
+/− > hccn2−/−). Moreover, CCl4-induced serum hyaluronic acid, hepatic tissue levels of α-SMA or acid-soluble collagen, and messenger RNA expression of α-SMA, collagen α1 (I), matrix metalloprotease-2, or tissue inhibitor of metalloprotease-1 were greater in transgenic mice than in wild-type mice. Transgenic mice also exhibited enhanced hepatic deposition of collagen 2 weeks after bile duct ligation. Conclusion: Production of elevated CCN2 levels in hepatocytes of transgenic mice in vivo does not cause hepatic injury or fibrosis per se but renders the livers more susceptible to the injurious actions of other fibrotic stimuli. These studies support a central role of CCN2 in hepatic fibrosis and demonstrate a role of the microenvironment in regulating the profibrotic action of CCN2. (Hepatology 2009.)
Progesterone promotes the survival of newborn neurons in the dentate gyrus of adult male mice
Authors: Zhang Zhuo , Yang Rong , Zhou Rong , Li Liang , Sokabe Masahiro , Chen Ling
Published: May 2009

This study investigated the effects of progesterone (P4) on the production and survival of neurons in the hippocampal dentate gyrus of adult male mice. The administration of P4 (4 mg/kg) for 3 consecutive days beginning on the 0–2nd day after the first BrdU‐injection (BrdU‐D0–2) produced an approximately twofold increase in the number of 28‐ and 56‐day‐old BrdU+ cells in comparison to the controls, whereas it did not alter the number of 24/48‐h‐old BrdU+ cells. P4 preferentially promoted the survival of newborn neurons when administered at BrdU‐D5–7, but not at BrdU‐D10–12 and BrdU‐D15–17. Androstenedione (Ad), testosterone (TE), or estradiol (E2) at the same‐dose of P4, when administered at BrdU‐D0–2, could not replicate the effect of P4, while the inhibition of 5α‐reductase by finasteride did not affect the P4‐action, indicating that the P4‐effect is exerted by P4 itself but not by its metabolites. On the other hand, the P4R antagonist RU486 partially suppressed the P4‐effect, while inhibitors for Src, MEK, or PI3K totally suppressed the P4‐effect. Finally, the P4‐enhanced survival of newborn neurons was accompanied by a potentiation of spatial learning and memory, which was P4R‐dependent. These findings suggest that P4 enhances the survival of newborn neurons through P4R and/or the Src‐ERK and PI3K pathways independent of its influence on cell proliferation, which is well correlated with the potentiated spatial cognitive function of P4‐treated animals. © 2009 Wiley‐Liss, Inc.
Two New C21 Steroidal Glycosides from the Stems of Cynanchum paniculatumKitag.
Authors: Huang Xin , Tan Ai‐Min , Yang Shi‐Bao , Zhang An‐Yuan , Zhang Hua
Published: May 2009

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Two new glycosides, (3β,8β,9α,16α,17α)‐14,16β : 15,20α:18,20β‐triepoxy‐16α,17α‐dihydroxy‐14‐oxo‐13,14 : 14,15‐disecopregna‐5,13(18)‐dien‐3‐yl α‐cymaropyranosyl‐(1→4)‐α‐digitoxopyranosyl‐(1→4)‐α‐oleandropyranoside (1) and (3β,8β,9α,16α,17α)‐14,16β : 15,20α : 18,20β‐triepoxy‐16β : 17α‐dihydroxy‐14‐oxo‐13,14 : 14,15‐disecopregna‐5,13(18)‐dien‐3‐yl α‐oleandropyranosyl‐(1→4)‐α‐digitoxopyranosyl‐(1→4)‐α‐oleandropyranoside (2) were isolated from the stems of Cynanchum paniculatum (Bunge) Kitag. The structures of the new compounds were elucidated by means of spectral data, including HR‐ESI‐MS, and 1D‐, and 2D‐NMR.
Synthesis and Evaluation of N‐Acetyl‐2‐amino‐2‐deoxy‐α‐D‐galactosyl 1‐Thio‐7‐oxaceramide, a New Analogue of α‐D‐Galactosyl Ceramide
Authors: Rajan Roshini , Mathew Thresen , Buffa Radovan , Bornancin Frédéric , Cavallari Marco , Nussbaumer Peter , De Libero Gennaro , Vasella Andrea
Published: May 2009

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The N‐acetyl‐2‐amino‐2‐deoxy‐α‐D‐galactopyranosyl 1‐thio‐7‐oxaceramide 1 was synthesized by substituting the 7‐oxasphingosine triflate 3 with α‐D‐N‐acetyl‐1‐thiogalactosamine (2). The triflate 3 was obtained from azide 4. Thiol 2 was prepared according to a known procedure from α‐D‐galactosamine hydrochloride. As compared to ceramide (Cer), 1 is neither a substrate of ceramide kinase (CerK), consistent with the absence of the C(1)OH group, nor an inhibitor of Cer phosphorylation by CerK. While 1 partially displaced CD1d‐bound lipids, it failed to stimulate invariant natural killer T (iNKT) cells when presented by human CD1d‐transfected cells. These results suggest that 1 binds weakly to recombinant CD1d, but does not form immunogenic complexes with CD1d.
Syntheses of 5‐Chlorouracils/Thymines with 1‐[Phosphono(Methyl/Difluoromethyl)]‐1,2‐Unsaturated‐Moiety‐Substituted Methyl Groups at N(1) and Human Thymidine Phosphorylase Inhibitory Activity
Authors: Birck Matthew R. , Clinch Keith , Gainsford Graeme J. , Schramm Vern L. , Tyler Peter C.
Published: May 2009

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By attaching (methyl)‐ or (difluoromethyl)‐phosphonate groups to the 1‐positions of ethene, cyclopentene or benzene, and attaching 1‐(methyl)‐5‐chlorouracil or 1‐(methyl)thymine groups to the corresponding 2‐positions, compounds 1–5 were prepared as potential inhibitors of recombinant human thymidine phosphorylase (TP). The products were designed to mimic the interatomic distance (ca. 3.41 Å) between the incoming phosphate and leaving pyrimidine groups at the transition state for the putative SN2 mechanism of TP. Free rotation around the (unsaturated‐CH2)–pyrimidine bonds in 1–5 enabled a span of ca. 2.40–4.40 Å between the CH2 or CF2 C‐atoms in the phosphonates and N(1) of the pyrimidines to be covered. The products were found to be ineffective inhibitors, and some reasons for this are given.
Continuous infusion idarubicin and intravenous busulphan as conditioning regimen to autologous stem cell transplantation for patients with acute myeloid leukaemia
Authors: Ferrara Felicetto , Mele Giuseppina , Palmieri Salvatore , Pedata Mariangela , Copia Carolina , Riccardi Cira , Izzo Tiziana , Criscuolo Clelia , Musto Pellegrino
Published: May 2009

The current study aimed to evaluate the efficacy and toxicity of a combination of intravenous (iv) busulfan (Bu) and continuous infusion Idarubicin (IDA) as a conditioning regimen to autologous haematopoietic stem cell transplantation (ASCT) in patients with acute myeloid leukaemia (AML). The protocol included IDA at 20 mg/sqm daily as 3 days continuous infusion (from day −13 to −11) and intravenous BU at 3.2 mg/kg daily from day −5 to −2. Patients aged over 60 years received a reduced schedule (2 days IDA and 3 days BU at the same dose). Twenty‐five patients with a median age of 51 years (28–72) were enrolled. All patients received peripheral blood stem cells (PBSC). The median interval between diagnosis and ASCT was 4 months. The median number of CD34+ cells infused was 5.9 × 10E6/kg. The median number of days to PMN >500/cmm and platelets >20000/cmm was 10 and 13, respectively. In order to perform a comparison in terms of haematological and non haematological toxicity, a group of 30 patients, who were previously autografted after conditioning with IDA and oral Bu was considered. Selection of factors for a matched pair analysis included median age, percentage of subjects aged over 60 years, median CD34+ cell received, cytogenetic and molecular findings and per cent of secondary AML. As compared to previous series, the occurrence of severe mucositis was dramatically reduced (80% vs. 12%, p < 0.0001). In addition, need and duration of total parenteral nutrition (TPN), iv antibiotic therapy and hospitalization were also significantly reduced. We conclude that replacement of oral with intravenous BU results in a more favourable toxicity profile. A longer follow‐up is required to assess a potential advantage in terms of disease free survival (DFS). Copyright © 2009 John Wiley & Sons, Ltd.
Effects of acute ultra‐low dose mecamylamine on cognition in adult attention‐deficit/hyperactivity disorder (ADHD)
Authors: Potter Alexandra S. , Ryan Katherine K. , Newhouse Paul A.
Published: May 2009

Objective

Nicotinic cholinergic stimulation has known beneficial effects in attention‐deficit/hyperactivity disorder (ADHD). Mecamylamine is a non‐competitive nicotinic antagonist which is reported in several animal studies to have paradoxical positive effects on cognition at ultra‐low doses. Comparable studies in humans have not been conducted. The aim of this study was to determine the effects of acute ultra‐low doses of mecamylamine on cognition in adult ADHD.

Methods

Fifteen (6 female) non‐smokers with ADHD completed this acute, within subjects, double blind study of 0.2, 0.5, 1.0 mg of oral mecamylamine and placebo. Behavioral inhibition, recognition memory, and delay aversion were assessed at each dose.

Results

The 0.5 mg dose of mecamylamine significantly improved recognition memory and reduced tolerance for delay. Mecamylamine increased participant rated irritability and investigator rated restlessness. There were no effects on vital signs or physical side effects.

Conclusion

This is the first study to find measurable effects of ultra‐low doses of mecamylamine in humans. Mecamylamine did not improve core ADHD cognitive symptoms, but significantly improved recognition memory. These effects may represent mixed receptor activity (activation and blockade) at the doses tested. The finding of beneficial effects on memory processes has important clinical implications and further exploration of this effect is warranted. Copyright © 2009 John Wiley & Sons, Ltd.
Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors
Authors: Wickersheim Anke , Kerber Mark , de Miguel Lourdes Sanchez , Plate Karl H. , Machein Marcia Regina
Published: May 2009

Despite extensive research, the contribution of bone‐marrow‐derived endothelial progenitor cells (BM‐EPC) to tumor angiogenesis remains controversial. In previous publications, the extent of incorporation of BM‐EPCs into the endothelial cell (EC) layer in different tumor models has been reported as significant in some studies but undetectable in others. Here, we studied the differentiation of BM‐EPCs and its contribution to tumor vessels in experimental and spontaneous lung metastasis (B16 melanoma and prostate carcinoma), in an autochthonous transgenic model of prostate tumorigenesis, in orthotopically implanted lung tumors [Lewis lung carcinoma (LLC)], in heterotopic subcutaneous models (LLC and C1 prostate carcinoma) growing in green fluorescent protein (GFP)‐expressing bone marrow (BM) chimeras. Immunofluorescence was performed with a set of endothelial and hematopoietic markers and confocal microscopy was used to generate 3D reconstruction images. By performing rigorously conducted morphological studies, we found no evidence of BM‐EPCs differentiation into tumor endothelium independently of tumor type, grade and organ site in primary and metastatic tumors. The vast majority of GFP+ cells were trafficking leucocytes or periendothelial myeloid cells. To explore the possibility that local overexpression of vascular endothelial growth factor (VEGF) might increase the numbers of incorporated BM‐EPCs, we analyzed tumors genetically manipulated to overexpress VEGF164. Local VEGF production induces a massive infiltration of bone‐marrow‐derived cells, but did not lead to vessel wall integration of these cells. Collectively, these findings suggest that during tumor progression vascularization occurs primarily via classical tumor angiogenesis (e.g., sprouting of pre‐existing ECs), whereas BM‐EPCs do not incorporate into the vessel wall to any significant extent. © 2009 UICC
Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model
Authors: Vitali Roberta , Mancini Camillo , Cesi Vincenzo , Tanno Barbara , Piscitelli Marta , Mancuso Mariateresa , Sesti Fabiola , Pasquali Emanuela , Calabretta Bruno , Dominici Carlo , Raschellà Giuseppe
Published: May 2009

Stage 4 neuroblastoma (NB) is a devastating childhood cancer whose poor outcome has remained essentially unchanged in the last 20 years. Receptor tyrosine kinases have important roles in the control of proliferation, differentiation and apoptosis of NB cells. Thus, we tested the activity of second‐generation tyrosine kinase inhibitor Dasatinib in human NB cell lines in vitro and in an orthotopic mouse model. Dasatinib inhibited cell viability with an IC50 in the submicromolar range in 7 of 10 tested cell lines. In sensitive cells, Dasatinib reduced anchorage‐independent growth and, in some instances, induced senescence and apoptosis. In HTLA‐230 cells, Dasatinib treatment caused down‐regulation of c‐Kit and c‐Src phosphorylation in conjunction with strong inhibition of Erk1/2 and Akt activity. To test the efficacy of Dasatinib in vivo, HTLA‐230 and SY5Y cells were orthotopically injected in the adrenal gland of nude mice and drug treatments carried out until day 40. In mice injected with HTLA‐230 cells, tumour growth was significantly inhibited at the dose of 30 mg/(kg day) when treatment was started 7 days after injection. In animals injected with SY5Y cells that were exquisitely sensitive in vitro (IC50= 92 nM), the antitumour effect of Dasatinib was observed at the dose of 60 mg/(kg day) but only when treatment was started 1 day after injection. However, the anti‐tumour effect of Dasatinib in vivo was partial in both orthotopic models, emphasizing the importance of testing candidate new drugs in animal environments closely mimicking the human tumour. © 2009 UICC
The equity premium and the business cycle: the role of demand and supply shocks
Authors: Smith Peter N. , Sorensen Steffen , Wickens Michael
Published: May 2009

This paper explores the effects of the US business cycle on US stock market returns through an analysis of the equity risk premium. We propose a new methodology based on the SDF approach to asset pricing that allows us to uncover the different effects of aggregate demand and supply shocks. We find that negative shocks are more important that positive shocks, and that supply shocks have a much greater impact than demand shocks. Copyright © 2009 John Wiley & Sons, Ltd.
Preoperative therapeutic plasma exchange in patients with thyrotoxicosis
Authors: Ezer Ali , Caliskan Kenan , Parlakgumus Alper , Belli Sedat , Kozanoglu Ilknur , Yildirim Sedat
Published: May 2009

The purpose of this report was to determine the effectiveness of therapeutic plasma exchange (TPE) in preoperative preparation of patients with thyrotoxicosis scheduled for either thyroid or nonthyroid surgery. We retrospectively reviewed 11 patients with thyrotoxicosis and those who prepared surgery with plasmapheresis between 1999 and 2008 at our institution. Ten patients underwent thyroid surgery and one patient was operated for femur fracture during antithyroid drug treatment. The indications for plasmapheresis in all patients with severe thyrotoxicosis were poor response to medical treatment (seven patients), agronulocytosis due to antithyroid drugs (three patients), iodine‐induced thyrotoxicosis (Jodd Basedow effect in one patient), and rapid preparation for urgent orthopedic operation (one patient). After TPE, we observed a marked decrease in free thyroxin (FT3) and free triiodothyronin (FT4) levels; however, the decline in the biochemical values were not statically significant (P > 0.62, P > 0.15). Although both FT3 and FT4 levels remained above the normal limits in two of 11 patients, the signs and symptoms of thyrotoxicosis improved in all patients and no thyroid storm observed during the perioperative period. TPE can be considered a safe and effective alternative to prepare patients with thyrotoxicosis for surgery when drug treatment fails or is contraindicated and when emergency surgery is required. J. Clin. Apheresis, 2009. © 2009 Wiley‐Liss, Inc.
Intestinal epithelial cancer cell anoikis resistance: EGFR‐mediated sustained activation of Src overrides Fak‐dependent signaling to MEK/Erk and/or PI3‐K/Akt‐1
Authors: Demers Marie‐Josée , Thibodeau Sonya , Noël Dominique , Fujita Naoya , Tsuruo Takashi , Gauthier Rémy , Arguin Mélina , Vachon Pierre H.
Published: May 2009

Herein, we investigated the survival roles of Fak, Src, MEK/Erk, and PI3‐K/Akt‐1 in intestinal epithelial cancer cells (HCT116, HT29, and T84), in comparison to undifferentiated and differentiated intestinal epithelial cells (IECs). We report that: (1) cancer cells display striking anoikis resistance, as opposed to undifferentiated/differentiated IECs; (2) under anoikis conditions and consequent Fak down‐activation, cancer cells nevertheless exhibit sustained Fak–Src interactions and Src/MEK/Erk activation, unlike undifferentiated/differentiated IECs; however, HCT116 and HT29 cells exhibit a PI3‐K/Akt‐1 down‐activation, as undifferentiated/differentiated IECs, whereas T84 cells do not; (3) cancer cells require MEK/Erk for survival, as differentiated (but not undifferentiated) IECs; however, T84 cells do not require Fak and HCT116 cells do not require PI3‐K/Akt‐1, in contrast to the other cells studied; (4) Src acts as a cornerstone in Fak‐mediated signaling to MEK/Erk and PI3‐K/Akt‐1 in T84 cells, as in undifferentiated IECs, whereas PI3‐K/Akt‐1 is Src‐independent in HCT116, HT29 cells, as in differentiated IECs; and (5) EGFR activity inhibition abrogates anoikis resistance in cancer cells through a loss of Fak–Src interactions and down‐activation of Src/MEK/Erk (T84, HCT116, HT29 cells) and PI3‐K/Akt‐1 (T84 cells). Hence, despite distinctions in signaling behavior not necessarily related to undifferentiated or differentiated IECs, intestinal epithelial cancer cells commonly display an EGFR‐mediated sustained activation of Src under anoikis conditions. Furthermore, such sustained Src activation confers anoikis resistance at least in part through a consequent sustenance of Fak–Src interactions and MEK/Erk activation, thus not only overriding Fak‐mediated signaling to MEK/Erk and/or PI3‐K/Akt‐1, but also the requirement of Fak and/or PI3‐K/Akt‐1 for survival. J. Cell. Biochem. 107: 639–654, 2009. © 2009 Wiley‐Liss, Inc.
Notch‐1 signaling is lost in prostate adenocarcinoma and promotes PTEN gene expression
Authors: Whelan Jarrett T. , Kellogg Anne , Shewchuk Brian M. , Hewan‐Lowe Karlene , Bertrand Fred E.
Published: May 2009

Prostate tumorigenesis is associated with loss of PTEN gene expression. We and others have recently reported that PTEN is regulated by Notch‐1 signaling. Herein, we tested the hypothesis that alterations of the Notch‐1 signaling pathway are present in human prostate adenocarcinoma and that Notch‐1 signaling regulates PTEN gene expression in prostate cells. Prostate adenocarcinoma cases were examined by immunohistochemistry for ligand cleaved (activated) Notch‐1 protein. Tumor foci exhibited little cleaved Notch‐1 protein, but expression was observed in benign tissue. Both tumor and benign tissue expressed total (uncleaved) Notch‐1. Reduced Hey‐1 expression was seen in tumor foci but not in benign tissue, confirming loss of Notch‐1 signaling in prostate adenocarcinoma. Retroviral expression of constitutively active Notch‐1 in human prostate tumor cell lines resulted in increased PTEN gene expression. Incubation of prostate cell lines with the Notch‐1 ligand, Delta, resulted in increased PTEN expression indicating that endogenous Notch‐1 regulates PTEN gene expression. Chromatin immunoprecipitation demonstrated that CBF‐1 was bound to the PTEN promoter. These data collectively indicate that defects in Notch‐1 signaling may play a role in human prostate tumor formation in part via a mechanism that involves regulation of the PTEN tumor suppressor gene. J. Cell. Biochem. 107: 992–1001, 2009. © 2009 Wiley‐Liss, Inc.
Nit1 and Fhit tumor suppressor activities are additive
Authors: Sun Jin , Okumura Hiroshi , Yearsley Martha , Frankel Wendy , Fong Louise Y. , Druck Teresa , Huebner Kay
Published: May 2009

The fragile histidine triad gene (human FHIT, mouse Fhit) has been shown to act as a tumor suppressor gene. Nit1 and Fhit form a fusion protein, encoded by the NitFhit gene in flies and worms, suggesting that mammalian Nit1 and Fhit proteins, which are encoded by genes on different chromosomes in mammals, may function in the same signal pathway(s). A previous study showed that Nit1 deficiency in knockout mice confers a cancer prone phenotype, as does Fhit deficiency. We have now assessed the tumor susceptibility of Fhit−/−Nit1−/− mice and observed that double knockout mice develop more spontaneous and carcinogen‐induced tumors than Fhit−/− mice, suggesting that the extent of tumor susceptibility due to Nit1 and Fhit deficiency is additive, and that Nit1 and Fhit affect distinct signal pathways in mammals. Nit1, like Fhit, is present in cytoplasm and mitochondria but not nuclei. Because Fhit deficiency affects responses to replicative and oxidative stress, we sought evidence for Nit1 function in response to such stresses in tissues and cultured cells: when treated with hydroxyurea, the normal kidney‐derived double‐deficient cells appear not to activate the pChk2 pathway and when treated with H2O2, show little evidence of DNA damage, compared with wild type and Fhit−/− cells. The relevance of Nit1 deficiency to human cancers was examined in human esophageal cancer tissues, and loss of Nit1 expression was observed in 48% of esophageal adenocarcinomas. J. Cell. Biochem. 107: 1097–1106, 2009. © 2009 Wiley‐Liss, Inc.
Pex3p‐dependent peroxisomal biogenesis initiates in the endoplasmic reticulum of human fibroblasts
Authors: Toro Andrés A. , Araya Claudia A. , Córdova Gonzalo J. , Arredondo Cristian A. , Cárdenas Hugo G. , Moreno Regina E. , Venegas Alejandro , Koenig Cecilia S. , Cancino Jorge , Gonzalez Alfonso , Santos Manuel J.
Published: May 2009

The mechanisms of peroxisomal biogenesis remain incompletely understood, specially regarding the role of the endoplasmic reticulum (ER) in human cells, where genetic disorders of peroxisome biogenesis lead to Zellweger syndrome (ZS). The Pex3p peroxisomal membrane protein (PMP) required for early steps of peroxisome biogenesis has been detected in the ER in yeast but not in mammalian cells. Here, we show that Pex3p‐GFP expressed in a new ZS cell line (MR), which lacks peroxisomes due to a mutation in the PEX3 gene, localizes first in the ER and subsequently in newly formed peroxisomes. Pex3p bearing an artificial N‐glycosylation site shows an electrophoretic shift indicative of ER targeting while en route to preformed peroxisomes in normal fibroblast. A signal peptide that forces its entry into the ER does not eliminate its capability to drive peroxisome biogenesis in ZS cells. Thus, Pex3p is able to drive peroxisome biogenesis from the ER and its ER pathway is not privative of ZS cells. Cross‐expression experiments of Pex3p in GM623 cells lacking Pex16p or Pex16p in MR cells lacking Pex3p, showed evidence that Pex3p requires Pex16p for ER location but is dispensable for the ER location of Pex16p. These results indicate that Pex3p follows the ER‐to‐peroxisomal route in mammalian cells and provides new clues to understand its function. J. Cell. Biochem. 107: 1083–1096, 2009. © 2009 Wiley‐Liss, Inc.
Neural crest‐derived stem cells display a wide variety of characteristics
Authors: Nagoshi Narihito , Shibata Shinsuke , Nakamura Masaya , Matsuzaki Yumi , Toyama Yoshiaki , Okano Hideyuki
Published: May 2009

A recent burst of findings has shown that neural crest‐derived stem cells (NCSCs) can be found in diverse mammalian tissues. In addition to their identification in tissues that are known to be derived from the neural crest, recent studies have revealed NCSCs in tissues that are not specifically derived from the neural crest, such as bone marrow. NCSCs can express a wide range of characteristics, and which properties are expressed mainly depends on their tissue sources and the ontogenic stage of the animal. The identification of NCSCs in various tissues opens an entirely new avenue of approach to developing autologous cell replacement therapies for use in regenerative medicine. In this review, we discuss the origin, migration, and lineage potential of NCSCs from various mammalian tissue sources. J. Cell. Biochem. 107: 1046–1052, 2009. © 2009 Wiley‐Liss, Inc.
Force field dependence of phospholipid headgroup and acyl chain properties: Comparative molecular dynamics simulations of DMPC bilayers
Authors: Prakash Priyanka , Sankararamakrishnan Ramasubbu
Published: May 2009

The reliability of molecular simulations largely depends on the quality of the empirical force field parameters. Force fields used in lipid simulations continue to be improved to enhance the agreement with experiments for a number of different properties. In this work, we have carried out molecular dynamics simulations of neat DMPC bilayers using united‐atom Berger force field and three versions of all‐atom CHARMM force fields. Three different systems consisting of 48, 72, and 96 lipids were studied. Both particle mesh Ewald (PME) and spherical cut‐off schemes were used to evaluate the long‐range electrostatic interactions. In total, 21 simulations were carried out and analyzed to find out the dependence of lipid properties on force fields, system size, and schemes to calculate long‐range interactions. The acyl chain order parameters calculated from Berger and the recent versions of CHARMM simulations have shown generally good agreement with the experimental results. However, both sets of force fields deviate significantly from the experimentally observed P‐C dipolar coupling values for the carbon atoms that link the choline and glycerol groups with the phosphate groups. Significant differences are also observed in several headgroup parameters between CHARMM and Berger simulations. Our results demonstrate that when changes were introduced to improve CHARMM force field using PME scheme, all the headgroup parameters have not been reoptimized. The headgroup properties are likely to play a significant role in lipid–lipid, protein–lipid, and ligand–lipid interactions and hence headgroup parameters in phospholipids require refinement for both Berger and CHARMM force fields. © 2009 Wiley Periodicals, Inc.J Comput Chem, 2010
SMILES‐based optimal descriptors: QSAR analysis of fullerene‐based HIV‐1 PR inhibitors by means of balance of correlations
Authors: Toropov Andrey A. , Toropova Alla P. , Benfenati Emilio , Leszczynska Danuta , Leszczynski Jerzy
Published: May 2009

Quantitative structure‐activity relationships (QSAR) for prediction of binding affinities (pEC50, i.e., minus decimal logarithm of the 50% effective concentration) of 20 fullerene derivatives inhibitors of the HIV‐1 PR (human immunodeficiency virus type 1 protease) have been developed by application of the optimal descriptors approach calculated with SMILES (simplified molecular input line entry system). The applied models were constructed by the balance of correlations. Three various splits of the experimental data into subtraining set, calibration set, and test set were examined. Comparison of classic scheme (training‐test system) and the balance of correlations (subtraining‐calibration‐test system) show that the balance of correlations gives more robust predictions than the classic scheme for the pEC50 of the fullerene derivatives. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
Effect of microbial treatment on brightness and heat‐induced brightness reversion of high‐yield pulps
Authors: Tang Wenzhu , Li Xuezhi , Zhao Jian , Yue Jun , Yue Hua , Qu Yinbo
Published: May 2009

BACKGROUND: The manufacture of high‐yield pulps is attractive due to its efficient utilization of lignocellulosic material. However, their rapid brightness reversion when exposed to heat and light restricts their more widespread use in high‐quality papers. This study investigated the potential of bio‐treatment with more than 30 species of fungi and yeasts to inhibit heat‐induced yellowing of high‐yield pulps.

RESULTS: Treatment with Penicillium sp. ZCF34, Saccharomyces cerevisiae INVS2 and 724 reduced the brightness reversion and increased the brightness of wheat straw semi‐chemical pulp after 4 days incubation (postcolor number decreased by 33.96%, 66.42% and 57.09%, and brightness increased by 0.84%ISO, 0.48%ISO and 0.89%ISO, respectively). Phanerochaete chrysosporium W14 treatment was best for depressing yellowing of bleached aspen CTMP (chemi‐thermo‐mechanical pulp) and Saccharomyces cerevisiae AH22 treatment gave the highest brightness and a lower postcolor number. For unbleached aspen CTMP, treatment with Fusarium concolor X4 and Saccharomyces cerevisiae H158 was effective in improving brightness and brightness stability after 2 and 4 days incubation, respectively.

CONCLUSION: Treatment with some microorganisms increased pulp brightness and strongly suppressed heat‐induced yellowing. It offers an option for improving the brightness stability of high yield pulps and some valuable information for bio‐pulping and bio‐bleaching with microbial treatment. Copyright © 2009 Society of Chemical Industry
Fate of horseradish peroxidase during oxidation of monobrominated phenols
Authors: Cohen‐Yaniv Vered , Dosoretz Carlos G.
Published: May 2009

BACKGROUND: Peroxidase‐catalyzed polymerization of phenols is accompanied by substantial enzyme precipitation with reaction products. The enzyme fate during the polymerization of monobromophenols by horseradish peroxidase (HRP) was studied. Enzyme fate was simultaneously monitored by protein, total nitrogen mass balance and gel electrophoresis (SDS‐PAGE) analysis of both soluble and precipitate fractions.

RESULTS: SDS‐PAGE analysis revealed that molecular weight bands of protein in the precipitate shifted upwards toward higher molecular weights, compared with protein control. When co‐polymerization was practiced higher HRP precipitation occurred compared with polymerization of a single substrate, regardless of substrate combination applied. Addition of polyethylene glycol (PEG) to the reaction mixture decreased the extent of HRP precipitation. At 2 mmol L−1 H2O2, corresponding to the stoichiometric equivalent concentration, 50% precipitation occurred after 1 h (∼70% after 24 h) compared with 97–98% (∼100% after 24 h) without PEG. Nevertheless, further increase of H2O2 increased HRP precipitation regardless of PEG (85% at 4 mmol L−1 and 95% at 5 mmol L−1). The lowest degree of enzyme inactivation was observed for metabromophenol, which displayed the lowest transformation yield, compared to the other congeners.

CONCLUSIONS: Results from SDS‐PAGE indicate that an interaction stronger than hydrophobic, resisting the denaturative conditions, may take place between HRP and the reaction products, suggesting the occurrence of a covalent link between them. Oxidation was enhanced by inclusion of PEG, which partially suppressed product‐dependent inactivation. The extent of enzyme inactivation depends on the substrate used, while highest inactivation occurred when co‐polymerization was practiced. Copyright © 2009 Society of Chemical Industry
Regioselective synthesis of bioactive spiro heterocyclic compounds containing both indoline and quinolone moieties by aryl radical cyclization
Authors: Majumdar K. C. , Kundu N.
Published: May 2009

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The tin hydride‐mediated aryl radical cyclization of a number of 4‐(2′‐bromo‐N‐methylanilino)methyl‐1‐alkylquinolin‐2(1H)‐ones under mild neutral condition afforded 1‐alkyl‐3,4‐dihydroquinolin‐2(1H)‐one‐4‐spiro‐3′‐(1‐methylindolines) in excellent yield. The starting materials, amines were derived from 4‐bromomethyl‐N‐methyl quinolin‐2(1H)‐ones and 2‐bromo‐N‐methyl anilines by refluxing in acetone in the presence of anhydrous potassium carbonate and sodium iodide (Finkelstein condition). J. Heterocyclic Chem., 46, 492 (2009).
An efficient synthesis of indeno[1,2‐b]pyridine and benzo[h]quinoline derivatives under solvent‐free conditions
Authors: Rong Liangce , Han Hongxia , Jiang Hong , Tu Shujiang
Published: May 2009

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An efficient and convenient multicomponent reaction for the preparation of 4‐aryl‐2‐oxo‐2,5‐dihydro‐1H‐indeno[1,2‐b]pyridine‐3‐carbonitrile and 4‐aryl‐2‐oxo‐1,2,5,6‐tetrahydrobenzo[h]quinoline‐3‐carbonitrile derivatives by the 2,3‐dihydroinden‐1‐one or 3,4‐dihydronaphthalen‐1(2H)‐one, aromatic aldehydes, and malononitrile in the presence of sodium hydroxide under solvent‐free condition is reported. The short reaction time coupled with the simplicity of the reaction procedure makes this method one of the most efficient methods for the synthesis of these classes of compounds. J. Heterocyclic Chem., 46, 465 (2009).
Ring‐expansion of 5‐methylene‐thiazolidine‐2‐thione with hydrazine
Authors: Safarov Saifidin , Pulatov Elmurod , Kukaniev Muhamacho Amadovich , Kolshorn Heinz , Meier Herbert
Published: May 2009

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The treatment of 5‐methylene‐thiazolidine‐2‐thione with hydrazine hydrate in boiling dioxane leads in a novel type of ring‐expansion reaction to 6‐methyl‐1,2,4‐triazine‐3‐thione. J. Heterocyclic Chem., 46, 552 (2009).
Synthesis and properties of diaza‐, triaza‐, and tetraazaphenothiazines
Authors: Pluta Krystian , Morak‐Młodawska Beata , Jeleń Małgorzata
Published: May 2009

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The review surveys the chemistry of diaza‐, triaza‐, and tetraazaphenothiazines and their benzo and dibenzo derivatives consisting of over 30 different heterocyclic systems. J. Heterocyclic Chem., 46, 355 (2009).
Suzuki–Miyaura arylations of tetramic acid sulfonates: Evaluation of lactam protection, sulfonate esters, and sterics
Authors: Yoon‐Miller Sarah J. P. , Dorward Kathryn M. , White Kimberly P. , Pelkey Erin T.
Published: May 2009

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The synthesis of 3,4‐diaryl‐3‐pyrrolin‐2‐ones and 4‐aryl‐3‐pyrrolin‐2‐ones using Suzuki–Miyaura cross‐coupling reactions of tetramic acid sulfonates with arylboronic acids has been studied. The effect that sulfonate ester, sterics, and lactam protection has on the cross‐coupling reaction was evaluated. As expected, triflates were better cross‐coupling partners than the corresponding tosylates. The yields were only partially affected by the incorporation of aryl groups at the 3‐position. Importantly, tetramic acid triflates (and to a lesser extent tosylates) lacking a lactam protecting group were still competent substrates. J. Heterocyclic Chem., 46, 447 (2009).
Expanding leadership diversity through formal mentoring programs
Authors: Olson Deborah A. , Jackson Deborrah
Published: May 2009

To attract and retain people, it is essential that organizations design and successfully implement programs and processes that develop people and nurture their talents. For those who aspire to a leadership role, the opportunity to engage in mentoring relationships with senior‐level leaders is a powerful way to accelerate growth. In the majority of informal mentoring relationships, mentors and protégés share similar racial, gender, and cultural backgrounds. Senior leaders in most large organizations are still primarily white males. As a result, it can be difficult for people from diverse backgrounds who aspire to higher level leadership roles to find senior executives with whom they can develop a mentoring relationship. To address this challenge, some organizations have implemented formal mentoring programs that are specifically designed to facilitate development of people from diverse backgrounds. Unfortunately, previous research studies conducted on the impact of formal mentoring relationships have shown that these programs do not consistently achieve the desired outcomes. The change intervention described in this article suggests that formal mentoring programs can significantly influence the movement of protégés from diverse backgrounds into higher level leadership positions.
Practicing talent life cycle management
Authors: Kirwan Karen S.
Published: May 2009

As far back as the ninth century BCE in Greece, a talent was a form of currency. In the 21st century, talents remain currency as the special gifts of knowledge, skills, and personal characteristics that individuals bring to organizations. Talent management, also known as human capital management, HCM, is a focus of leadership studies that increasingly strives to acknowledge and measure the tangible contributions that individuals make to the bottom line. In this symposium, we offer a position paper by Ted Harro and Leslie Miller who detail an innovative approach to address how leaders of organizations can create a consistent, positive flow of talent necessary to support success. Our respondents, Karen Kirwan, Dave Wondra, and Edward Perez, each add their perspectives to this timely discussion.
Analyzing single‐molecule manipulation experiments
Authors: Calderon Christopher P. , Harris Nolan C. , Kiang Ching‐Hwa , Cox Dennis D.
Published: May 2009

Single‐molecule manipulation studies can provide quantitative information about the physical properties of complex biological molecules without ensemble artifacts obscuring the measurements. We demonstrate computational techniques which aim at more fully utilizing the wealth of information contained in noisy experimental time series. The “noise” comes from multiple sources e.g., inherent thermal motion, instrument measurement error, etc. The primary focus of this paper is a methodology that uses time domain based methods to extract the effective molecular friction from single‐molecule pulling data. We studied molecules composed of eight tandem repeat titin I27 domains, but the modeling approaches have applicability to other single‐molecule mechanical studies. The merits and challenges associated with applying such a computational approach to existing single‐molecule manipulation data are also discussed. Copyright © 2009 John Wiley & Sons, Ltd.
Two decades of hepatitis B infections among drug users in Amsterdam: Are they still a high‐risk group?
Authors: van Houdt Robin , van den Berg Charlotte H.S.B. , Stolte Ineke G. , Bruisten Sylvia M. , Dukers Nicole H.T.M. , Bakker Margreet , Wolthers Katja C. , Prins Maria , Coutinho Roel A.
Published: May 2009

In general, little is known about the incidence of hepatitis B virus (HBV) among drug users, especially among non‐injecting drug users. Therefore, changes in incidence, risk factors, and circulating genotypes over time were determined among drug users in Amsterdam over an 18‐year period (1985–2002). Sera of 1,268 drug users, both injecting and non‐injecting, were screened for anti‐HBc. HBV genotypes of the anti‐HBc seroconverters were determined. Poisson regression was used to test for temporal trends in incidence and to identify risk factors for seroconversion. Of the 598 participants who were anti‐HBc negative at entry, 83 seroconverted for anti‐HBc. The incidence of HBV declined from 5.9/100 Person Years up to 1993 to 0/100 Person Years in 2002. Of the drug users infected acutely, both injecting and non‐injecting, 88% were infected with the same genotype D, serotype ayw3 strain. Multivariate analyses revealed current injecting, age, and calendar year of visit as independent risk factors. The decline in the incidence of HBV among drug users in Amsterdam is probably caused by a decline in injecting behavior. Injecting and non‐injecting drug users were infected with the same strain, indicating that drug users infect one another, regardless of their risk behavior. After 2000, no injecting drug users with an acute HBV infection were reported to the Public Health Service Amsterdam and the specific genotype D strain had disappeared. These findings suggest that drug users may no longer be a high‐risk group for HBV infection in Amsterdam. However, trends in drug use need to be monitored. J. Med. Virol. 81:1163–1169, 2009. © 2009 Wiley‐Liss, Inc.
Evidence that methylation of hepatitis B virus covalently closed circular DNA in liver tissues of patients with chronic hepatitis B modulates HBV replication
Authors: Guo Yanhai , Li Yongnian , Mu Shijie , Zhang Ju , Yan Zhen
Published: May 2009

Epigenetic factors may modulate chronic Hepatitis B viral infection by affecting virion gene transcription. The aim of this study was to compare the methylation status of the intrahepatic covalently closed circular DNA (cccDNA) CpG island 2 and HBV replication capability. HBV cccDNA was extracted from liver biopsies of 55 HBsAg‐positive patients with chronic hepatitis B (32 HBeAg‐positive and 23 HBeAg‐negative), and was analyzed for methylation status and quantity. The two Hpa II recognition sequences CCpGG in the CpG island 2 were methylated in infected liver tissues from 24 (43.6%) of 55 patients. Positive ratios of cccDNA methylation were significantly higher in HBeAg‐negative patients (15/23, 65.2%) than HBeAg‐positive patients (9/32, 28.1%) (P < 0.05). The percentage of methylated‐cccDNA/total‐cccDNA of HBeAg‐negative samples (a median of 48%, ranging from 5% to 83%) was significantly higher (P < 0.001) than HBeAg‐positive samples (a median of 14%, ranging from 0.26% to 35%). Ratios of relaxed circular DNA (rcDNA) to cccDNA molecules revealed that cccDNA methylation correlated with impaired virion productivity in HBeAg‐positive individuals (P < 0.05). The bisulfite DNA sequencing showed that methylation density was significantly higher in HBeAg‐negative than in HBeAg‐positive patients (P < 0.05). The methylation level of the CpG island 2 of the cccDNA in HBeAg‐negative patients was higher than that in HBeAg‐positive patients, suggesting that HBV cccDNA methylation may be relevant to replication capability of HBV. J. Med. Virol. 81:1177–1183, 2009. © 2009 Wiley‐Liss, Inc.
Characterization of cytotoxic T‐lymphocyte epitopes and immune responses to SARS coronavirus spike DNA vaccine expressing the RGD‐integrin‐binding motif
Authors: Poh W.P. , Narasaraju T. , Pereira N.A. , Zhong F. , Phoon M.C. , Macary P.A. , Wong S.H. , Lu J. , Koh D.R. , Chow Vincent T.K.
Published: May 2009

Integrins are critical for initiating T‐cell activation events. The integrin‐binding motif Arg‐Gly‐Asp (RGD) was incorporated into the pcDNA 3.1 mammalian expression vector expressing the codon‐optimized extracellular domain of SARS coronavirus (SARS‐CoV) spike protein, and tested by immunizing C57BL/6 mice. Significant cell‐mediated immune responses were characterized by cytotoxic T‐lymphocyte 51Cr release assay and interferon‐gamma secretion ELISPOT assay against RMA‐S target cells presenting predicted MHC class I H2‐Kb epitopes, including those spanning residues 884–891 and 1116–1123 within the S2 subunit of SARS‐CoV spike protein. DNA vaccines incorporating the Spike‐RGD/His motif or the Spike‐His construct generated robust cell‐mediated immune responses. Moreover, the Spike‐His DNA vaccine construct generated a significant antibody response. Immunization with these DNA vaccine constructs elicited significant cellular and humoral immune responses. Additional T‐cell epitopes within the SARS‐CoV spike protein that may contribute to cell‐mediated immunity in vivo were also identified. J. Med. Virol. 81:1131–1139, 2009. © 2009 Wiley‐Liss, Inc.
Neuronal expression of the proteolipid protein gene in the medulla of the mouse
Authors: Miller Martha J. , Kangas Cindy D. , Macklin Wendy B.
Published: May 2009

The proteolipid protein (PLP) gene (Plp) encodes the major myelin proteins, PLP and DM20. Expression of Plp occurs predominantly in oligodendrocytes, but evidence is accumulating that this gene is also expressed in neurons. In earlier studies, we demonstrated that myelin‐deficient (MD) rats, which carry a mutation in the Plp gene, exhibit lethal hypoxic ventilatory depression. Furthermore, we found that, in the MD rat, PLP accumulated in neuronal cell bodies in the medulla oblongata. In the current study, we sought to determine which neurons expressed the Plp gene in the medulla oblongata and whether Plp gene expression changed in neurons with maturation. A transgenic mouse expressing the Plp promoter driving expression of enhanced green fluorescent protein (Plp‐EGFP) was used to identify neurons expressing this gene. Plp expression in neurons was confirmed by immunostaining EGFP‐positive cells for NeuN and by in situ hybridization for PLP mRNA. The numbers of neurons expressing Plp‐EGFP and their distribution increased between P5 and P10 in the medulla. Immunostaining for surface receptors and classes of neurons expressing Plp‐EGFP revealed that Plp gene expression in brainstem neurons was restricted to neurons expressing specific ligand‐gated channels and biosynthetic enzymes, including glutamatergic NMDA receptors, GABAA receptors, and ChAT in defined areas of the medulla. Plp gene expression was rarely found in interneurons expressing GABA and was never found in AMPA receptor‐ or tyrosine hydroxylase‐expressing neurons. Thus, Plp expression in the mouse caudal medulla was found to be developmentally regulated and restricted to specific groups of neurons. © 2009 Wiley‐Liss, Inc.