bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibitory effects of caffeine and its metabolites on intracellular lipid accumulation in murine 3T3‐L1 adipocytes
Authors: Nakabayashi Hideo , Hashimoto Takashi , Ashida Hitoshi , Nishiumi Shin , Kanazawa Kazuki
Published: December 2009

To understand the mechanisms of the anti‐obesity effects of dietary caffeine, the effects of caffeine and its metabolites on adipocyte differentiation and insulin‐stimulated glucose uptake in murine 3T3‐L1 adipocytes were investigated. Caffeine did not inhibit the differentiation of 3T3‐L1 pre‐adipocytes to mature adipocytes, but it did suppress the intracellular lipid accumulation after complete differentiation in a dose‐dependent manner (0.125‐1.0 mM). This effect was also observed in 1,3,7‐trimethyluric acid‐ 3,7‐dimethyluric acid‐ and 5‐acetylamino‐6‐formylamino‐3‐methyluracil‐treated cells. Caffeine also inhibited insulin‐stimulated glucose uptake in differentiated 3T3‐L1 adipocytes in a dose‐dependent manner. Treatment with theophylline, paraxanthine, 1‐methylxanthine (MX), 3‐MX, or 7‐MX also inhibited glucose uptake in differentiated adipocytes. These results suggest that the anti‐obesity activity of dietary caffeine is due to the additive and/or synergistic inhibitory effects of caffeine and its metabolites on intracellular lipid accumulation and that caffeine does not affect adipocyte differentiation.
Modulation of energy metabolic enzyme expression in N‐nitrosodiethylamine‐mediated hepatocarcinogenesis by Chinese herbs, Huqi San
Authors: Wen Zhaoyang , Shi Zhengming , Feng Ping , Xue Xiaowei , Dong Kun , Wang Xuejiang
Published: December 2009

Aim: To elucidate the anticancer mechanism of Huqi San by assessing the expression of G‐6‐Pase, SDH, ATPase and AFP in N‐nitrosodiethylamine‐mediated hepatocarcinogenesis in rats.

Methods: A Solt‐Farber two‐step test model of hepatocarcino genesis was established by diethylnitrosamine (DEN) and 2‐acetylaminofluorene (AAF) in rats to investigate the modifying effects of expression of 6‐glucosephosphatase (G‐6‐Pase), succinodehydrogenase (SDH), adenosine triphosphatase (ATPase) in N‐nitrosodiethylamine‐mediated hepatocarcinogenesis. Hu Qisan compounded by eight medicinal herbs was prepared in glycoprival granules with wich 0.38 g crude herbs/mL solution was prepared for administration. γ‐Glutamy‐transpeptidase (γ‐GT), G‐6‐Pase, SDH and ATPase were immunohistochemically determined. The activity of alpha‐fetoglobulin (AFP) in the livers was measured with Immunofluorescence.

Results: Huqi San treated rats showed significant decrease in areas of ‐GT positive foci (P < 0.001). On the other hand, the expression of G‐6‐Pase, SDH and ATPase has obviously altered in Huqi San treated group. The activity of AFP also significantly decreased after the treatment with Huqi San (8 g/kg body weight or 4 g/kg body weight) or total alkali of mistletoe (0.12 g/kg body weight).
Hydrogen sulphide ameliorates ischaemia–reperfusion injury in an experimental model of non-heart-beating donor kidney transplantation
Authors: Hosgood S A , Nicholson M L
Published: December 2009

Background

Therapies to alleviate ischaemia–reperfusion (IR) injury have an important role in kidney transplantation. This study used a porcine model of non-heart-beating (NHB) donor kidneys to investigate the effects of hydrogen sulphide on IR injury.

Methods

Porcine kidneys were subjected to 25 min of warm ischaemia and 18 h of cold storage. They were reperfused ex vivo with autologous oxygenated blood to assess renal function. A group treated with hydrogen sulphide (0·5 mmol/l) infused 10 min before and after reperfusion (n = 6) was compared with an untreated control group (n = 7).

Results

Hydrogen sulphide significantly improved renal blood flow compared with control values (mean(s.d.) area under the curve (AUC) 614·9(165·5) versus 270·3(86·7) ml per min per 100 g.h; P = 0·001) and renal function (AUC creatinine: 1640(248) versus 2328(154) µmol/l.h; P = 0·001; AUC creatinine clearance: 6·94(5·03) versus 0·96(0·32) ml per min per 100 g.h; P = 0·004). Oxidative damage was also reduced by hydrogen sulphide (urinary 8-isoprostane at 1 h of reperfusion: 478·9(237·1) versus 1605·6(632·7) pg/ml per mmol/l creatinine; P = 0·032).

Conclusion

Hydrogen sulphide ameliorated the renal dysfunction associated with ischaemic damage, and has potential as a therapy against IR injury in NHB donor kidney transplantation.
Validated LC‐MS/MS assay for the quantitative determination of vardenafil in human plasma and its application to a pharmacokinetic study
Authors: Lake Simon T. , Altman Phillip M. , Vaisman Jack , Addison Russell S.
Published: December 2009

A sensitive high‐performance liquid chromatography–tandem mass spectrometric (HPLC‐MS/MS) assay has been developed for the quantitative analysis of vardenafil in human plasma. Vardenafil and the internal standard, alprazolam, were extracted from 0.2 mL aliquots of alkalinized plasma by a single solvent extraction into hexane : dichloromethane. Reversed‐phase chromatographic separation was affected by gradient elution with mobile phases consisting of 10 mM ammonium formate pH 7.0 (solvent A) and methanol (100%, solvent B), delivered at a flow rate of 0.4 mL/min. The analytes were detected by using an electrospray ion source on a 4000 QTrap triple quadrupole mass spectrometer operating in positive ionization mode. The mass transitions were m/z 489.3 → 312.2 for vardenafil and m/z 309.2 → 281.0 for alprazolam. The assay was linear over the concentration range of 0.2–100 ng/mL, with correlation coefficients ≥0.995. The intra‐ and inter‐day precision was less than 5.4% in terms of relative standard deviation and the accuracy was within 12.7% in terms of relative error. The lower limit of quantitation was set at 0.2 ng/mL. The high sensitivity and acceptable performance of the assay allowed its application to the analysis of plasma samples obtained following the oral administration of vardenafil to healthy male volunteers in a pharmacokinetic study. Copyright © 2009 John Wiley & Sons, Ltd.
Economical Feasibility Evaluation of an Ethanol Injection Liposome Production Plant
Authors: Justo O. R. , Moraes Â. M.
Published: December 2009

Over the past few decades liposomes, which are lipid vesicles useful for the controlled release of numerous bioactive compounds, have attracted significant industrial interest. Several techniques have evolved for the manufacture of liposomes on a small scale. However, production on a commercially feasible scale is still somewhat limited. Therefore, this research intends to evaluate the scale‐up potential of a liposome production unit using the ethanol injection method, through preliminary economical feasibility estimation, as an addendum to a pre‐existing bioactive compound manufacture plant, with the aim of increasing the compound aggregate value. The ethanol injection technique is selected due to its simplicity and low cost, characteristics that make it easily scalable. The preliminary economic evaluation involves the assessment of capital investment, estimation of operating costs, and analysis of profitability. The results of the economic analysis suggest that the process is economically feasible for a plant with a daily production capacity of 288 L of liposomal suspension.
Chiral Brønsted Acid Directed Iron‐Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles with β‐Aryl α′‐Hydroxy Enones
Authors: Yang Lei , Zhu Qiming , Guo Shengmei , Qian Bo , Xia Chungu , Huang Hanmin
Published: December 2009

A cooperative catalytic system established by the combination of an iron salt and a chiral Brønsted acid has proven to be effective in the asymmetric Friedel–Crafts alkylation of indoles with β‐aryl α′‐hydroxy enones. Good to excellent yields and enatioselectivities were observed for a variety of α′‐hydroxy enones and indoles, particularly for the β‐aryl α′‐hydroxy enones bearing an electron‐withdrawing group at the para position of the phenyl ring (up to 90 % yield and 91 % ee). The proton of the chiral Brønsted acid, the Lewis acid activation site, as well as the inherent basic site for the hydrogen‐bonding interaction of the Brønsted acid are responsible for the high catalytic activities and enantioselectivities of the title reaction. A possible reaction mechanism was proposed. The key catalytic species in the catalytic system, the phosphate salt of FeIII, which was thought to be responsible for the high activity and good enantioselectivity, was then confirmed by ESIMS studies.
Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors
Authors: Krüger Dennis M. , Evers Andreas
Published: December 2009

Structure‐ and ligand‐based virtual‐screening methods (docking, 2D‐ and 3D‐similarity searching) were analysed for their effectiveness in virtual screening against four different targets: angiotensin‐converting enzyme (ACE), cyclooxygenase 2 (COX‐2), thrombin and human immunodeficiency virus 1 (HIV‐1) protease. The relative performance of the tools was compared by examining their ability to recognise known active compounds from a set of actives and nonactives. Furthermore, we investigated whether the application of different virtual‐screening methods in parallel provides complementary or redundant hit lists. Docking was performed with GOLD, Glide, FlexX and Surflex. The obtained docking poses were rescored by using nine different scoring functions in addition to the scoring functions implemented as objective functions in the docking algorithms. Ligand‐based virtual screening was done with ROCS (3D‐similarity searching), Feature Trees and Scitegic Functional Fingerprints (2D‐similarity searching). The results show that structure‐ and ligand‐based virtual‐screening methods provide comparable enrichments in detecting active compounds. Interestingly, the hit lists that are obtained from different virtual‐screening methods are generally highly complementary. These results suggest that a parallel application of different structure‐ and ligand‐based virtual‐screening methods increases the chance of identifying more (and more diverse) active compounds from a virtual‐screening campaign.
Novel Bottom‐Up SERS Substrates for Quantitative and Parallelized Analytics
Authors: Strelau Katharina K. , Schüler Thomas , Möller Robert , Fritzsche Wolfgang , Popp Jürgen
Published: December 2009

Surface‐enhanced Raman spectroscopy (SERS) is an emerging technology in the field of analytics. Due to the high sensitivity in connection with specific Raman molecular fingerprint information SERS can be used in a variety of analytical, bioanalytical, and biosensing applications. However, for the SERS effect substrates with metal nanostructures are needed. The broad application of this technology is greatly hampered by the lack of reliable and reproducible substrates. Usually the activity of a given substrate has to be determined by time‐consuming experiments such as calibration or ultramicroscopic studies. To use SERS as a standard analytical tool, cheap and reproducible substrates are required, preferably with a characterization technique that does not interfere with the subsequent measurements. Herein we introduce an innovative approach to produce low‐cost and large‐scale reproducible substrates for SERS applications, which allows easy and economical production of micropatterned SERS active surfaces on a large scale. This approach is based on an enzyme‐induced growth of silver nanostructures. The special structural feature of the enzymatically deposited silver nanoparticles prevents the breakdown of SERS activity even at high particle densities (particle density >60 %) that lead to a conductive layer. In contrast to other approaches, this substrate exhibits a relationship between electrical conductivity and the resulting SERS activity of a given spot. This enables the prediction of the SERS activity of the nanostructure ensemble and therewith the controllable and reproducible production of SERS substrates of enzymatic silver nanoparticles on a large scale, utilizing a simple measurement of the electrical conductivity. Furthermore, through a correlation between the conductivity and the SERS activity of the substrates it is possible to quantify SERS measurements with these substrates.
Multispectral image analysis of binary encoded microspheres for highly multiplexed suspension arrays
Authors: Mathur Abhishek , Kelso David M.
Published: December 2009

To push the 100‐plex envelope of suspension array technology, we have developed fully automated methods to acquire multispectral images of multiplexed quantum‐dot (QD) encoded microspheres, to segment them in the images, to classify them based on their color code, and to quantify the multiplexed assays. Instead of coding microspheres with two colors and n levels, microspheres were coded with n colors and two levels (present or absent), thus transforming the classification problem from analog to digital. Images of multiplexed microspheres, sedimented at the bottom of microwells, were acquired through a tunable filter at the peak luminescence wavelength of each QD coding species in the system and the assay label wavelength. Another image of the light scattered from microspheres was captured in the excitation bandwidth that was utilized to localize microspheres in multispectral luminescence images. Objects in the acquired images are segmented and luminescence from each identified microsphere in each channel is recorded, based on which the “color code” of each microsphere is determined by applying a mathematical model and a classification algorithm. Our image analysis procedures could identify and classify microspheres with more than 97% accuracy, and the assay CVs were under 20%. These proof‐of‐principle results demonstrate that highly multiplexed quantification of specific proteins is possible with this rapid, small‐sample volume format. © 2009 International Society for Advancement of Cytometry
Synthesis and screening of substituted 1,4‐naphthoquinones (NPQs) as antifilarial agents
Authors: Mathew Nisha , Karunan Twinkle , Srinivasan Lakshmy , Muthuswamy Kalyanasundaram
Published: December 2009

Eleven amino‐substituted 1,4‐naphthoquinones were synthesized via the reaction of 1,4‐naphthoquinone with different primary and secondary mono‐ and diamines in the presence of dichloromethane ethanol (1:2) solvent at room temperature. All compounds were purified by flash column chromatography, characterized by TLC, HPLC, 13C‐NMR, 1H‐NMR, and FT‐IR spectral analysis and were evaluated in vitro for antifilarial activity using adult bovine filarial worm Setaria digitata by assessing worm motility and MTT (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) reduction. Seven of the 11 compounds had macrofilaricidal activity with compounds 9 (2‐[(1,3‐dimethylbutyl) amino] naphthalene‐1,4‐dione) and 11 (2‐(4‐methylpiperazin‐1‐yl) naphthalene‐1,4‐dione) having maximum activity (ED50 values of 0.91 and 1.2 µM, respectively, at 48 h). The effect of different substitutions on antifilarial activity is discussed. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.
Peroxisome proliferator‐activated receptor‐δ as emerging target in liver disease
Authors: Schnabl Bernd
Published: December 2009

Liver fibrosis is characterized by an excessive deposition of extracellular matrix (ECM) proteins that occurs in chronic liver disease of any origin, including nonalcoholic steatohepatitis (NASH), alcohol abuse, and viral hepatitis. Cirrhosis occurs with the development of regenerating nodules of hepatocytes and is a major health burden worldwide. Patients with decompensated liver cirrhosis have a poor prognosis, with liver transplantation often being necessary. The current treatment paradigm for patients with hepatic fibrosis is to treat the underlying liver disease. However, if this cannot be achieved, there are currently no effective antifibrotic treatments for patients with chronic liver diseases. With the advent of basic molecular technology providing insight into the mechanisms of the development of hepatic fibrosis, there is now an opportunity to develop therapeutic interventions for human clinical use. In this review, the function of peroxisome proliferator‐activated receptor‐δ (PPAR δ) will be summarized with a special emphasis on ligand activation as potential use in liver disease. Drug Dev Res 2009. © 2009 Wiley‐Liss, Inc.
Regulation of Sox9 by Sonic Hedgehog (Shh) is essential for patterning and formation of tracheal cartilage
Authors: Park Jinhyung , Zhang Jennifer J.R. , Moro Anne , Kushida Michelle , Wegner Michael , Kim Peter C.W.
Published: December 2009

We report that Sonic Hedgehog (Shh) regulates both formation and patterning of tracheal cartilage by controlling the expression pattern and level of the chondrogenic gene, Sox9. In Shh−/− tracheo‐esophageal tubes, Sox9 expression is transient and not restricted ventrally to the site of chondrogenesis, and is absent at the time of chondrogenesis, resulting in the failure of tracheal cartilage formation. Inhibition of Hedgehog signalling with cyclopamine in tracheal cultures prevents tracheal cartilage formation, while treatment of Shh−/− tracheal explant with exogenous Shh peptide rescues cartilage formation. Both exogenous Bmp4 and Noggin rescue cartilage phenotype in Shh−/− tracheal culture, while promoting excessive cartilage development in wild‐type trachea through induction of Sox9 expression. The ventral and segmented expression of Sox9 in tracheal primordia under Shh modulated by Bmp4 and Noggin thus determine where and when tracheal cartilage develops. These results indicate that Shh signalling is a critical determinant in tracheal cartilage development. Developmental Dynamics 239:514–526, 2010. © 2009 Wiley‐Liss, Inc.
Churchill and Sip1a repress fibroblast growth factor signaling during zebrafish somitogenesis
Authors: Kok Fatma O. , Shepherd Iain T. , Sirotkin Howard I.
Published: December 2009

Cell‐type specific regulation of a small number of growth factor signal transduction pathways generates diverse developmental outcomes. The zinc finger protein Churchill (ChCh) is a key effector of fibroblast growth factor (FGF) signaling during gastrulation. ChCh is largely thought to act by inducing expression of the multifunctional Sip1 (Smad Interacting Protein 1). We investigated the function of ChCh and Sip1a during zebrafish somitogenesis. Knockdown of ChCh or Sip1a results in misshapen somites that are short and narrow. As in wild‐type embryos, cycling gene expression occurs in the developing somites in ChCh and Sip1a compromised embryos, but expression of her1 and her7 is maintained in formed somites. In addition, tail bud fgf8 expression is expanded anteriorly in these embryos. Finally, we found that blocking FGF8 restores somite morphology in ChCh and Sip1a compromised embryos. These results demonstrate a novel role for ChCh and Sip1a in repression of FGF activity. Developmental Dynamics 239:548–558, 2010. © 2009 Wiley‐Liss, Inc.
A new production function estimate of the euro area output gap
Authors: Lemoine Matthieu , Mazzi Gian Luigi , Monperrus‐Veroni Paola , Reynes Frédéric
Published: December 2009

We develop a new version of the production function (PF) approach for estimating the output gap of the euro area. Assuming a CES (constant elasticity of substitution) technology, our model does not call for any (often imprecise) measure of the capital stock and improves the estimation of the trend total factor productivity using a multivariate unobserved components model. With real‐time data, we assess this approach by comparing it with the Hodrick–Prescott (HP) filter and with a Cobb–Douglas PF approach with common cycle and implemented with a multivariate unobserved components model. Our new PF estimate appears highly concordant with the reference chronology of turning points and has better real‐time properties than the univariate HP filter for sufficiently long time horizons. Its inflation forecasting power appears, like the other multivariate approach, less favourable than the statistical univariate method. Copyright © 2009 John Wiley & Sons, Ltd.
The use of tetradecanoylphorbol acetate‐stimulated peripheral blood cells enhances the prognostic value of interphase fluorescence in situ hybridization in patients with chronic lymphocytic leukemia
Authors: Delgado Julio , Aventin Anna , Briones Javier , Sanchez Jana , Nomdedeu Josep , Sierra Jorge
Published: December 2009

Interphase fluorescence in situ hybridization (I‐FISH) studies have a remarkable prognostic value in patients with chronic lymphocytic leukemia (CLL). I‐FISH studies can be performed either on tetradecanoylphorbol acetate stimulated peripheral blood cells (I‐FISH‐TPA) or unstimulated peripheral blood mononuclear cells (I‐FISH‐PBMC). The aim of the study was to evaluate whether this finding was clinically relevant in a group of 235 patients with CLL. Fifty‐six patients had both I‐FISH‐TPA and I‐FISH‐PBMC results. Compared with uncultured cells, the cytogenetic detection rate rose from 57 to 80% with the use of TPA‐stimulated cells (P = 0.014). I‐FISH‐TPA provided a better prediction of treatment‐free survival compared with I‐FISH‐PBMC (P = 0.031 vs. 0.166). Then, I‐FISH‐PBMC results from 93 historical patients were compared with 86 recent patients with I‐FISH‐TPA results. Genomic aberrations were detected in 46 and 67% of patients from the I‐FISH‐PBMC and I‐FISH‐TPA cohorts, respectively. The detection rate of 13q deletion as the only aberration increased from 10% with I‐FISH‐PBMC to 37% with I‐FISH‐TPA (P = 0.006). In conclusion, I‐FISH‐TPA increased the detection rate of 13q deletion and had an improved prognostic value compared with I‐FISH‐PBMC. © 2009 Wiley‐Liss, Inc.
Awareness of carer distress in people with dementia
Authors: Ablitt Astri , Jones Gregory , Muers Jane
Published: December 2009

Objectives

People caring for family members who have dementia often experience considerable levels of anxiety and depression. However, relatively little is known about the awareness of carer distress among people with dementia. This study investigated whether or not people with dementia are aware of the level of distress experienced by their carers.

Method

Two groups of participants were studied, a dementia group and a control group of people with arthritis. Each group consisted of pairs of people, the person with dementia or arthritis and the family member who acted as their main carer; 40 pairs participated in total. For both groups, the carer's psychological health was rated by the carer themselves and by the care‐recipient, using the Hospital Anxiety and Depression Scale. For the dementia group, memory functioning in the person with dementia was rated by the care‐recipient themselves and by the carer, using the Memory Function Scale. The ratings made by the carer and care‐recipient were compared to give an indication of the level of awareness in the care‐recipient.

Results

People with dementia have a significant level of awareness of their carers' state of psychological health. Their awareness follows the same pattern as that shown by a control group of people with arthritis. The level of awareness of carer psychological health shown by the dementia group was not related to their level of awareness of their own memory difficulties.

Conclusion

The clinical implications of awareness of carer distress in people with dementia should be considered. Copyright © 2009 John Wiley & Sons, Ltd.
Deletion of Cd39 on Natural Killer Cells Attenuates Hepatic Ischemia/Reperfusion Injury in Mice
Authors: Beldi Guido , Banz Yara , Kroemer Alexander , Sun Xiaofeng , Wu Yan , Graubardt Nadine , Rellstab Alyssa , Nowak Martina , Enjyoji Keiichi , Li Xian , Junger Wolfgang G. , Candinas Daniel , Robson Simon C.
Published: December 2009

Natural killer (NK) cells play crucial roles in innate immunity and express CD39 (Ecto-nucleoside triphosphate diphosphohydrolase 1 [E-NTPD1]), a rate-limiting ectonucleotidase in the phosphohydrolysis of extracellular nucleotides to adenosine. We have studied the effects of CD39 gene deletion on NK cells in dictating outcomes after partial hepatic ischemia/reperfusion injury (IRI). We show in mice that gene deletion of CD39 is associated with marked decreases in phosphohydrolysis of adenosine triphosphate (ATP) and adenosine diphosphate to adenosine monophosphate on NK cells, thereby modulating the type-2 purinergic (P2) receptors demonstrated on these cells. We note that CD39-null mice are protected from acute vascular injury after single-lobe warm IRI, and, relative to control wild-type mice, display significantly less elevation of aminotransferases with less pronounced histopathological changes associated with IRI. Selective adoptive transfers of immune cells into Rag2/common gamma null mice (deficient in T cells, B cells, and NK/NKT cells) suggest that it is CD39 deletion on NK cells that provides end-organ protection, which is comparable to that seen in the absence of interferon gamma. Indeed, NK effector mechanisms such as interferon gamma secretion are inhibited by P2 receptor activation

in vitro

. Specifically, ATPγS (a nonhydrolyzable ATP analog) inhibits secretion of interferon gamma by NK cells in response to interleukin-12 and interleukin-18, providing a mechanistic link between CD39 deletion and altered cytokine secretion.

Conclusion:

We propose that CD39 deficiency and changes in P2 receptor activation abrogate secretion of interferon gamma by NK cells in response to inflammatory mediators, thereby limiting tissue damage mediated by these innate immune cells during IRI. (Hepatology 2010.)
Mammalian Target of Rapamycin Regulates Vascular Endothelial Growth Factor–Dependent Liver Cyst Growth in Polycystin-2–Defective Mice
Authors: Spirli Carlo , Okolicsanyi Stefano , Fiorotto Romina , Fabris Luca , Cadamuro Massimiliano , Lecchi Silvia , Tian Xin , Somlo Stefan , Strazzabosco Mario
Published: December 2009

Polycystic liver disease may complicate autosomal dominant polycystic kidney disease (ADPKD), a disease caused by mutations in polycystins, which are proteins that regulate signaling, morphogenesis, and differentiation in epithelial cells. The cystic biliary epithelium [liver cystic epithelium (LCE)] secretes vascular endothelial growth factor (VEGF), which promotes liver cyst growth via autocrine and paracrine mechanisms. The expression of insulin-like growth factor 1 (IGF1), insulin-like growth factor 1 receptor (IGF1R), and phosphorylated mammalian target of rapamycin (p-mTOR) and the protein kinase A (PKA)–dependent phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) are also up-regulated in LCE. We have hypothesized that mammalian target of rapamycin (mTOR) represents a common pathway for the regulation of hypoxia-inducible factor 1 alpha (HIF1α)–dependent VEGF secretion by IGF1 and ERK1/2. Conditional polycystin-2–knockout (Pkd2KO) mice were used for in vivo studies and to isolate cystic cholangiocytes [liver cystic epithelial cells (LCECs)]. The expression of p-mTOR, VEGF, cleaved caspase 3 (CC3), proliferating cell nuclear antigen (PCNA), IGF1, IGF1R, phosphorylated extracellular signal-regulated kinase, p-P70S6K, HIF1α, and VEGF in LCE, LCECs, and wild-type cholangiocytes was studied with immunohistochemistry, western blotting, or enzyme-linked immunosorbent assays. The cystic area was measured by computer-assisted morphometry of pancytokeratin-stained sections. Cell proliferation in vitro was studied with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2

H

-tetrazolium and bromodeoxyuridine assays. The treatment of Pkd2KO mice with the mTOR inhibitor rapamycin significantly reduced the liver cyst area, liver/body weight ratio, pericystic microvascular density, and PCNA expression while increasing expression of CC3. Rapamycin inhibited IGF1-stimulated HIF1α accumulation and VEGF secretion in LCECs. IGF1-stimulated LCEC proliferation was inhibited by rapamycin and SU5416 (a vascular endothelial growth factor receptor 2 inhibitor). Phosphorylation of the mTOR-dependent kinase P70S6K was significantly reduced by PKA inhibitor 14-22 amide and by the mitogen signal-regulated kinase inhibitor U1026.

Conclusion:

These data demonstrate that PKA-dependent up-regulation of mTOR has a central role in the proliferative, antiapoptotic, and pro-angiogenic effects of IGF1 and VEGF in polycystin-2–defective mice. This study also highlights a mechanistic link between PKA, ERK, mTOR, and HIF1α-mediated VEGF secretion and provides a proof of concept for the potential use of mTOR inhibitors in ADPKD and conditions with aberrant cholangiocyte proliferation. (Hepatology 2010.)
The effect of dopamine partial agonists on the nicotine dependency in patients with schizophrenia
Authors: Kim Se Hee , Han Doug Hyun , Joo So Youn , Min Kyung Joon
Published: December 2009

Objective

We compared the effects of haloperidol and three atypical antipsychotics (risperidone, olanzapine, and aripiprazole) on nicotine dependence in schizophrenic patients.

Methods

One hundred and thirty nine schizophrenic patients, who began using antipsychotic medication, were assessed for severity of nicotine dependence and for cigarette craving at baseline and following 8 weeks of treatment using the Fagerström Tolerance Questionnaire (FTQ) and a Likert‐style, seven point, visual‐analogue rating scale.

Results

Nicotine dependence increased in the haloperidol group, but not in atypical antipsychotics groups. Patients treated with aripiprazole showed a reduction both in nicotine dependence and cigarette craving.

Conclusions

The effects of aripiprazole, a partial agonist of the dopamine D2 receptor, may reduce the severity of nicotine dependence in schizophrenic patients. Copyright © 2009 John Wiley & Sons, Ltd.
Prediction of interactiveness between small molecules and enzymes by combining gene ontology and compound similarity
Authors: Chen Lei , Qian Ziliang , Fen Kaiyan , Cai Yudong
Published: December 2009

Determination of whether a small organic molecule interacts with an enzyme can help to understand the molecular and cellular functions of organisms, and the metabolic pathways. In this research, we present a prediction model, by combining compound similarity and enzyme similarity, to predict the interactiveness between small molecules and enzymes. A dataset consisting of 2859 positive couples of small molecule and enzyme and 286,056 negative couples was employed. Compound similarity is a measurement of how similar two small molecules are, proposed by Hattori et al., J Am Chem Soc 2003, 125, 11853 which can be availed athttp://www.genome.jp/ligand‐bin/search_compound, while enzyme similarity was obtained by three ways, they are blast method, using gene ontology items and functional domain composition. Then a new distance between a pair of couples was established and nearest neighbor algorithm (NNA) was employed to predict the interactiveness of enzymes and small molecules. A data distribution strategy was adopted to get a better data balance between the positive samples and the negative samples during training the prediction model, by singling out one‐fourth couples as testing samples and dividing the rest data into seven training datasets—the rest positive samples were added into each training dataset while only the negative samples were divided. In this way, seven NNAs were built. Finally, simple majority voting system was applied to integrate these seven models to predict the testing dataset, which was demonstrated to have better prediction results than using any single prediction model. As a result, the highest overall prediction accuracy achieved 97.30%. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
Force field‐dependant structural divergence revealed during long time simulations of Calbindin d9k
Authors: Project Elad , Nachliel Esther , Gutman Menachem
Published: December 2009

The structural and the dynamic features of the Calbindin (CaB) protein in its holo and apo states are compared using molecular dynamics simulations under nine different force fields (FFs) (G43a1, G53a6, Opls‐AA, Amber94, Amber99, Amber99p, AmberGS, AmberGSs, and Amber99sb). The results show that most FFs reproduce reasonably well the majority of the experimentally derived features of the CaB protein. However, in several cases, there are significant differences in secondary structure properties, root mean square deviations (RMSDs), root mean square fluctuations (RMSFs), and S2 order parameters among the various FFs. What is more, in certain cases, these parameters differed from the experimentally derived values. Some of these deviations became noticeable only after 50 ns. A comparison with experimental data indicates that, for CaB, the Amber94 shows overall best agreement with the measured values, whereas several others seem to deviate from both crystal and nuclear magnetic resonance data. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
Comparison of different treatment alternatives for removal of pesticide from water solution
Authors: Al Momani Fares A. , Shawaqfeh Ahmad T. , Al‐Zoubi Hani
Published: December 2009

BACKGROUND: Removal of recalcitrant chemicals is an essential step in conventional wastewater treatment plants. Among these, pesticides are of great environmental concern. Different treatment options were compared in this work: the combination of advanced oxidation processes (AOPs) with biological treatment, an aerobic process and anaerobic biological treatments. The role of chemical processes in improving solution biodegradability was verified. Oxidation by‐products were identified and biological process kinetics are reported. The performance of biological processes and their kinetics were studied.

RESULTS: Chemical oxidation increased the solution biodegradability index to 0.25. Oxidation by‐products were identified as maleic acid, phenol and a mixture of catechol, resorcinol and hydroquinone. The combined processes resulted in 98% organic matter removal. Pesticide degradation followed pseudo‐first‐order kinetics with a rate constant in the range 0.5–1.2 L g−1TVSS h−1. An anaerobic process was found to be an attractive option with 92% removal efficiency. The aerobic process had a long adaptation time (>200 days), 80% removal efficiency and an average pseudo‐first‐order rate constant of 0.18 L g−1TVSS h−1.

CONCLUSION: Comparison of the investigated processes favoured the use of combined AOPs and biological and/or aerobic biological treatment due to its practical operating conditions. Copyright © 2009 Society of Chemical Industry
Separation of bovine serum albumin (BSA) using γ‐Al2O3–clay composite ultrafiltration membrane
Authors: Monash P. , Majhi Abhijit , Pugazhenthi G.
Published: December 2009

BACKGROUND: Ceramic membranes have received more attention than polymeric membranes for the separation and purification of bio‐products owing to their superior chemical, mechanical and thermal properties. Commercially available ceramic membranes are too expensive. This could be overcome by fabricating membranes using low‐cost raw materials. The aim of this work is to fabricate a low‐cost γ‐Al2O3–clay composite membrane and evaluate its potential for the separation of bovine serum albumin (BSA) as a function of pH, feed concentration and applied pressure. To achieve this, the membrane support is prepared using low‐cost clay mixtures instead of very expensive alumina, zirconia and titania materials. The cost of the membrane can be further reduced by preparing a γ‐alumina surface layer on the clay support using boehmite sol synthesized from inexpensive aluminium chloride instead of expensive aluminium alkoxide using a dip‐coating technique.

RESULTS: The pore size distribution of the γ‐Al2O3‐clay composite membrane varied from 5.4–13.6 nm. The membrane was prepared using stable boehmite sol of narrow particle size distribution and mean particle size 30.9 nm. Scanning electron microscopy confirmed that the surface of the γ‐Al2O3–clay composite membrane is defect‐free. The pure water permeability of the support and the composite membrane were found to be 4.838 × 10−6 and 2.357 × 10−7 m3 m−2 s−1 kPa−1, respectively. The maximum rejection of BSA protein was found to be 95%. It was observed that the separation performance of the membrane in terms of flux and rejection strongly depends on the electrostatic interaction between the protein and charged membrane.

CONCLUSION: The successively prepared γ‐Al2O3‐clay composite membrane proved to possess good potential for the separation of BSA with high yield and could be employed as a low cost alternate to expensive ceramic membranes. Copyright © 2009 Society of Chemical Industry
Collision‐induced dissociation mass spectra of glucosinolate anions
Authors: Bialecki Jason B. , Ruzicka Josef , Weisbecker Carl S. , Haribal Meena , Attygalle Athula B.
Published: December 2009

Collision‐induced dissociation (CID) mass spectra of differently substituted glucosinolates were investigated under negative‐ion mode. Data obtained from several glucosinolates and their isotopologues (34S and 2H) revealed that many peaks observed are independent of the nature of the substituent group. For example, all investigated glucosinolate anions fragment to produce a product ion observed at m/z 195 for the thioglucose anion, which further dissociates via an ion/neutral complex to give two peaks at m/z 75 and 119. The other product ions observed at m/z 80, 96 and 97 are characteristic for the sulfate moiety. The peaks at m/z 259 and 275 have been attributed previously to glucose 1‐sulfate anion and 1‐thioglucose 2‐sulfate anion, respectively. However, based on our tandem mass spectrometric experiments, we propose that the peak at m/z 275 represents the glucose 1‐thiosulfate anion. In addition to the common peaks, the spectrum of phenyl glucosinolate (β‐D‐Glucopyranose, 1‐thio‐, 1‐[N‐(sulfooxy)benzenecarboximidate] shows a substituent‐group‐specific peak at m/z 152 for C6H5‐C(NOH)S−, the CID spectrum of which was indistinguishable from that of the anion of synthetic benzothiohydroxamic acid. Similarly, the m/z 201 peak in the spectrum of phenyl glucosinolate was attributed to C6H5‐C(S)OSO2−. Copyright © 2009 John Wiley & Sons, Ltd.
Numerical study of electromagnetic wave propagation through layered structures with chiral media
Authors: Barba Ismael , Gómez Álvaro , Cabeceira Ana C. L. , Represa José , Vegas Ángel , Solano Miguel A.
Published: December 2009

In this paper, the characteristics of layered structures (photonic or electromagnetic bandgaps), including chiral media, are studied by means of two different numerical methods, one in the time domain (finite differences in the time domain, FDTD) and the other in the frequency domain (coupled‐mode method, CMM). The results (reflection and transmission coefficients for a plane wave normally incident over a layered structure) obtained by means of both well different techniques are practically identical. Copyright © 2009 John Wiley & Sons, Ltd.
Simple and sensitive LC‐ESI‐MS method for the quantitation of sildenafil in plasma samples
Authors: Alkharfy Khalid M.
Published: December 2009

Sildenafil is a selective inhibitor of phosphodiesterase type 5 enzyme. A simple and sensitive LC‐MS assay was developed to determine the concentration of sildenafil in human plasma. Sildenafil and omeprazole (internal standard) were extracted from the plasma with diethyl ether. The extract was evaporated under nitrogen and the residue was constituted with ACN and injected onto Novapak C18 column (75×3.9 mm, 4 μm). The mobile phase consisted of 90% ACN plus 10% ammonium acetate (20 mM) containing 0.02% formic acid and was delivered isocratically at a flow rate of 0.2 mL/min. Sildenafil and omeprazole were monitored using a positive electrospray mode with single‐ion recording set at m/z 475 and 346, respectively, which are consistent with [M+H]+ molecular ions, and the run time was less than 5 min. The detection limit of sildenafil was 0.5 ng/mL, and the calibration curve was linear between 0.5 and 2000 ng/mL (R2>0.99). Within‐ and between‐day coefficients of variation were less than 7%. This method has been successfully used to measure sildenafil plasma concentrations in a beagle dog model following an oral administration of the drug.
Fluorescence correlation spectroscopy in vivo
Authors: Mütze J. , Ohrt T. , Schwille P.
Published: December 2009

This review will focus on the application and potential of FCS and FCCS in vivo. Practical issues and sources of artifacts when performing measurements in living cells are discussed. Finally, several extensions to conventional FCS, such as multiphoton excitation, scanning FCS, Fluorescence Lifetime Correlation Spectroscopy, multiplexing FCS and recent approaches to reach smaller excitation volumes are reviewed
Morphology Control of Highly Sulfonated Block Copolymers by a Simple Thermal Process
Authors: Baek Kyung‐Youl , Kim Hyun‐Ji , Lee Sang‐Ho , Cho Kie‐Yong , Kim Hyeong Tae , Hwang Seung Sang
Published: December 2009

Well‐defined sulfonated block copolymers were prepared by direct thermolysis with block copolymers of n‐butyl acrylate (nBA) and neopentyl styrene sulfonated (NSS), which were synthesized by Cu‐based living radical polymerization ($\overline M _{\rm w} /\overline M _{\rm n}$ <1.20). A simple thermal process for 10 min at 150 °C completely deprotected the neopentyl groups in the poly(NSS) block segment to give fully sulfonated polystyrene backbone. SAXS profile of the block copolymer with 47 wt.‐% of poly(NSS) showed lamella structure, which appeared more clearly with long ranged order after sulfonation of the block copolymer.

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Thermodynamic Model of Structure and Shape in Rigid Polymer‐Laden Membranes
Authors: Murugesan Yogesh K. , Rey Alejandro D.
Published: December 2009

A mechanical formulation for multi‐component rigid‐rod‐like polymer‐laden membranes is integrated with the Gibbs‐Duhem equation to describe the role of temperature and adsorption on membrane shape and on the nematic liquid crystal order of the embedded polymer. The rigid‐rod polymer model incorporates curvo‐philic effects promoting polymer re‐orientation along curvature directions and curvo‐phobic effects promoting polymer re‐orientation away from curvature directions, while the membrane curvature energy is described with the Helfrich formulation. The couplings between thermodynamical variables, polymer liquid crystalline order, and membrane curvature are demonstrated and characterized. The theory provides a road‐map to manipulate shape and structure in membranes containing fibers, proteins, and rod‐like polymers.

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Online Monitoring of Polyolefin Particle Growth in Catalytic Olefin Slurry Polymerization by Means of Lasentec Focused Beam Reflectance Measurement (FBRM) and Video Microscopy (PVM) Probes
Authors: Xalter Rainer , Mülhaupt Rolf
Published: December 2009

Polymer particle growth in catalytic ethylene slurry polymerizations with SiO2‐supported metallocene and post‐metallocene catalysts was monitored online using a Lasentec FBRM probe inserted into the stirred reactor. FBRM enabled the online monitoring of particle numbers and size distributions. Trend analyses provided time‐resolved information on selected variables of the particle growth processes. FBRM was combined with simultaneous ethylene mass flow measurements in order to distinguish between ideal particle growth and more complex growth processes involving particle fragmentation and aggregation. Additional use of a Lasentec PVM video microscopy probe during ethylene polymerization on a MgCl2‐supported Ziegler catalyst enabled the online visualization of PE particles, complementing the data generated by FBRM online monitoring.

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Berühmte Enden
Authors: Zündorf Ilse , Dingermann Theo
Published: December 2009

Welche Molekülenden haben ihren Erforschern schon zu solchen Auszeichnungen verholfen? Kaum hatten die US‐Wissenschaftlerin Elizabeth H. Blackburn von der Universität Kalifornien in San Francisco und Carol W. Greider von der Johns‐Hopkins‐Universität in Baltimore den renommierten deutschen “Paul Ehrlich und Ludwig Darmstädter Preis” erhalten, wurde ihnen – zusammen mit Jack W. Szostak von der amerikanischen Harvard‐Universität – der Nobelpreis für Medizin und Physiologie 2009 verliehen. All das nur, weil sie sich eingehend mit den Enden unserer Chromosomen, den Telomeren, beschäftigen.
Notfallzulassung von Peramivir in den USA
Authors: Bennack Edith , Holzgrabe Ulrike
Published: December 2009

Am 23. Oktober 2009 hat die Food and Drug Administration (FDA) auf Empfehlung des Centers for Disease Control (CDC) den Neuraminidaseinhibitor (NAI) Peramivir im Rahmen einer “Emergency Use Authorization” (EUA) zur Behandlung der 2009‐H1N1‐Influenza (“Schweinegrippe”) in den USA zugelassen. Nach Oseltamivir (oral) und Zanamivir (inhalativ) steht nun mit Peramivir der erste NAI zur parenteralen Gabe zur Verfügung.
Dengue‐ und West‐Nil‐Virus. Antivirale Strategien
Authors: Klein Christian
Published: December 2009

Infektionen mit Flaviviren, beispielsweise dem West‐Nil‐ und dem Dengue‐Virus, stellen ein zunehmendes medizinisches Problem in den Tropen und Subtropen dar. Für die Zukunft kann, bedingt durch eine Ausbreitung der Überträgerinsekten in gemäßigte Breiten, ein endemisches Auftreten auch in Mitteleuropa nicht ausgeschlossen werden. Die Bekämpfung von Flaviviren erfolgt momentan insbesondere durch die Kontrolle der Überträgerinsekten. Die Entwicklung von Impfstoffen und antiviralen Arzneimitteln wird intensiv betrieben, mit der Zulassung entsprechender Präparate ist jedoch erst in einigen Jahren zu rechnen.
Reiseapotheke für die Tropen. Gesundbleiben bei Fernreisen ist mehr als Glück
Authors: Stich August
Published: December 2009

Die Sorge um ihre Gesundheit verfolgt viele bei den Vorbereitungen einer Tropenreise. Manch einer fürchtet, sich im Urlaub gegen Angriffe von Giftschlangen oder alle Arten exotischer Krankheitserreger wappnen zu müssen. Die meisten dieser Befürchtungen lassen sich leicht entkräften.
Direct visual control on cord coagulation using a fetoscopy‐guided bipolar forceps. Description of a new technique
Authors: Yamamoto Masami , Barki Gerard , Ville Yves
Published: December 2009

Objective

We describe a new technique to achieve permanent umbilical cord occlusion.

Methods

A 3 mm in diameter bipolar diathermy forceps was built to house a 1.2 mm fetoscope, emerging between the blades of the forceps. The device can be inserted percutaneously through a 10 Fr Trocar into the amniotic cavity under local analgesia and ultrasound guidance. A monochorionic (MC) twin pregnancy with a twin reversed arterial perfusion sequence at 18 weeks of gestation underwent cord occlusion of the acardiac twin using this new device in 2004.

Results

The instrument allowed cord coagulation under direct visual control. The pregnancy continued until 33 weeks of gestation when a male infant of 1980 g was delivered by cesarean section following preterm labor.

Conclusion

This new instrument might allow easier access to the cord and reduce operation time by direct visualization of the targe and, therefore, improve the outcome after the procedure. Copyright © 2009 John Wiley & Sons, Ltd.