bluuebunny/crossref_metadata_2025 huggingface dataset:
Discovery and Biological Activity of New Chondramides from Chondromyces sp.
Authors: Herrmann Jennifer , Hüttel Stephan , Müller Rolf
Published: August 2013

Myxobacteria have proven to be highly valuable sources of natural products, as they produce a variety of secondary metabolites with unique structures and often new modes of action. In this study, high‐content screening is demonstrated to be a convenient tool for bioactivity‐guided isolation of natural products from crude bacterial extracts. By the application of focused, image‐based screens we were able to identify over 30 novel chondramide derivatives from Chondromyces sp. MSr9030, some of which were present in only minute amounts. These cyclic depsipeptides were shown to target actin filaments with a similar binding mode to that of the mushroom toxin phalloidin. Fermentations of the myxobacterial strain were carried out under improved cultivation conditions, and supplementation of the culture broth with potassium bromide afforded the production of brominated analogues that are superior (in terms of biological activity) to all chondramides described to date. Initial biological profiling of 11 new derivatives in comparison to the reference compounds (chondramides A–C) showed that bromo‐chondramide C3 and propionyl‐bromo‐chondramide C3 are the most active in cell‐based studies, with GI50 values on human cancer cell lines in the low nanomolar range. Given that these brominated C3 analogues were also less potent on noncancerous human cells (by a factor of 2 to 4 in comparison to cancer cell lines), our results can aid further structure–activity relationship‐guided development of chondramides, either as molecular probes or pharmaceutical agents.
Effect of leptin on the gluconeogenesis in calf hepatocytes cultured in vitro
Authors: Li Yu , Li Xiaobing , Song Yuxiang , Shi Xiaoxia , Ding Hongyan , Yang Wentao , Liu Zhaoxi , Chen Hui , Li Xinwei , Wang Jianguo , Liu Guowen , Wang Zhe
Published: August 2013

We have investigated the effect of leptin on gluconeogenesis in the liver. Hepatocytes were cultured and treated with 0, 2.5, 5, 10, 50, 100 ng/mL of leptin in groups I, II, III, IV, V, and VI, respectively. mRNA expression and enzyme activity of pyruvate carboxylase and phosphoenolpyruvate carboxykinase were determined by real‐time fluorescence quantitative RT‐PCR and biochemical kits, respectively. Compared with group I, mRNA expression of pyruvate carboxylase and phosphoenolpyruvate carboxykinase in groups III, IV, V, and VI were significantly lower (P < 0.01). Pyruvate carboxylase and phosphoenolpyruvate carboxykinase enzyme activity decreased significantly (P < 0.05) when leptin concentration exceeded 5 and 10 ng/mL, respectively. These results indicate that leptin markedly downregulated mRNA expression and enzyme activity of pyruvate carboxylase and phosphoenolpyruvate carboxykinase in hepatocytes, which suggests that high concentrations of LP inhibit hepatocyte gluconeogenesis, thus making negative energy balance more serious.
A novel recombinant Salmonella vaccine enhances the innate immunity of NK cells against acute myeloid leukaemia cells Kasumi‐1 in vitro
Authors: Zhang Bei , Liu Yuan , Wang Xiuju , Jiang Ling , Lu Zhigang , Zhang Xing , Li Kunpeng , Hu Haiyan
Published: August 2013

Minor histocompatibility antigen HA‐1‐specific cytotoxic lymphocyte (CTL) clones have apparent anti‐leukaemic efficacy, and the AML/ETO gene is a special fusion gene in leukaemic cells. Thus, we hypothesised that a vaccine targeting HA‐1 and AML/ETO could stimulate NK cells to target leukaemia cells. Furthermore, we packaged the vaccine using attenuated Salmonella to enhance its immuno‐activity. Expression of the NK cell‐activating ligand ULBP2 was notably elevated upon packaging in a co‐recombinant group. An AML/ETO single plasmid gave the weakest vaccine. The level of miR‐182, which targets ULBP2, significantly decreased with increasing IFN‐γ and granzyme B in a co‐recombinant group. In summary, DNA vaccines including AML/ETO and HA‐1 fragments significantly enhance the innate immunity of NK cells in vitro.
Interaction between optineurin and the bZIP transcription factor NRL
Authors: Wang Chunxia , Hosono Katsuhiro , Ohtsubo Masafumi , Ohishi Kentaro , Gao Jie , Nakanishi Nobuo , Hikoya Akiko , Sato Miho , Hotta Yoshihiro , Minoshima Shinsei
Published: August 2013

Although the gene encoding optineurin (OPTN) is a causative gene for glaucoma and amyotrophic lateral sclerosis, it is ubiquitously expressed in all body tissues, including the retina. To study the function of OPTN in retinal ganglion cells as well as the whole retina, we previously isolated OPTN‐interacting proteins and identified the gene encoding the bZIP transcription factor neural retina leucine zipper (NRL), which is a causative gene for retinitis pigmentosa. Herein, we investigated the binding between OPTN and NRL proteins in HeLaS3 cells. Co‐expression of HA‐tagged NRL and FLAG‐tagged OPTN in HeLaS3 cells followed by immunoprecipitation and Western blotting with anti‐tag antibodies demonstrated the binding of these proteins in HeLaS3 cells, which was confirmed by proximity ligation assay. NRL is the first OPTN‐binding protein to show eye‐specific expression. A series of partial‐deletion OPTN plasmids demonstrated that the tail region (423–577 amino acids [aa]) of OPTN was necessary for binding with NRL. Immunostaining showed that Optn (rat homologue of OPTN) was expressed in rat photoreceptors and localised in the cytoplasm of photoreceptor cells. This is a novel demonstration of Optn expression in photoreceptor cells. OPTN was not detected in photoreceptor nuclei under our experimental conditions. Further analyses are necessary to elucidate the function of OPTN and the significance of its possible binding with NRL in photoreceptor cells.
Gadolinium(III)‐Hydroxy Ladders Trapped in Succinate Frameworks with Optimized Magnetocaloric Effect
Authors: Chen Yan‐Cong , Guo Fu‐Sheng , Zheng Yan‐Zhen , Liu Jun‐Liang , Leng Ji‐Dong , Tarasenko Róbert , Orendáč Martin , Prokleška Jan , Sechovský Vladimír , Tong Ming‐Liang
Published: August 2013

Two kinds of inorganic gadolinium(III)‐hydroxy “ladders”, [2×n] and [3×n], were successfully trapped in succinate (suc) coordination polymers, [Gd2(OH)2(suc)2(H2O)]n⋅ 2n H2O (1) and [Gd6(OH)8(suc)5(H2O)2]n⋅4n H2O (2), respectively. Such coordination polymers could be regarded as alternating inorganic–organic hybrid materials with relatively high density. Magnetic and heat capacity studies reveal a large cryogenic magnetocaloric effect (MCE) in both compounds, namely (ΔH=70 kG) 42.8 J kg−1 K−1 for complex 1 and 48.0 J kg−1 K−1 for complex 2. The effect of the high density is evident, which gives very large volumetric MCEs up to 120 and 144 mJ cm−3 K−1 for complexes 1 and 2, respectively.
Heteroleptic Alkyl and Amide Iminoanilide Alkaline Earth and Divalent Rare Earth Complexes for the Catalysis of Hydrophosphination and (Cyclo)Hydroamination Reactions
Authors: Liu Bo , Roisnel Thierry , Carpentier Jean‐François , Sarazin Yann
Published: August 2013

[{N^N}M(X)(thf)n] alkyl (X=CH(SiMe3)2) and amide (X=N(SiMe3)2) complexes of alkaline earths (M=Ca, Sr, Ba) and divalent rare earths (YbII and EuII) bearing an iminoanilide ligand ({N^N}−) are presented. Remarkably, these complexes proved to be kinetically stable in solution. X‐ray diffraction studies allowed us to establish size–structure trends. Except for one case of oxidation with [{N^N}YbII{N(SiMe3)2}(thf)], all these complexes are stable under the catalytic conditions and constitute effective precatalysts for the cyclohydroamination of terminal aminoalkenes and the intermolecular hydroamination and intermolecular hydrophosphination of activated alkenes. Metals with equal sizes across alkaline earth and rare earth families display almost identical apparent catalytic activity and selectivity. Hydrocarbyl complexes are much better catalyst precursors than their amido analogues. In the case of cyclohydroamination, the apparent activity decreases with metal size: Ca>Sr>Ba, and the kinetic rate law agrees with RCHA=k[precatalyst]1[aminoalkene]1. The intermolecular hydroamination and hydrophosphination of styrene are anti‐Markovnikov regiospecific. In both cases, the apparent activity increases with the ionic radius (Ca<Sr<Ba) but the rate laws are different, and obey RHA=k[styrene]1[amine]1[precatalyst]1 and RHP=k[styrene]1[HPPh2]0[precatalyst]1, respectively. Mechanisms compatible with the rate laws and kinetic isotopic effects are proposed. [{N^N}Ba{N(SiMe3)2}(thf)2] (3) and [{N^N}Ba{CH(SiMe3)2}(thf)2] (10) are the first efficient Ba‐based precatalysts for intermolecular hydroamination and hydrophosphination, and display activity values that are above those reported so far. The potential of the precatalysts for CN and CP bond formation is detailed and a rare cyclohydroamination–intermolecular hydroamination “domino” sequence is presented.
Synthesis, G‐Quadruplex Stabilisation, Docking Studies, and Effect on Cancer Cells of Indolo[3,2‐b]quinolines with One, Two, or Three Basic Side Chains
Authors: Lavrado João , Borralho Pedro M. , Ohnmacht Stephan A. , Castro Rui E. , Rodrigues Cecília M. P. , Moreira Rui , Santos Daniel J. V. A. dos , Neidle Stephen , Paulo Alexandra
Published: August 2013

G‐quadruplex (G4) DNA structures in telomeres and oncogenic promoter regions are potential targets for cancer therapy, and G4 ligands have been shown to modulate telomerase activity and oncogene transcription. Herein we report the synthesis and G4 thermal stabilisation effects, determined by FRET melting assays, of 20 indolo[3,2‐b]quinolines mono‐, di‐, and trisubstituted with basic side chains. Molecular modelling studies were also performed in an attempt to rationalise the ligands′ binding poses with G4. Overall, the results suggest that ligand binding and G4 DNA thermal stabilisation increase with an N5‐methyl or a 7‐carboxylate group and propylamine side chains, whereas selectivity between G4 and duplex DNA appears to be modulated by the number and relative position of basic side chains. From all the indoloquinoline derivatives studied, the novel trisubstituted compounds 3 d and 4 d, bearing a 7‐(aminoalkyl)carboxylate side chain, stand out as the most promising compounds; they show high G4 thermal stabilisation (ΔTm values between 17 and 8 °C) with an inter‐G4 ΔTm trend of Hsp90A>KRas21R≈F21T>c‐Kit2, 10‐fold selectivity for G4 over duplex DNA, and 100‐fold selectivity for the HCT116 cancer cell line (IC50 and IC90: <10 μM) over primary rat hepatocytes. Compounds 3 d and 4 d also decreased protein expression levels of Hsp90 and KRas in HCT116 cancer cells.
Highly Efficient Graphene‐Based Ternary Composite Catalyst with Polydopamine Layer and Copper Nanoparticles
Authors: Hu Hua‐Wen , Xin John H. , Hu Hong
Published: August 2013

A synergistically integrated graphene‐based ternary composite (rG‐Cu) consisting of uniform natural polydopamine (Pdop)‐functionalized graphene sheets (Dop‐rG) and well‐dispersed Cu nanoparticles (NPs) has been developed. By a one‐step reduction and modification of graphene oxide with dopamine, water‐dispersible Dop‐rG was first prepared. Cu NPs were then incorporated homogeneously onto Dop‐rG by a simple solution route leading to activated rG‐Cu, which showed an ultrahigh catalytic activity and good reusability for catalytic reductions of different types of dyes, including methylene blue and azo‐based acid and reactive dyes. It took only 30 s for complete reduction of methylene blue. In addition to the main action of the catalytically active component of the well‐dispersed Cu NPs, the uniform adhesive Pdop layer and graphene base with large surface area and superior electron‐transfer capacity are also believed to assist synergistically the catalytic reduction. The work has opened up a new avenue for synthesis of a graphene‐based ternary composite with extraordinary catalytic activity for practical applications in addressing environmental protection issues.
Dualism of Ion‐Pairing Effects in Nucleophilic Vinylic Substitution with Transition‐Metal Carbonyl Anions
Authors: Sazonov Petr K. , Beletskaya Irina P.
Published: August 2013

Ion pairing with cations has a marked but nonuniform effect on the chemistry of carbonylmetalate anions and can either inhibit or facilitate their reactions. A study of the effect of cation‐solvating agents ([18]crown‐6, hexamethylphosphoramide) on the reactions of carbonylmetalates [Na(K)][M(CO)nL] with vinyl halides activated with strong electron‐withdrawing groups, which at the same time could serve as hard donor centers for sodium or potassium cations is presented. The addition of a cation‐solvating agent to the solution in THF produced a sharp drop in the rate of the reactions of Na[Re(CO)5] or K[Mn(CO)5] with the vinyl chlorides studied; the effect (kobs(THF)/kobs(THF+[18]crown‐6)) increased along the series: PhCClC(CN)2 (4)<(Z)‐PhC(CN)CHCl (17)<PhCClC(CO2Et)2 (80)<(E)‐ClCHCHCO2Me (200). This strong cation assistance is contrasted by “normal” effects observed for the reaction of K[Mn(CO)5] with 1‐chloro‐2‐methyl perfluorocyclopentene, accelerated by [2.2.2]cryptand, as well as for the other fluorine‐activated vinyl halides studied previously. The characteristic increase in cation assistance effect in the order CO2R>CN≫CF allows us to explain assistance from cation coordination to the donor centers in these groups, which stabilizes the transition state. The effect of ion pairing is also dependent on the leaving group in the vinyl halide, almost disappearing for (Z)‐PhC(CN)CHBr, with only minor cation assistance observed for (E)‐PhCOCHCHI. This prompted us to examine the effect of the leaving group in the reactions of carbonylmetalates with Z and E isomers of Ph(CN)CCHHal (Hal=I, Br, Cl, or F).
Functionalized Porphyrins as Red Fluorescent Probes for Metal Cations: Spectroscopic, MALDI‐TOF Spectrometry, and Doped‐Polymer Studies
Authors: Moura Nuno M. M. , Nuñez Cristina , Santos Sérgio M. , Faustino M. Amparo F. , Cavaleiro José A. S. , Neves M. Graça P. M. S. , Capelo José Luis , Lodeiro Carlos
Published: August 2013

The sensing ability of benzoporphyrins1–5and porphyrin‐2‐ylpyridines6–10towards different metal ions Na+, K+, Ca2+, Mg2+, Pb2+, Cu2+, Ni2+, Zn2+, Cd2+, Hg2+, and Cr3+was explored in solution by absorption and fluorescence spectroscopy. Strong changes in the ground and excited state were detected only in the case of the soft metal ions Zn2+, Cd2+, Hg2+, and Cu2+. A one metal per ligand molar ratio was obtained in all cases for compounds 1–5. In addition, a remarkable increase of the emission intensity for1–5was observed in the presence of Hg2+. In this series the highest association constant was obtained for compound 1(log Kass=(8.71±4.81)×10−3), which was able to quantify 32 ppb of Hg2+. For compounds 6–10containing an additional pyridine unit, a metal‐to‐ligand stoichiometry of 1:2 was determined. The gas‐phase detection abilities of compounds 1–10using MALDI‐TOF‐MS spectrometry confirmed that their sensorial ability and theoretical calculations are in accordance with the stoichiometry observed. Our preliminary studies show that some of the compounds supported in polymethylmethacrylate (PMMA) films can be used as promising metal‐ion solid chemosensors; it was found that compound1in PMMA is able to distinguish between Zn2+and Hg2+in the solid phase.
Evidence for an Intermediate in the Methylation of CB11H12−with Methyl Triflate: Comparison of Electrophilic Substitution in Cage Boranes and in Arenes
Authors: Kaleta Jiří , Akdag Akin , Crespo Raül , Piqueras Mari‐Carmen , Michl Josef
Published: August 2013

The trideuteriomethylation of BH vertices in CB11H12−and its derivatives with CD3OTf (OTf=triflate, trifluoromethanesulfonate) yields a mixture of BCD3and BCHD2substitution products, thus demonstrating the intermediacy of a species with a long enough lifetime for hydrogen scrambling between the boron vertex and the methyl substituent. No such scrambling is observed if CD3OTf is used to methylate toluene. According to density functional theory calculations, the intermediate in BH vertex methylation is a three‐center bonded σ adduct of a methyl cation to the BH bond and the proton scrambling occurs via a transition structure containing a distorted square‐pyramidal methane attached axially to a “naked” boron vertex. The subsequent proton or deuteron loss is presently not understood in detail. A general comparison of electrophilic substitution oncloso‐boranes and arenes is provided and similarities as well as differences are discussed. A recalculation of the optimized geometry of the CB11Me12.radical produced a second Jahn–Teller distorted minimum and resulted in a somewhat improved agreement between calculated and measured proton hyperfine coupling constants.
Ambient and high‐pressure synthesis, composition, and crystal structure of B‐mullites
Authors: Lührs H. , Soellradl S. , King S. P. , Hanna J. V. , Konzett J. , Fischer R.X. , Schneider H.
Published: August 2013

The chemical compositions of several B‐doped mullite samples were analyzed using prompt gamma activation analyses (PGAA) indicating that 15% of the Si in the crystal structure of mullite can be replaced by B during sol‐gel synthesis at ambient pressure and 1200°C without the formation of impurities. Furthermore the PGAA results agree very well with the chemical compositions derived from Rietveld refinements based on neutron diffraction data. High‐pressure and high‐temperature synthesis yielded a B‐mullite with significantly higher B‐content than observed before (close to composition Al8Si2B2O19). The results of PGAA, XRD, and neutron diffraction experiments show linear behavior of lattice parameters b and c as well as of the inclination angle ω of the AlO6 octahedra in the ab‐plane with increasing B‐content. The Rietveld refinements support the substitution mechanism known for B‐mullites, involving the formation of oxygen vacancies and the replacement of 40% of the tetrahedral Si by BO3 units during the synthesis at 875°C and 10 kbar. However, the refined chemical composition as well as a very low lattice parameter a suggest a second mechanism for the incorporation of B into mullite. This is clearly supported by the 11B MAS NMR experiment indicating the presence of B in BO4 configuration but BO3 being dominant. Here for the first time a B‐mullite crystal structure is presented yielding BO3 and BO4 units in space group Pbam.
The elevated gene expression level of the A2B adenosine receptor is associated with hyperglycemia in women with gestational diabetes mellitus
Authors: Wojcik Marzena , Zieleniak Andrzej , Mac‐Marcjanek Katarzyna , Wozniak Lucyna A. , Cypryk Katarzyna
Published: August 2013

Background

Adenosine receptors denoted by A1, A2A, A2B, and A3 and encoded by ADORA1, ADORA2A, ADORA2B, and ADORA3 genes, respectively, are adenosine‐activated G‐protein‐coupled receptors that play an important role in obesity and type 2 diabetes mellitus. However, little is known about their significance in gestational diabetes mellitus (GDM). The purpose of this study was to investigate whether there are changes in leukocyte AR expression in GDM patients and whether these alterations are linked to well‐known diabetic genes.

Methods

Leukocytes were isolated from the blood of normal glucose tolerant (NGT; n = 35) and GDM (n = 82) pregnant women, and expression of ARs was determined by a semi‐quantitative polymerase chain reaction (PCR). Univariate correlation analysis was performed to investigate associations between expression of ARs and anthropometric and metabolic parameters of patients. Furthermore, the identification of diabetic genes linked to significantly differentiated leukocyte adenosine receptors expression in GDM women was also carried out with the use of the human diabetes RT2 profiler PCR arrays.

Results

ADORA2B mRNA expression was significantly higher in GDM versus NGT pregnant women (p < 0.05), and positively correlated with the glucose level at 1‐h 75‐g oral glucose tolerance test (OGTT; r = 0.21, p = 0.044). Nineteen diabetic genes linked to leukocyte ADORA2B overexpression associated with hyperglycemia in GDM women were also identified.

Conclusions

Maternal leukocyte ADORA2B overexpression is associated with hyperglycemia in GDM subjects, and it is accompanied by complex alterations in the expression of diabetes‐related genes involved in insulin action, carbohydrate and lipid metabolism, oxidative stress, and inflammation. Copyright © 2013 John Wiley & Sons, Ltd.
A Powerful Method for Combining P‐Values in Genomic Studies
Authors: Chen Huann‐Sheng , Pfeiffer Ruth M. , Zhang Shunpu
Published: August 2013

After genetic regions have been identified in genomewide association studies (GWAS), investigators often follow up with more targeted investigations of specific regions. These investigations typically are based on single nucleotide polymorphisms (SNPs) with dense coverage of a region. Methods are thus needed to test the hypothesis of any association in given genetic regions. Several approaches for combining P‐values obtained from testing individual SNP hypothesis tests are available. We recently proposed a sequential procedure for testing the global null hypothesis of no association in a region. When this global null hypothesis is rejected, this method provides a list of significant hypotheses and has weak control of the family‐wise error rate. In this paper, we devise a permutation‐based version of the test that accounts for correlations of tests based on SNPs in the same genetic region. Based on simulated data, the method has correct control of the type I error rate and higher or comparable power to other tests.
Numerical modeling of phase separation at Main Endeavour Field, Juan de Fuca Ridge
Authors: Singh Shreya , Lowell Robert P. , Lewis Kayla C.
Published: August 2013

Before being disrupted by a magmatic event in 1999, the vent temperatures and salinities along the axis of the Main Endeavour Field on the Juan de Fuca Ridge exhibited a quasi‐steady spatial gradient in which the southern vent fluids were hotter and less saline than the northern vent fluids. We present 2‐D numerical models of two phase flow in a NaCl‐H2O system to understand these gradients. We consider homogenous permeability models with a range of bottom boundary temperature distributions and heterogeneous permeability models by imposing layer 2A extrusives with a constant bottom boundary temperature distribution. The aim is to understand the impact of both bottom boundary temperature and layer 2A permeability on hydrothermal fluids and to determine what combination of these controlling factors could cause the observed trend. We find that variations in bottom boundary temperature alone cannot explain the span of surface temperatures and salinities measured at the Main Endeavour Field. Heterogeneous permeability within layer 2A that has higher overall permeability in the northern part of the vent field than the southern part can reproduce the observed north to south temperature gradient, but such a permeability distribution cannot reproduce the observed salinity gradient. We conclude that both deep‐seated heterogeneous permeability, perhaps localized by a fault zone, and a heterogeneous layer 2A are required to produce the trend of temperatures and salinities in vent fluids at the Main Endeavour Field prior to the 1999 event.
Modeling CO2 injection at Cranfield, Mississippi: Investigation of methane and temperature effects
Authors: Doughty Christine , Freifeld Barry M.
Published: August 2013

A large‐scale carbon dioxide (CO2) injection pilot is ongoing at Cranfield, Mississippi, in a saline aquifer with high dissolved methane (CH4) content, employing one injection well and two observation wells. The breakthrough of CH4 and CO2 at the observation wells provides insights to phase partitioning and the multipath nature of flow through the formation. Injected CO2 is cooler than the formation temperature, making temperature another useful observation. Simulations of the first year of CO2 injection were conducted with the numerical simulator TOUGH2 and the equation of state module EOS7C, which includes CO2, CH4, and H2O, using an axisymmetric model with layering based on well logs from the injection well. Although the simplification of an axisymmetric model precludes study of formation dip or lateral heterogeneity, its simple structure enables a focus on physical processes involving the phase partitioning of CH4 and CO2, and temperature effects. Field observations that the model reproduces include the arrival of a bank of free‐phase CH4 ahead of the main CO2 plume at each observation well, and non‐monotonic changes in CH4 and CO2 mole fraction as a function of time, suggesting that multiple distinct flow paths exist between the injection well and the observation wells, each with its own bank of free‐phase CH4 leading the CO2. Model results are compared with temperature observations made in the field with a Distributed Temperature Sensor (DTS) system, suggesting that a well‐defined thermal response reached the near observation well within the seven‐month monitoring period, but not the more distant observation well. © 2013 Society of Chemical Industry and John Wiley & Sons, Ltd
Type-1 hepatorenal syndrome associated with infections in cirrhosis: Natural history, outcome of kidney function, and survival
Authors: Barreto Rogelio , Fagundes Claudia , Guevara Mónica , Solà Elsa , Pereira Gustavo , Rodríguez Ezequiel , Graupera Isabel , Martín-Llahí Marta , Ariza Xavier , Cárdenas Andrés , Fernández Javier , Rodés Juan , Arroyo Vicente , Ginès Pere
Published: August 2013

Type-1 hepatorenal syndrome (HRS) is a common complication of bacterial infections in cirrhosis, but its natural history remains undefined. To assess the outcome of kidney function and survival of patients with type-1 HRS associated with infections, 70 patients diagnosed during a 6-year period were evaluated prospectively. Main outcomes were no reversibility of type-1 HRS during treatment of the infection and 3-month survival. Forty-seven (67%) of the 70 patients had no reversibility of type-1 HRS during treatment of the infection. [Correction to previous sentence added March 10, 2014, after first online publication: “Twenty-three (33%)” was changed to “Forty-;seven (67%).”] The main predictive factor of no reversibility of type-1 HRS was absence of infection resolution (no reversibility: 96% versus 48% in patients without and with resolution of the infection; P < 0.001). Independent predictive factors of no reversibility of type-1 HRS were age, high baseline serum bilirubin, nosocomial infection, and reduction in serum creatinine <0.3 mg/dL at day 3 of antibiotic treatment. No reversibility was also associated with severity of circulatory dysfunction, as indicated by more marked activity of the vasoconstrictor systems. In the whole series, 3-month probability of survival was only 21%. Factors associated with poor prognosis were baseline serum bilirubin, no reversibility of type-1 HRS, lack of resolution of the infection, and development of septic shock after diagnosis of type-1 HRS. Conclusion: Type-1 HRS associated with infections is not reversible in two-thirds of patients with treatment of infection only. No reversibility of type-1 HRS is associated with lack of resolution of the infection, age, high bilirubin, and no early improvement of kidney function and implies a poor prognosis. These results may help advance the management of patients with type-1 HRS associated with infections. (HEPATOLOGY 2014;59:1505-1513)
Dysbiosis Contributes to Fibrogenesis in the Course of Chronic Liver Injury in Mice
Authors: De Minicis Samuele , Rychlicki Chiara , Agostinelli Laura , Saccomanno Stefania , Candelaresi Cinzia , Trozzi Luciano , Mingarelli Eleonora , Facinelli Bruna , Magi Gloria , Palmieri Claudio , Marzioni Marco , Benedetti Antonio , Svegliati-Baroni Gianluca
Published: August 2013

Nonalcoholic fatty liver disease (NAFLD) may lead to hepatic fibrosis. Dietary habits affect gut microbiota composition, whereas endotoxins produced by Gram-negative bacteria stimulate hepatic fibrogenesis. However, the mechanisms of action and the potential effect of microbiota in the liver are still unknown. Thus, we sought to analyze whether microbiota may interfere with liver fibrogenesis. Mice fed control (CTRL) or high-fat diet (HFD) were subjected to either bile duct ligation (BDL) or CCl4 treatment. Previously gut-sterilized mice were subjected to microbiota transplantation by oral gavage of cecum content obtained from donor CTRL- or HFD-treated mice. Fibrosis, intestinal permeability, bacterial translocation, and serum endotoxemia were measured. Inflammasome components were evaluated in gut and liver. Microbiota composition (dysbiosis) was evaluated by Pyrosequencing. Fibrosis degree was increased in HFD+BDL versus CTRL+BDL mice, whereas no differences were observed between CTRL+CCl4 and HFD+CCl4 mice. Culture of mesenteric lymph nodes showed higher density of infection in HFD+BDL mice versus CTRL+BDL mice, suggesting higher bacterial translocation rate. Pyrosequencing revealed an increase in percentage of Gram-negative versus Gram-postive bacteria, a reduced ratio between Bacteroidetes and Firmicutes, as well as a dramatic increase of Gram-negative Proteobacteria in HFD+BDL versus CTRL+BDL mice. Inflammasome expression was increased in liver of fibrotic mice, but significantly reduced in gut. Furthermore, microbiota transplantation revealed more liver damage in chimeric mice fed CTRL diet, but receiving the microbiota of HFD-treated mice; liver damage was further enhanced by transplantation of selected Gram-negative bacteria obtained from cecum content of HFD+BDL-treated mice.

Conclusions :

Dietary habits, by increasing the percentage of intestinal Gram-negative endotoxin producers, may accelerate liver fibrogenesis, introducing dysbiosis as a cofactor contributing to chronic liver injury in NAFLD. (Hepatology 2014;59:1738–1749)
Identification of a novel, recurrent MBTD1‐CXorf67 fusion in low‐grade endometrial stromal sarcoma
Authors: Dewaele Barbara , Przybyl Joanna , Quattrone Anna , Finalet Ferreiro Julio , Vanspauwen Vanessa , Geerdens Ellen , Gianfelici Valentina , Kalender Zeynep , Wozniak Agnieszka , Moerman Philippe , Sciot Raf , Croce Sabrina , Amant Frederic , Vandenberghe Peter , Cools Jan , Debiec‐Rychter Maria
Published: August 2013

Endometrial stromal sarcomas (ESSs) are a genetically heterogeneous group of rare uterine neoplasms that are commonly driven by recurrent gene rearrangements. In conventional low‐grade ESS, JAZF1‐SUZ12, PHF1‐JAZF1, EPC1‐PHF1 and MEAF6‐PHF1, and recently described ZC3H7‐BCOR chimeric fusions have been reported in > 50% of cases. Conversely, oncogenic t(10;17)(q22;p13) translocation yields YWHAE‐FAM22A/B chimeric proteins that are associated with histologically high‐grade and clinically more aggressive ESS. Integrating whole‐transcriptome paired‐end RNA sequencing with fluorescence in situ hybridization (FISH) and banding cytogenetics, we identified MBTD1 (malignant brain tumor domain‐containing 1) and CXorf67 (chromosome X open reading frame 67) as the genes involved in the novel reciprocal t(X;17)(p11.2;q21.33) translocation in two independent low‐grade ESS of classical histology. The presence of the MBTD1‐CXorf67 fusion transcript was validated in both cases using reverse‐transcription polymerase chain reaction followed by Sanger sequencing. A specific FISH assay was developed to detect the novel t(X;17) translocation in formalin‐fixed paraffin‐embedded material, and resulted in identification of an additional low‐grade ESS case positive for the MBTD1‐CXorf67 fusion among 25 uterine stromal tumors [14 ESS and 11 undifferentiated endometrial sarcomas (UESs)] that were negative for JAZF1 and YWHAE rearrangements. Gene expression profiles of seven ESS (including three with YWHAE and two with JAZF1 rearrangements) and four UES without specific chromosomal aberrations indicated clustering of tumors with MBTD1‐CXorf67 fusion together with low‐grade JAZF1‐associated ESS. The chimeric MBTD1‐CXorf67 fusion identifies yet another cytogenetically distinct subgroup of low‐grade ESS and offers the opportunity to shed light on the functions of two poorly characterized genes.
A study of embryonic stem cell‐related proteins in human astrocytomas: Identification of Nanog as a predictor of survival
Authors: Elsir Tamador , Edqvist Per‐Henrik , Carlson Joseph , Ribom Dan , Bergqvist Michael , Ekman Simon , Popova Svetlana N. , Alafuzoff Irina , Ponten Fredrik , Nistér Monica , Smits Anja
Published: August 2013

Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low‐grade (WHO Grade II) and 98 high‐grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC‐related proteins Nanog, Klf4, Oct4, Sox2 and c‐Myc by immunohistochemistry. While similar patterns of co‐expressed proteins between low‐ and high‐grade gliomas were present, we found up‐regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high‐grade gliomas. Survival analysis by Kaplan‐Meier analysis revealed a significant shorter survival in the subgroups of low‐grade astrocytomas (n = 42) with high levels of Nanog protein (p = 0.0067) and of Klf4 protein (p = 0.0368), in high‐grade astrocytomas (n = 85) with high levels of Nanog (p = 0.0042), Klf4 (p = 0.0447), and c‐Myc (p = 0.0078) and in glioblastomas only (n = 71) with high levels of Nanog (p = 0.0422) and of c‐Myc (p = 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low‐grade astrocytomas (p = 0.0039), high‐grade astrocytomas (p = 0.0124) and glioblastomas only (p = 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC‐related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.
Phosphatidylinositol‐3‐kinase pathway aberrations in gastric and colorectal cancer: Meta‐analysis, co‐occurrence and ethnic variation
Authors: Chong Mei‐Ling , Loh Marie , Thakkar Bhavin , Pang Brendan , Iacopetta Barry , Soong Richie
Published: August 2013

Inhibition of the phosphatidylinositol‐3‐kinase (PI3K) signaling pathway is a cancer treatment strategy that has entered into clinical trials. We performed a meta‐analysis on the frequency of prominent genetic (PIK3CA mutation, PIK3CA amplification and PTEN deletion) and protein expression (high PI3K, PTEN loss and high pAkt) aberrations in the PI3K pathway in gastric cancer (GC) and colorectal cancer (CRC). We also performed laboratory analysis to investigate the co‐occurrence of these aberrations. The meta‐analysis indicated that East Asian and Caucasian GC patients differ significantly for the frequencies of PIK3CA Exon 9 and 20 mutations (7% vs. 15%, respectively), PTEN deletion (21% vs. 4%) and PTEN loss (47% vs. 78%), while CRC patients differed for PTEN loss (57% vs. 26%). High study heterogeneity (I2 > 80) was observed for all aberrations except PIK3CA mutations. Laboratory analysis of tumors from East Asian patients revealed significant differences between GC (n = 79) and CRC (n = 116) for the frequencies of PIK3CA amplification (46% vs. 4%) and PTEN loss (54% vs. 78%). The incidence of GC cases with 0, 1, 2 and 3 concurrent aberrations was 14%, 52%, 27% and 8%, respectively, while for CRC it was 10%, 60%, 25% and 4%, respectively. Our study consolidates knowledge on the frequency, co‐occurrence and clinical relevance of PI3K pathway aberrations in GC and CRC. Up to 86% of GC and 90% of CRC have at least one aberration in the PI3K pathway, and there are significant differences in the frequencies of these aberrations according to cancer type and ethnicity.
Electronic nose can discriminate colorectal carcinoma and advanced adenomas by fecal volatile biomarker analysis: proof of principle study
Authors: de Meij Tim G. , Larbi Ilhame Ben , van der Schee Marc P. , Lentferink Yvette E. , Paff Tamara , Terhaar sive Droste Jochim S. , Mulder Chris J. , van Bodegraven Adriaan A. , de Boer Nanne K.
Published: August 2013

In the course and prognosis of colorectal cancer (CRC), early detection and treatment are essential factors. Fecal immunochemical tests (FITs) are currently the most commonly used non‐invasive screening tests for CRC and premalignant (advanced) adenomas, however, with restricted sensitivity. We hypothesized that fecal volatile organic compounds (VOCs) may serve as a diagnostic biomarker of CRC and adenomas. In this proof of concept study, we aimed to assess disease‐specific VOC smellprints in fecal gas to distinguish patients with CRC and advanced adenomas from healthy controls. Fecal samples of patients who were scheduled to undergo an elective colonoscopy were collected. An electronic nose (Cyranose 320®) was used to measure VOC patterns in fecal gas from patients with histopathologically proven CRC, with advanced adenomas and from controls (no abnormalities seen at colonoscopy). Receiver operator characteristic curves and corresponding sensitivity and specificity for detection of CRC and advanced adenomas were calculated. A total of 157 stool samples (40 patients with CRC, 60 patients with advanced adenomas, and 57 healthy controls) were analyzed by electronic nose. Fecal VOC profiles of patients with CRC differed significantly from controls (area under curve ± 95%CI, p‐value, sensitivity, specificity; 0.92 ± 0.03, <0.001, 85%, 87%). Also VOC profiles of patients with advanced adenomas could be discriminated from controls (0.79 ± 0.04, <0.001, 62%, 86%). The results of this proof of concept study suggest that fecal gas analysis by an electronic nose seems to hold promise as a novel screening tool for the (early) detection of advanced neoplasia and CRC.
PIAS3 activates the intrinsic apoptotic pathway in non‐small cell lung cancer cells independent of p53 status
Authors: Dabir Snehal , Kluge Amy , McColl Karen , Liu Yu , Lam Minh , Halmos Balazs , Wildey Gary , Dowlati Afshin
Published: August 2013

Protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3) (PIAS3) is an endogenous inhibitor of STAT3 that negatively regulates STAT3 transcriptional activity and cell growth and demonstrates limited expression in the majority of human squamous cell carcinomas of the lung. In this study, we sought to determine whether PIAS3 inhibits cell growth in non‐small cell lung cancer cell lines by inducing apoptosis. Our results demonstrate that overexpression of PIAS3 promotes mitochondrial depolarization, leading to cytochrome c release, caspase 9 and 3 activation and poly (ADP‐ribose) polymerase cleavage. This intrinsic pathway activation was associated with decreased Bcl‐xL expression and increased Noxa expression and was independent of p53 status. Furthermore, PIAS3 inhibition of STAT3 activity was also p53 independent. Microarray experiments were performed to discover STAT3‐independent mediators of PIAS3‐induced apoptosis by comparing the apoptotic gene expression signature induced by PIAS3 overexpression with that induced by STAT3 siRNA. The results showed that a subset of apoptotic genes was uniquely expressed only after PIAS3 expression. Thus, PIAS3 may represent a promising lung cancer therapeutic target because of its p53‐independent efficacy and its potential to synergize with Bcl‐2 targeted inhibitors.
The recolonization of the river Elbe with benthic and hyporheic Ostracoda (Crustacea) after the reunion of Germany in 1989
Authors: Scharf Burkhard , Brunke Matthias
Published: August 2013

In the year 2000, the benthic and hyporheic ostracod species were investigated in the groynes and the groyne fields of the river Elbe. In total only 12 species were found. The low number of species is owing to the few mesohabitats that occurred in the channel that was altered for navigation purposes, and that the river was severely polluted in the past, which led to an extinction of most species. Since about 1992 the Elbe is in a continuing phase of recolonization. Remarkably, the juveniles of the two species Pseudocandona albicans and Limnocythere inopinata occurred predominantly in the hyporheal within gravel of subaqueous dunes.
HSF1 and Sp1 Regulate FUT4 Gene Expression and Cell Proliferation in Breast Cancer Cells
Authors: Yang Xuesong , Wang Jiao , Liu Shuiai , Yan Qiu
Published: August 2013

Lewis Y (LeY) is a carbohydrate tumor‐associated antigen. The majority of cancer cells derived from epithelial tissues express LeY type difucosylated oligosaccharides. Fucosyltransferase IV (FUT4) is an essential enzyme that catalyzes the synthesis of LeY oligosaccharides. In a previous study we reported that FUT4 is associated with cell proliferation; however, despite the important role of FUT4 in cancer proliferation and apoptosis, little is known about the mechanisms underlying the regulation of FUT4 transcription. In the current study we investigated the regulation of FUT4 transcription in human breast cancer. We compared the regulation of human FUT4 gene transcription in human breast cancer cells (MCF‐7 and MDA‐MB‐231) using promoter/luciferase analyses. Using a series of promoter deletion constructs, we identified a potential regulatory site located between 0.8 and 1.6 kb of the FUT4 promoter. As shown by EMSA and ChIP analyses, heat‐shock factor 1 (HSF1) and Sp1are required for FUT4 promoter activity. In addition, we explored the role of HSF1 and Sp1 on cell proliferation, and found that the ERK1/2 MAPK and PI3K/Akt signaling pathways regulate the expression of FUT4, which play a role in cell proliferation via HSF1 and Sp1. These results suggest that FUT4 is a target gene for HSF1 and Sp1 that is required for cell cycle progression in breast cancer epithelial cells. J. Cell. Biochem. 115: 168–178, 2014. © 2013 Wiley Periodicals, Inc.
Neuroprotective Activity of pDING in Response to HIV‐1 Tat
Authors: Darbinian Nune , Khalili Kamel , Amini Shohreh
Published: August 2013

Although neurons are not productively infected with HIV‐1, neuronal injury and death are frequently seen in the brains of AIDS patients with neurological and neurocognitive disorders. Evidently, viral proteins including Tat and cellular inflammatory factors released by activated and/or infected microglia, macrophages, and astrocytes contribute to neuronal cell death. Several studies have demonstrated that HIV‐1 associated neuronal cell injury is mediated by dysregulation of signaling pathways that are controlled, in part, by a class of serine/threonine kinases. In this study, we demonstrate that pDING, a novel plant‐derived phosphate binding protein has the capacity to reduce the severity of injury and death caused by HIV‐1 and its neurotoxic Tat protein. We demonstrate that pDING, also called p27SJ/p38SJ, protects cells from the loss of neuronal processes induced by Tat and promotes neuronal outgrowth after Tat‐mediated injury. Further, expression of pDING prevents Tat‐induced oxidative stress and mitochondrial permeability. With its profound phosphatase activity, pDING controls the activity of several kinases including MAPK, Cdk5, and their downstream target protein, MEF2, which is implicated in neuronal cell protection. Our results show that expression of pDING in neuronal cells diminishes the level of hyperphosphorylated forms of Cdk5 and MEF2 caused by Tat and the other neurotoxic agents that are secreted by the HIV‐1 infected cells. These observations suggest that pDING, through its phosphatase activity, has the ability to manipulate the state of phosphorylation and activity of several factors involved in neuronal cell health in response to HIV‐1. J. Cell. Physiol. 229: 153–161, 2014. © 2013 Wiley Periodicals, Inc.
Kelvin‐Helmholtz instability of the magnetospheric boundary in a three‐dimensional global MHD simulation during northward IMF conditions
Authors: Merkin V. G. , Lyon J. G. , Claudepierre S. G.
Published: August 2013

We present results of a global, fully three‐dimensional, high‐resolution magnetohydrodynamic (MHD) simulation of the magnetosphere during steady northward interplanetary magnetic field (IMF) conditions. We investigate the stability of the magnetospheric boundary with respect to the growth of the Kelvin‐Helmholtz instability (KHI) driven by the velocity shear between the nearly stagnant magnetospheric plasma and the magnetosheath flow past it. We find the magnetospheric boundary to be globally unstable, including the high‐latitude boundary layer (meridional plane), where magnetic tension is not sufficient to stabilize the growth of oscillations. Roughly beyond the terminator, global modes coupled into the surface modes become most apparent, so that the entire body of the magnetosphere is engaged in an oscillatory motion. The wave vector of the surface oscillations has a component perpendicular to the background flow and tangential to the shear layer (in the equatorial plane, kz component of the wave vector), which is consistent with the generation of field‐aligned currents that flow on closed field lines between the inner portion of the boundary layer and the ionosphere. The distribution of wave power in the equatorial plane is consistent with the existence of a double‐vortex sheet, with vortex trains propagating along the inner and outer edges of the boundary layer. The double‐vortex sheet is most apparent in the simulation past the terminator plane but is transient and appears to be unstable and is most likely a consequence of nonlinear development of the velocity shear layer with a finite width. For the simulation with the solar wind velocity of 600 km/s, we find the width of the layer to be Δ≈1 RE at the terminator and the phase speed there to be similar to half of the total velocity drop across the layer (∼440 km/s), which is expected for a shear layer with uniform background density. We calculate the spatial growth rate for the dominant frequency mode in this region (∼4.4 mHz) to be ∼0.19RE−1, which is in excellent agreement with linear theory. For this mode, we find kΔ≈0.9, where k is the wave number, which corresponds to the fastest growing mode predicted by the linear theory. Finally, we find that the plasma compressibility is a key factor in controlling the growth rate of the KHI at the magnetosphere flanks in our simulation.
Influence of the Orinoco River on the primary production of eastern Caribbean surface waters
Authors: López Ramón , López José M. , Morell Julio , Corredor Jorge E. , Del Castillo Carlos E.
Published: August 2013

Key Points

River plume increases primary production of eastern Caribbean waters.

Climate fluctuations are observed in remote sensed primary production.

River plume coverage and seasonality influences primary production gradients.
Eddy energy sources and sinks in the South China Sea
Authors: Yang Haiyuan , Wu Lixin , Liu Hailong , Yu Yongqiang
Published: August 2013

The eddy energy sources and sinks in the South China Sea (SCS) are studied based on a high‐resolution ocean circulation model. Eddies are found to acquire their energy from barotropic instability (BT), the release of available potential energy (APE) associated with baroclinic instability (BC) and horizontal convergence from surrounding areas, while they lose energy due to turbulent processes. Both the eddy energy sources and sinks show western intensification with their maximum around the southwestern SCS where most of the wind‐input energy occurs, and the Luzon Strait where the Kuroshio intrudes the SCS in winter. Unlike that in the open ocean, the eddy energy in the inner SCS is confined to the upper layer. Besides, the eddy energy indicates clear seasonal variability, especially at the Luzon Strait where the eddy activity is much stronger in winter than in summer. Energy budget analysis suggests that APE releasing is found to be the most important eddy energy source, accounting for over 60% of the total, followed by energy convergence from surrounding areas in horizontal direction (around 20%) and energy released from BT (around 15%). Most of the generated energy is mainly balanced by the turbulent processes, while both of the downward energy flux and tendency term are negligible.