bluuebunny/crossref_metadata_2025 huggingface dataset:
XLP1 inhibitory effect by 2B4 does not affect DNAM‐1 and NKG2D activating pathways in NK cells
Authors: Meazza Raffaella , Tuberosa Claudia , Cetica Valentina , Falco Michela , Loiacono Fabrizio , Parolini Silvia , Micalizzi Concetta , Moretta Alessandro , Mingari Maria C. , Moretta Lorenzo , Bottino Cristina , Aricò Maurizio , Pende Daniela
Published: February 2014

X‐linked lymphoproliferative disease 1 (XLP1) is a rare congenital immunodeficiency caused by SH2D1A (Xq25) mutations resulting in lack or dysfunction of SLAM‐associated protein adaptor molecule. In XLP1 patients, upon ligand (CD48) engagement, 2B4 delivers inhibitory signals that impair the cytolytic activity of NK (and T) cells. This causes the selective inability to control EBV infections and the occurrence of B‐cell lymphomas. Here, we show that in the absence of SLAM‐associated protein, co‐engagement of 2B4 with different activating receptors, either by antibodies or specific ligands on target cells, inhibits different ITAM‐dependent signaling pathways including activating killer Ig‐like receptors. In XLP1 NK cells, 2B4 affected both the cytolytic and IFN‐γ production capabilities, functions that were restored upon disruption of the 2B4/CD48 interactions. Notably, we provide evidence that 2B4 dysfunction does not affect the activity of DNAM‐1 and NKG2D triggering receptors. Thus, while CD48+ B‐EBV and lymphoma B cells devoid of NKG2D and DNAM‐1 ligands were resistant to lysis, the preferential usage of these receptors allowed XLP1 NK cells to kill lymphomas that expressed sufficient amounts of the specific ligands. The study sheds new light on the XLP1 immunological defect and on the cross‐talk of inhibitory 2B4 with triggering NK (and T) receptors.
Speciation Behavior of Copper(II) Acetate in Simple Organic Solvents – Revealing the Effect of Trace Water
Authors: Tsybizova Alexandra , Ryland Bradford L. , Tsierkezos Nikos , Stahl Shannon S. , Roithová Jana , Schröder Detlef
Published: February 2014

Copper(II) acetate is frequently used as a catalyst for bond‐forming reactions in organic synthesis. Unlike aqueous solutions, in which complete heterolysis to CuOAc+(aq) and AcO–(aq) prevails at low concentrations, it is clear that copper(II) acetate shows a large degree of aggregation in typical organic solvents. Here, the speciation behavior of Cu(OAc)2 in organic solvents is probed by electrospray ionization mass spectrometry (ESI‐MS), which reveals an extensive clustering of copper acetate species to form ions of the general composition [Cun(X)2n–1]+ and [Cun(X)2n+1]– (X = OAc and OCH3), along with (solvated) monomeric species such as [Cu(OAc)(CH3OH)n]+. The ESI‐MS measurements are complemented by solution‐phase studies of Cu(OAc)2 by electron paramagnetic resonance spectroscopy, which support an extensive aggregation of Cu(OAc)2 in organic solvents. Collisional experiments reveal that either simple degradation or redox processes can be observed, depending on the coordinative saturation of the copper clusters. The formation of the copper clusters can be efficiently suppressed by contamination of the organic solvents by a small amount of water.
Chlorine Atom Transfer Radical 6‐exo Cyclizations of Carbamoyldichloroacetate‐Tethered Alkenes, Enol Acetates and α,β‐Unsaturated Nitriles Leading to Morphans
Authors: Diaba Faïza , Martínez‐Laporta Agustín , Bonjoch Josep
Published: February 2014

The CuI‐mediated atom transfer radical cyclization of amino‐tethered dichloromalonamides and electron‐rich, electron‐poor, and nonactivated double bonds is a useful methodology for the synthesis of 2‐azabicyclo[3.3.1]nonanes. A study of the reaction conditions and the scope of the process is reported. Cyclopropane ring formation was observed from the resulting 1,3‐dichlorides in some morphan substrates using either CuI, Pd, or Zn.
Self‐Folded Silyl Cavitands with In‐ and Outwardly Directed Allyl Groups
Authors: Ohashi Kazuhiro , Ito Kouhei , Iwasawa Tetsuo
Published: February 2014

Cavitands endowed with in‐ and outwardly directed allylsilanes are described; epoxidation reactions of the allyl groups with meta‐chloroperbenzoic acid are included. The synthesis of introverted and extroverted allylsilanes tethered to triquinoxaline‐spanned resorcinarenes was successfully achieved. Competitive epoxidation experiments between the two isomers disclosed that the introverted allyl was more reactive than the extroverted allyl, despite a clearly congested nuisance: the vase‐formed cavity would actively stabilize the reaction process.
Development of an efficient statistical volumes of fluid–Lagrangian particle tracking coupling method
Authors: Grosshans H. , Szász R.‐Z. , Fuchs L.
Published: February 2014

The breakup of a liquid jet into irregular liquid structures and droplets leading to the formation of a dilute spray has been simulated numerically. To overcome the shortcomings of certain numerical methods in specific flow regimes, a combined approach has been chosen. The intact liquid core, its primary breakup and the dense spray regime are simulated using the volumes of fluid (VOF) method in combination with LES, whereas the Lagrangian particle tracking (LPT) approach in the LES context is applied to the dilute spray regime and the secondary breakup of droplets. A method has been developed to couple both simulation types on a statistical basis. This statistical coupling approach (SCA) reflects the dominating physical mechanisms of the two‐phase flow in each regime to a high degree. The main benefit of the SCA is computational efficiency as compared with the more straightforward approach where one follows each structure, denoted here as the direct coupling approach. The computational benefits stem from the reduction of computational time since the VOF simulation is run only until statistical convergence and not during the whole spray development. A second benefit using the SCA is the possibility to use the stochastic parcel method in the LPT simulation whereby a large number of droplets may be handled. The coupling approach is applied to the atomization of a fuel jet in a high pressure chamber, demonstrating the gain of efficiency of the SCA as compared with direct coupling approach. Copyright © 2014 The Authors. International Journal for Numerical Methods in Fluids published by John Wiley & Sons Ltd.
Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome
Authors: Volkert Sarah , Kohlmann Alexander , Schnittger Susanne , Kern Wolfgang , Haferlach Torsten , Haferlach Claudia
Published: February 2014

We analyzed 1,200 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a 5q deletion in order to clarify whether the type of 5q loss is associated with other biological markers and prognosis. We investigated all patients by chromosome banding analysis, FISH with a probe for EGR1 (5q31) and, if necessary, to resolve complex karyotypes with 24‐color‐FISH. Moreover, 420 patients were analyzed for mutations in the TP53 gene. The patient cohort was subdivided based on type of 5q loss: Patients with interstitial deletions and patients with 5q loss due to unbalanced rearrangements or monosomy 5. Loss of the long arm of chromosome 5 due to an unbalanced rearrangement occurred more often in AML (286/627; 45.6%) than MDS (188/573; 32.8%; P < 0.001). In both entities, patients with 5q loss due to unbalanced translocations showed complex karyotypes more frequently (MDS: 179/188; 95.2% vs. 124/385; 32.2%; P < 0.001; AML: 274/286; 95.8% vs. 256/341; 75.1%; P < 0.001). Moreover, in MDS unbalanced 5q translocations were associated with clonal evolution (109/188; 58.0% vs. 124/385; 32.2%; P < 0.001), mutation of TP53 (64/67; 95.5% vs. 40/120; 40.0%; P < 0.001), and shorter survival (15.3 months vs. not reached; P < 0.001). In MDS, complex karyotype was an independent adverse prognostic factor (HR = 5.34; P = 0.032), whereas in AML presence of TP53 mutations was the strongest adverse prognostic factor (HR = 2.21; P = 0.026). In conclusion, in AML and MDS, loss of the long arm of chromosome 5 due to unbalanced translocations is associated with complex karyotype and in MDS, moreover, with clonal evolution, mutations in the TP53 gene and adverse prognosis. © 2014 Wiley Periodicals, Inc.
Universal Public Finance of Tuberculosis Treatment in India: An Extended Cost‐Effectiveness Analysis
Authors: Verguet Stéphane , Laxminarayan Ramanan , Jamison Dean T.
Published: February 2014

Universal public finance (UPF)—government financing of an intervention irrespective of who is receiving it—for a health intervention entails consequences in multiple domains. First, UPF increases intervention uptake and hence the extent of consequent health gains. Second, UPF generates financial consequences including the crowding out of private expenditures. Finally, UPF provides insurance either by covering catastrophic expenditures, which would otherwise throw households into poverty or by preventing diseases that cause them. This paper develops a method—extended cost‐effectiveness analysis (ECEA)—for evaluating the consequences of UPF in each of these domains. It then illustrates ECEA with an evaluation of UPF for tuberculosis treatment in India. Using plausible values for key parameters, our base case ECEA concludes that the health gains and insurance value of UPF would accrue primarily to the poor. Reductions in out‐of‐pocket expenditures are more uniformly distributed across income quintiles. A variant on our base case suggests that lowering costs of borrowing for the poor could potentially achieve some of the health gains of UPF, but at the cost of leaving the poor more deeply in debt. © 2014 The Authors. Health Economics published by John Wiley Ltd.
Plasmacytoid Dendritic Cell-Derived IFN-α Promotes Murine Liver Ischemia/Reperfusion Injury by Induction of Hepatocyte IRF-1
Authors: Castellaneta Antonino , Yoshida Osamu , Kimura Shoko , Yokota Shinichiro , Geller David A. , Murase Noriko , Thomson Angus W.
Published: February 2014

Plasmacytoid dendritic cells (pDC) constitute the body's principal source of type I interferon (IFN) and are comparatively abundant in the liver. Among various cytokines implicated in liver ischemia and reperfusion (I/R) injury, type I IFNs have been described recently as playing an essential role in its pathogenesis. Moreover, type I IFNs have been shown to up-regulate hepatocyte expression of IFN regulatory factor 1 (IRF-1), a key transcription factor that regulates apoptosis and induces liver damage after I/R. Our aim was to ascertain the capacity of IFN-α released by liver pDC to induce liver damage through hepatic IRF-1 up-regulation after I/R injury. Our findings show that liver pDC mature and produce IFN-α in response to liver I/R. Liver pDC isolated after I/R induced elevated levels of IRF-1 production by hepatocytes compared with liver pDC isolated from sham-operated mice. Notably, hepatic IRF-1 expression was reduced significantly by neutralizing IFN-α.

In vivo,

IFN-α neutralization protected the liver from I/R injury by reducing hepatocyte apoptosis. This was associated with impaired expression of IRF-1 and proapoptotic molecules such as Fas ligand, its receptor (Fas) and death receptor 5, which are regulated by IRF-1. Furthermore, pDC-depleted mice failed to up-regulate hepatic IFN-α and displayed less liver injury associated with reduced levels of hepatic interleukin (IL)-6, tumor necrosis factor-α, and hepatocyte apoptosis after I/R compared with controls.

Conclusion :

these data support the hypothesis that IFN-α derived from liver pDC plays a key role in the pathogenesis of liver I/R injury by enhancing apoptosis as a consequence of induction of hepatocyte IRF-1 expression. (Hepatology 2014;60:267–277)
Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation: Potential therapeutic target for liver injury
Authors: Li Ting , Eheim Ashley L. , Klein Sabine , Uschner Frank E. , Smith Amber C. , Brandon-Warner Elizabeth , Ghosh Sriparna , Bonkovsky Herbert L. , Trebicka Jonel , Schrum Laura W.
Published: February 2014

Hepatic stellate cell (HSC) transdifferentiation from a quiescent, adipocyte-like cell to a highly secretory and contractile myofibroblast-like phenotype contributes to negative pathological consequences, including fibrosis/cirrhosis with portal hypertension (PH). Antiadipogenic mechanisms have been shown to underlie activation of HSCs. We examined the role of heme-sensing nuclear receptor Rev-erbα, a transcriptional repressor involved in metabolic and circadian regulation known to promote adipogenesis in preadipocytes, in HSC transdifferentiation. We discovered that Rev-erbα protein was up-regulated in activated HSCs and injured livers; however, transcriptional repressor activity was not affected by fibrogenic treatments. Surprisingly, increased protein expression was accompanied with increased cytoplasmic accumulation of Rev-erbα, which demonstrated distributions similar to myosin, the major cellular motor protein. Cells overexpressing a cytoplasm-localized Rev-erbα exhibited enhanced contractility. Ectopically expressed Rev-erbα responded to both adipogenic ligand and fibrogenic transforming growth factor beta treatment. Rev-erb ligand SR6452 down-regulated cytoplasmic expression of Rev-erbα, decreased expression of fibrogenic markers and the activated phenotype in HSCs, and ameliorated fibrosis and PH in rodent models. Conclusions: Up-regulation of Rev-erbα is an intrinsic fibrogenic response characterized by cytoplasmic accumulation of the protein in activated HSCs. Cytoplasmic expression of Rev-erbα promotes a contractile phenotype. Rev-erbα acts as a bifunctional regulator promoting either anti- or profibrogenic response, depending on milieu. Rev-erb ligand SR6452 functions by a previously undescribed mechanism, targeting both nuclear activity and cytoplasmic expression of Rev-erbα. Our studies identify Rev-erbα as a novel regulator of HSC transdifferentiation and offers exciting new insights on the therapeutic potential of Rev-erb ligands. (Hepatology 2014;59:2383–2396)
Human bile contains MicroRNA-laden extracellular vesicles that can be used for cholangiocarcinoma diagnosis
Authors: Li Ling , Masica David , Ishida Masaharu , Tomuleasa Ciprian , Umegaki Sho , Kalloo Anthony N. , Georgiades Christos , Singh Vikesh K. , Khashab Mouen , Amateau Stuart , Li Zhiping , Okolo Patrick , Lennon Anne-Marie , Saxena Payal , Geschwind Jean-Francois , Schlachter Todd , Hong Kelvin , Pawlik Timothy M. , Canto Marcia , Law Joanna , Sharaiha Reem , Weiss Clifford R. , Thuluvath Paul , Goggins Michael , Shin Eun Ji , Peng Haoran , Kumbhari Vivek , Hutfless Susan , Zhou Liya , Mezey Esteban , Meltzer Stephen J. , Karchin Rachel , Selaru Florin M.
Published: February 2014

Cholangiocarcinoma (CCA) presents significant diagnostic challenges, resulting in late patient diagnosis and poor survival rates. Primary sclerosing cholangitis (PSC) patients pose a particularly difficult clinical dilemma because they harbor chronic biliary strictures that are difficult to distinguish from CCA. MicroRNAs (miRs) have recently emerged as a valuable class of diagnostic markers; however, thus far, neither extracellular vesicles (EVs) nor miRs within EVs have been investigated in human bile. We aimed to comprehensively characterize human biliary EVs, including their miR content. We have established the presence of extracellular vesicles in human bile. In addition, we have demonstrated that human biliary EVs contain abundant miR species, which are stable and therefore amenable to the development of disease marker panels. Furthermore, we have characterized the protein content, size, numbers, and size distribution of human biliary EVs. Utilizing multivariate organization of combinatorial alterations (MOCA), we defined a novel biliary vesicle miR-based panel for CCA diagnosis that demonstrated a sensitivity of 67% and specificity of 96%. Importantly, our control group contained 13 PSC patients, 16 with biliary obstruction of varying etiologies (including benign biliary stricture, papillary stenosis, choledocholithiasis, extrinsic compression from pancreatic cysts, and cholangitis), and 3 with bile leak syndromes. Clinically, these types of patients present with a biliary obstructive clinical picture that could be confused with CCA. Conclusion: These findings establish the importance of using extracellular vesicles, rather than whole bile, for developing miR-based disease markers in bile. Finally, we report on the development of a novel bile-based CCA diagnostic panel that is stable, reproducible, and has potential clinical utility. (Hepatology 2014;60:896–907)
Fibroblast growth factor 21 protects against acetaminophen-induced hepatotoxicity by potentiating peroxisome proliferator-activated receptor coactivator protein-1α-mediated antioxidant capacity in mice
Authors: Ye Dewei , Wang Yudong , Li Huating , Jia Weiping , Man Kwan , Lo Chung Mau , Wang Yu , Lam Karen S.L. , Xu Aimin
Published: February 2014

Acetaminophen (APAP) overdose is a leading cause of drug-induced hepatotoxicity and acute liver failure worldwide, but its pathophysiology remains incompletely understood. Fibroblast growth factor 21 (FGF21) is a hepatocyte-secreted hormone with pleiotropic effects on glucose and lipid metabolism. This study aimed to investigate the pathophysiological role of FGF21 in APAP-induced hepatotoxicity in mice. In response to APAP overdose, both hepatic expression and circulating levels of FGF21 in mice were dramatically increased as early as 3 hours, prior to elevations of the liver injury markers alanine aminotransferase (ALT) and aspartate aminotransferase (AST). APAP overdose-induced liver damage and mortality in FGF21 knockout (KO) mice were markedly aggravated, which was accompanied by increased oxidative stress and impaired antioxidant capacities as compared to wild-type (WT) littermates. By contrast, replenishment of recombinant FGF21 largely reversed APAP-induced hepatic oxidative stress and liver injury in FGF21 KO mice. Mechanistically, FGF21 induced hepatic expression of peroxisome proliferator-activated receptor coactivator protein-1α (PGC-1α), thereby increasing the nuclear abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and subsequent up-regulation of several antioxidant genes. The beneficial effects of recombinant FGF21 on up-regulation of Nrf2 and antioxidant genes and alleviation of APAP-induced oxidative stress and liver injury were largely abolished by adenovirus-mediated knockdown of hepatic PGC-1α expression, whereas overexpression of PGC-1α was sufficient to counteract the increased susceptibility of FGF21 KO mice to APAP-induced hepatotoxicity. Conclusion: The marked elevation of FGF21 by APAP overdose may represent a compensatory mechanism to protect against the drug-induced hepatotoxicity, by enhancing PGC-1α/Nrf2-mediated antioxidant capacity in the liver. (Hepatology 2014;60:977–989)
Lipopolysaccharide exposure augments isoniazide‐induced liver injury
Authors: Su Yijing , Zhang Yun , Chen Mi. , Jiang Zhenzhou , Sun Lixin , Wang Tao , Zhang Luyong
Published: February 2014

Isoniazide (INH) is a classic antituberculosis drug associated with clinical idiosyncratic drug‐induced liver injury. It has been hypothesized that the interaction between a drug and modest inflammation results in a decreased threshold for drug toxicity. In this study, we tested the hypothesis that INH causes liver injury in rats when coadministered with lipopolysaccharide (LPS). Neither INH nor LPS alone caused liver injury. The coadministration of INH and LPS was associated with increases in serum and histopathological markers of liver injury. Tumour necrosis factor‐α expression was significantly increased in the coadministered group. The downregulation of the bile acid transporter, bile salt export pump, and multidrug resistance protein 2 at both mRNA and protein levels was observed. Furthermore, the level of Farnesoid X receptor, which regulates the bile salt export pump and multidrug resistance protein 2, were clearly decreased. These results indicate that the coadministration of nontoxic doses of LPS and INH causes liver injury; the disruption of biliary excretion is considered the primary inflammation‐related characteristic of INH‐induced hepatotoxicity. Copyright © 2014 John Wiley & Sons, Ltd.
Modulation of Gene‐Expression Profiles Associated with Sodium Arsenite‐Induced Cardiotoxicity by p‐Coumaric Acid, a Common Dietary Polyphenol
Authors: Prasanna Nagalakshmi , Rasool Mahaboobkhan
Published: February 2014

In the present study, the purpose was to investigate the effect of p‐coumaric acid on the mRNA‐expression levels of inflammatory cytokines, transcription factor, MAP kinases, and apoptotic proteins by real time reverse transcription polymerase chain reaction in the cardiac tissue of sodium arsenite exposed rats. Sodium arsenite administration (5 mg/kg/b.wt, once daily for 30 days) upregulated the mRNA‐expression levels of inflammatory cytokines (interleukin–1 beta, interleukin–6, tumor necrosis factor–alpha, and tumor growth factor–beta), transcription factor (NF‐Kb‐Rel A), protein kinases (Janus kinase and p38), caspase 3, and proapoptotic protein Bax in the cardiac tissue of rats, but the antiapoptotic protein Bcl‐2 mRNA expression was found be downregulated. However, p‐coumaric acid (75, 100 mg/kg/b. wt. oral) pretreatment daily before the sodium arsenite exposure protected the changes in the above mRNA‐expression profiles observed in the cardiac tissues. In conclusion, this study confirmed that p‐coumaric acid could be a promising dietary agent for protecting against the sodium arsenite‐induced cardiotoxicity.
The reliability of DFT methods to predict electronic structures and minimum energy crossing point for [FeIVO](OH)2 models: A comparison study with MCQDPT method
Authors: Liu Kun , Li Yu‐Xue , Su Jia‐Ling , Wang Bin
Published: February 2014

In order to test the reliability of DFT methods for calculating electronic structures of [FeIVO] system, detailed calculations of [FeIVO](OH)2 models were performed for several low‐energy states using multiconfiguration quasidegenerate perturbation theory (MCQDPT) as well as DFT‐based methods. The minimum energy crossing points (MECP) of 5A1/5B2 and 3B2/5B2 were investigated based on Lagrange–Newton approach. The results show that M06 functional produce energy gaps close to those of MCQDPT results. Another topic in this article is that the electron configurations of [FeIVO](OH)2 models strongly depend on the type of surface ligand used, and the two lowest states of these can facile transition each other by the MECP. The practicability of M06 method in locating the MECP is validated by the results of MCQDPT which demonstrate the two‐state reactivity (TSR) can be studied with proper DFT method. These inspections provide the basis for further TSR study of larger [FeIVO] system. © 2014 Wiley Periodicals, Inc.
Comparison of global versus Asian clinical trial strategies supportive of registration of drugs in Japan
Authors: Shirotani Mari , Kurokawa Tatsuo , Chiba Koji
Published: February 2014

The number of worldwide and Asian multiregional clinical trials (MRCTs) submitted for Japanese New Drug Applications increased markedly between 2009 and 2013, with an increasing number performed for simultaneously submission in the USA, EU, and Japan. Asian studies accounted for 32% of MRCTs (14/44 studies) and had comparatively small sample sizes (<500 subjects). Moreover, the number of Japanese subjects in Asian studies was 2.1‐ to 13.4‐fold larger than the sample size estimated using the method described in Japanese MRCT guidelines, whereas the ratio for worldwide studies was 0.05‐ to 4.9‐fold. Before the introduction of this guidelines, bridging or domestic clinical development strategies were used as the regional development strategy in accordance with ICH E5 guidelines. The results presented herein suggest that Asian studies were conducted when the drug had already been approved in the US/EU, when phase 3 clinical trials were not be planned in the USA/EU, when there was insufficient knowledge of ethnic differences in drug efficacy and safety, or when Caucasian data could not be extrapolated to the Japanese population. New strategies with Asian studies including the Japanese population could be conducted instead of Japanese domestic development strategy.
Single‐dose pharmacokinetics and glucodynamics of the novel, long‐acting basal insulin LY2605541 in healthy subjects
Authors: Sinha Vikram P. , Choi Siak Leng , Soon Danny Kwang Wei , Mace Kenneth F. , Yeo Kwee Poo , Lim Shufen T. H. , Howey Daniel C.
Published: February 2014

LY2605541 is a novel basal insulin analog with a prolonged duration of action. Two Phase I studies assessed LY2605541 pharmacokinetics (PK), glucodynamics (GD), and tolerability in healthy subjects. In Study 1, 33 subjects received single subcutaneous (SC) doses of LY2605541 (0.01–2.22 U/kg) and insulin glargine (0.5–0.8 U/kg) followed by euglycemic clamp for up to 24–36 hours. In Study 2, absolute bioavailability of SC LY2605541 was assessed in 8 subjects by comparing dose normalized area under concentration versus time curve of SC against IV administration. Time‐to‐maximum plasma concentration (medians) and geometric means for half‐life (t1/2) and apparent clearance, respectively, ranged from 18.0 to 42.0 hours, 24.4–45.5 hours, and 1.8–2.8 L/h for SC LY2605541, versus 10.0–12.0 hours, 12.2–14.9 hours, and 51.4–65.2 L/h for SC insulin glargine. LY2605541 glucose infusion rate (GIR) profiles were sustained for ≥36 hours versus glargine GIR profiles, which waned at 24 hours. After IV administration, LY2605541's geometric mean t1/2 was 2.3 hours. LY2605541 intra‐subject variability (CV%) was <18% for PK and <32% for GD parameters. The most common adverse events were related to study procedures and were mild‐moderate in severity. These results established a well‐tolerated baseline dose for LY2605541 with a relatively flat PK profile and low intra‐subject variability.
Domino Reactions of 3‐Vinylchromone Leading to Different Heterocyclic Compounds
Authors: El‐Desoky S. I. , Abozeid M. A. , Kandeel E. A. , Abdel‐Rahman A. H.
Published: February 2014

A range of heterocyclic systems incorporating chromone and related scaffolds was synthesized via domino reactions of 3‐vinylchromone. These cascade processes resulted in the construction of various heterocyclic nuclei such as xanthone and enaminone as well as diazolo and triazolo chomenopyrimidine heterocycles.
Formation and structure of the ephippium (resting egg case) in relation to molting and egg laying in the water flea Daphnia pulex De Geer (Cladocera: Daphniidae)
Authors: Hiruta Chizue , Tochinai Shin
Published: February 2014

Resting eggs produced by daphnid species in response to environmental deterioration play an important role in colonizing new habitats or in re‐establishing extinct populations. Females lay resting eggs into the space within the dorsal part of their carapace and form an egg case called the ephippium to protect them. Previous studies mainly reported the morphology of the completely formed ephippium and/or the forming ephippium of an uncertain stage. To understand ephippium formation and to clarify key transitions in the formation of resting eggs, we examined the structure and formation of the ephippium in the water flea Daphnia pulex De Geer (Cladocera: Daphniidae) by stereomicroscopy, histology, and scanning electron microscopy. The females used in this study produced resting eggs by obligate parthenogenesis. We divided ephippium formation into four stages based on two molts and a single ovulation, as follows. Stage I begins 13 min after molting in adult females that do not ovulate. In Stage II, immediately after the first molt, a protuberance appears beneath the neck region and the carapace begins to thicken. In Stage III, the resting eggs ovulate and the carapace in the area of the forming ephippium becomes much thicker than the normal carapace and accumulates dark pigmentation. In Stage IV, following the second molt, the female sheds the ephippium with the enclosed resting eggs and forms a new carapace. These stages will provide a useful reference for future studies on resting egg formation. J. Morphol. 275:760–767, 2014. © 2014 Wiley Periodicals, Inc.
Mixed‐effects modeling of clinical DCE‐MRI data: Application to colorectal liver metastases treated with bevacizumab
Authors: Ferl Gregory Z. , O'Connor James P.B. , Parker Geoffrey J.M. , Carano Richard A.D. , Acharya Shiv J. , Jayson Gordon C. , Port Ruediger E.
Published: February 2014

Purpose

Most dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) data are evaluated for individual patients with cohorts analyzed to detect significant changes from baseline values, repeating the process at each posttreatment timepoint. Our study aimed to develop a statistically valid model for the complete time course of DCE‐MRI data in a patient cohort.

Materials and Methods

Data from 10 patients with colorectal cancer liver metastases were analyzed, including two baseline scans and four post‐bevacizumab scans. Apparent changes in tumor median Ktrans were adjusted for changes in observed enhancing tumor fraction (EnF) by multiplying Ktrans by EnF (KEnF). A mixed‐effects model (MEM) was defined to describe the KEnF time course for all patients simultaneously by assuming a three‐parameter indirect response model with model parameters lognormally distributed across patients.

Results

The typical cohort time course showed a KEnF reduction to 59% of baseline at 24 hours, returning to 65% of baseline values by day 12. Interpatient variability of model parameters ranged from 11% to 307%.

Conclusion

The MEM approach has potential for comparing responses at a group level in clinical trials with different doses, schedules, or combination regimens. Furthermore, the KEnF biomarker successfully resolved confounds in interpreting Ktrans arising from therapy induced changes in the volume of enhancing tumor. J. Magn. Reson. Imaging 2015;41:132–141. © 2014 Wiley Periodicals, Inc.
Skill of precipitation prediction with GCMs over north India during winter season
Authors: Tiwari P. R. , Kar S. C. , Mohanty U. C. , Kumari S. , Sinha P. , Nair A. , Dey S.
Published: February 2014

This study aims to analyse the skill of state‐of‐the‐art of five general circulation models (GCMs) in predicting winter precipitation over northern India. The precipitation in winter season (December, January and February) is very important for Rabi crops in north India, particularly for wheat, as it supplements moisture and maintains low temperature for the development of the crops. The GCM outputs (seasonal mean forecasts issued in November) from various organizations are compared with the observed high‐resolution gridded rainfall data obtained from India Meteorological Department (IMD). Prediction skill of such GCMs is examined for the period 1982–2009. The climatology, interannual standard deviation (ISD) and correlation coefficients have been computed for the five GCMs and compared with observation. It is found that the models are able to reproduce the climatology and ISD to varying degrees; however, skill of predictions is too low. Multi‐model ensemble (MME) approaches have been employed. It is found that the weighted MME using multiple linear regression technique improves the prediction skill of winter precipitation over northern India. The teleconnection between the sea surface temperature (SST) and winter precipitation revealed that the SST over the Pacific Ocean affects the precipitation over north India in winter season. While this observed feature is represented well by some models with high fidelity, most models are unable to respond to SST variations in the Pacific Ocean in a realistic manner. Lagged correlations between the north India rainfall and SST over the Niño‐3.4 region reveal that only two of the five GCMs get the observed simultaneous teleconnection correctly. Furthermore, only one of these two models has the observed phase lag with the strongest correlation as observed.
Quality determination of wheat: genetic determination, biochemical markers, seed storage proteins – bread and durum wheat germplasm
Authors: Varzakas Theo , Kozub Natalia , Xynias Ioannis N
Published: February 2014

BACKGROUND

Quality is an important determinant in wheat breeding since its genetic background is less affected by the environment and sufficiently influences the commercial value of a cultivar. Thus, if a certain cultivar possesses some specific allele combination at crucial loci, then it appears quite possible to exhibit valuable qualitative traits in terms of end‐product quality. This is also true if either durum or bread wheat germplasm is involved.

RESULTS

Biochemical investigation of the wheat germplasm gives important information on the allele constitution of a cultivar, with reference to either the quality or its resistance to stressing factors. The last is crucial since it affects the safe use of this cultivar. The Hellenic wheat germplasm possesses valuable allele combination or chromosome constitution (presence of the 1BL.1RS translocation, which is verified by the presence of a certain allele) with reference to quality. Genotypes having the aforementioned translocation exhibit excellent resistance to various stressing factors, but have a serious handicap, i.e. inferior bread‐making quality. This negative effect on quality, although influenced by the genotype, can be overcome if some other alleles are present in a cultivar.

CONCLUSION

The Hellenic cultivar Acheron is a good example since, despite the presence of the translocation, it also has very good bread‐making quality and high yielding ability. It must be also mentioned that most of the Hellenic durum germplasm carries the gene locus Gli‐B1 component, similar to γ45, which can be considered as an index of good end‐product quality. © 2014 Society of Chemical Industry
Easy Daylight Fabricated Hydrogel Array for Colorimetric DNA Analysis
Authors: Beyer Antje , Pollok Sibyll , Berg Albrecht , Weber Karina , Popp Jürgen
Published: February 2014

The fabrication of 3D hydrogel microarrays for DNA analytics that allow simple visual signal readout for on‐site applications is described. A convenient one‐step polymerization of the hydrogel including in situ capture oligonucleotide immobilization is accomplished by using N,N′‐dimethylacrylamide/polyethylene glycol (PEG1900)‐bisacrylamide monomers. The implementation of an acylphosphine‐oxide photoinitiator even allows polymerization at daylight, whereas other approaches require exposure with light in the UV‐range. This minimizes the risk of UV‐caused DNA damages within the capture DNA‐strand that could adversely affect the subsequent hybridization step. The porous network of these gel segments allows DNA as well as protein penetration. Thus, the successful in‐gel DNA hybridization is monitored by the deposition of silver nanoparticles. These metal particles allow naked eye signal readout.
Effect of Side Chains on Charge Transport of Anthracene‐Based PPE–PPV Copolymers
Authors: Tinti Francesca , Sabir Fedlu K. , Gazzano Massimo , Righi Sara , Usluer Özlem , Ulbricht Christoph , Yohannes Teketel , Egbe Daniel A. M. , Camaioni Nadia
Published: February 2014

The variation of the drift mobility of positive and negative charge carriers in films of anthracene‐containing poly(p‐phenylene‐ethynylene)‐alt‐poly(p‐phenylene‐vinylene)s (AnE‐PVs), differently substituted, is investigated as a function of the applied electric field. Branched 2‐ethylhexyl and linear alkoxy side chains of different lengths are considered, as well as well‐defined and random distributions of lateral substituents. The same conditions are used both for the deposition of the polymer films and for their characterization, which allows for the establishment of a clear relationship between the chemical structure and the charge carrier mobility.

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Synthesis and Gas Adsorption Properties of Tetra‐Armed Microporous Organic Polymer Networks Based on Triphenylamine
Authors: Yang Xiao , Yao Shuwen , Yu Miao , Jiang Jia‐Xing
Published: February 2014

Two novel tetra‐armed microporous organic polymers have been designed and synthesized via a nickel‐catalyzed Yamamoto‐type Ullmann cross‐coupling reaction or Suzuki cross‐coupling polycondensation. These polymers are stable in various solvents, including concentrated hydrochloric acid, and are thermally stable. The homocoupled polymer YPTPA shows much higher Brunauer–Emmet–Teller‐specific surface area up to 1557 m2 g−1 than the copolymer SPTPA (544 m2 g−1), and a high CO2 uptake ability of 3.03 mmol g−1 (1.13 bar/273 K) with a CO2/N2 sorption selectivity of 17.3:1. Both polymers show high isosteric heats of CO2 adsorption (22.7–26.5 kJ mol−1) because the incorporation of nitrogen atoms into the skeleton of microporous organic polymers enhances the interaction between the pore wall and the CO2 molecules. The values are higher than those of the porous aromatic frameworks, which contain neither additional polar functional groups nor nitrogen atoms, and are rather close to those of previously reported microporous organic polymers containing the nitrogen atoms on the pore wall. These data show that these materials would be potential candidates for applications in post‐combustion CO2 capture and sequestration technology.

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Facile Assembly of 3D Binary Colloidal Crystals from Soft Microgel Spheres
Authors: Liu Yang , Guan Ying , Zhang Yongjun
Published: February 2014

It still remains a big challenge to fabricate binary colloidal crystals (binary CCs) from hard colloidal spheres, although a lot of efforts have been made. Here, for the first time, binary CCs are assembled from soft hydrogel spheres, PNIPAM microgels, instead of hard spheres. Different from hard spheres, microgel binary CCs can be facilely fabricated by simply heating binary microgel dispersions to 37 °C and then allowing them to cool back to room temperature. The formation of highly ordered structure is indicated by the appearance of an iridescent color and a sharp Bragg diffraction peak. Compared with hard sphere binary CCs, the assembly of PNIPAM microgel binary CCs is much simpler, faster and with a higher “atom” economy. The easy formation of PNIPAM microgel binary CC is attributed to the thermosensitivity and soft nature of the PNIPAM microgel spheres. In addition, PNIPAM microgel binary CCs can respond to temperature change, and their stop band can be tuned by changing the concentration of the dispersion.

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[unittitleWOL]
Authors: Gläser H. J.
Published: February 2014

Algenwuchs auf der Außenoberfläche von Wärmedämmverbundsystemen (WDVS) wird verursacht durch länger andauernde Benetzung. Die derzeitigen Bekämpfungsmethoden greifen längerfristig nicht. Insbesondere Tau‐ und Reifbeschlag sind eine wesentliche Ursache, die entscheidend durch die hohe Wärmedämmung der Wärmeverbundsysteme hervorgerufen werden. Im folgenden Beitrag wird auf der Basis des kritischsten Szenarios für Außenbeschlag simuliert, wann dieser auftreten und ob er durch eine niedrig emittierende Außenoberfläche, wie bei hoch wärmedämmenden Verglasungen schon erprobt, vermieden werden können. Die Untersuchungen ergaben, dass mit einem thermischen Emissionsvermögen ε im Bereich von 0,05 bis 0,1 Außenbeschlag auf Wärmedämmverbundsystemen mit einem Wärmedurchgangskoeffizient U von 0,1 bis 0,2 W/(m2 K) theoretisch nicht zu vermeiden ist. Da jedoch das bei der Simulation zu Grunde gelegte kritischste Szenario für Außenbeschlag sehr stringent ist und mit ihm Außenbeschlag erst für relative Luftfeuchte rHo ≥ 95 % auftritt, kann gefolgert werden, dass er unter den vorgegebenen Bedingungen in der Praxis, wenn überhaupt, nur äußerst selten auftreten kann. Eine bzgl. Witterungsbeständigkeit und gegenüber Witterungsverschmutzung beständige Oberfläche kann mit Aluminium realisiert werden, das ggf. noch mit einer Titandioxidschicht passiviert ist. Wegen der fotokatalytischen Eigenschaften von TiO2 sind die Vorteile einer solchen Zusatzbeschichtung darüber hinaus Selbstreinigungseffekt und schnelles Abtrocknung der Oberfläche nach Regen. Letzteres wirkt dem Algenwuchs dann auch entgegen.
Coupling of compressible and incompressible flow regions using the multiple pressure variables approach
Authors: Boger Markus , Jaegle Felix , Klein Rupert , Munz Claus‐Dieter
Published: February 2014

In many cases, multiphase flows are simulated on the basis of the incompressible Navier–Stokes equations. This assumption is valid as long as the density changes in the gas phase can be neglected. Yet, for certain technical applications such as fuel injection, this is no longer the case, and at least the gaseous phase has to be treated as a compressible fluid. In this paper, we consider the coupling of a compressible flow region to an incompressible one based on a splitting of the pressure into a thermodynamic and a hydrodynamic part. The compressible Euler equations are then connected to the Mach number zero limit equations in the other region. These limit equations can be solved analytically in one space dimension that allows to couple them to the solution of a half‐Riemann problem on the compressible side with the help of velocity and pressure jump conditions across the interface. At the interface location, the flux terms for the compressible flow solver are provided by the coupling algorithms. The coupling is demonstrated in a one‐dimensional framework by use of a discontinuous Galerkin scheme for compressible two‐phase flow with a sharp interface tracking via a ghost‐fluid type method. The coupling schemes are applied to two generic test cases. The computational results are compared with those obtained with the fully compressible two‐phase flow solver, where the Mach number zero limit is approached by a weakly compressible fluid. For all cases, we obtain a very good agreement between the coupling approaches and the fully compressible solver. Copyright © 2014 John Wiley & Sons, Ltd.
Role of ceramic reinforcement in composite polymer electrolyte
Authors: Malathi M. , Tamilarasan K. , Ganesan V.
Published: February 2014

Composite polymer electrolytes were prepared from PEO (polyethylene oxide), lithium perchlorate (LiClO4), and with three different dielectric reinforcements such as lead zirconium titanate (PZT)‐12000, barium titanate (BT)‐1000, and Alumina (Al2O3)‐6. Differential scanning calorimetry and X‐ray diffractometry were employed to reveal the crystalline nature of the electrolytes. The conductivity of the composite polymer electrolytes were measured by impedance spectrometry. Among the three systems, PZT reinforced composite exhibits maximum ionic conductivity of 2.9 × 10−5 S/cm at room temperature. The ionic conductivity of the polymer composites increases with increase in dielectric constant of the reinforcement. The composite with alumina reinforcement displayed strongly modified properties with very weak temperature dependence of conductivity. POLYM. COMPOS., 36:42–46, 2015. © 2014 Society of Plastics Engineers
Rheological and morphological characteristics of multicomponent polysulfone/poly(vinyl alcohol) systems
Authors: Filimon Anca , Avram Ecaterina , Stoica Iuliana
Published: February 2014

A series of blends obtained from polysulfone (PSF) or chloromethylated polysulfone (CMPSF) and poly(vinyl alcohol) (PVA) inN‐methyl‐2‐pyrrolidone were investigated by means of attenuated total reflection Fourier transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), rheology and atomic force microscopy (AFM). Mechanisms through which specific interactions developed via hydrogen bonding in ternary systems affect the blend properties were established fromFTIRspectra. The results confirm the presence of hydrogen bonding inPSF/PVAandCMPSF/PVAblends at 0.5 and 0.75 weight fractions ofPVA, respectively. Consequently, the type of interactions and structural peculiarity of polymers in the blends as well as the composition of polymer mixtures modify the rheological functions, evidencing the orientation or mobility of chain segments in the shear field. The results derived from rheological measurements are consistent with those above, evidencing significant changes for blends with a greater amount ofPVA(i.e. 50/50 and 25/75 (w/w)PSF/PVAandCMPSF/PVAblends, respectively). These blends represent the optimum compositions and possess specific properties, confirmed by the glass transition temperatures. Additionally, the specific microarchitecture of the blends, determined usingAFM, represents excellent scaffolds as porous membranes for biomedical applications. © 2014 Society of Chemical Industry
An experimental strategy for the identification of AMPylation targets from complex protein samples
Authors: Pieles Kathrin , Glatter Timo , Harms Alexander , Schmidt Alexander , Dehio Christoph
Published: February 2014

AMPylation is a posttranslational modification (PTM) that has recently caught much attention in the context of bacterial infections as pathogens were shown to secrete Fic proteins that AMPylate Rho GTPases and thus interfere with host cell signaling processes. Although Fic proteins are widespread and found in all kingdoms of life, only a small number of AMPylation targets are known to date. A major obstacle to target identification is the limited availability of generic strategies allowing sensitive and robust identification of AMPylation events. Here, we present an unbiased MS‐based approach utilizing stable isotope‐labeled ATP. The ATP isotopes are transferred onto target proteins in crude cell lysates by in vitro AMPylation introducing specific reporter ion clusters that allow detection of AMPylated peptides in complex biological samples by MS analysis. Applying this strategy on the secreted Fic protein Bep2 of Bartonella rochalimae, we identified the filamenting protein vimentin as an AMPylation target that was confirmed by independent assays. Vimentin represents a new class of target proteins and its identification emphasizes our method as a valuable tool to systematically uncover AMPylation targets. Furthermore, the approach can be generically adapted to study targets of other PTMs that allow incorporation of isotopically labeled substrates.
Nitrosonium complexes of 2,11‐dithia‐5,6,8,9‐tetramethyl[32](1,4)cyclophane: a combined experimental and theoretical study
Authors: Borodkin Gennady I. , Elanov Innokenty R. , Andreev Rodion V. , Shakirov Makhmut M. , Shubin Vyacheslav G.
Published: February 2014

1H and 13C NMR studies and quantum chemical calculations show the interaction between 2,11‐dithia‐5,6,8,9‐tetramethyl[32](1,4)cyclophane and nitrosonium cation to result in the formation of π‐ and n‐complexes. According to DFT/B3LYP/6‐31G(2d,p) calculations, formation of nitrosonium complexes is a strongly exothermic process both in gas phase and in SO2. Affinity of single‐charged complexes to NO+ is usually larger than that of double‐charged and triple‐charged complexes, affinity of all the charged complexes to nitrosonium cation in SO2 being larger than that in gas phase. The π‐complex with nitrosonium cation coordinated to the methylated aromatic ring is the most stable with structural characteristics being close to those obtained by X‐ray diffraction for nitrosonium π‐complexes of hexamethylbenzene and other arenes. The N―O bond lengths in all the complexes are quite close to each other and larger than that in NO+ cation. The S―N bond length increases upon transition from single‐charged to double‐charged and polycharged complexes. Copyright © 2014 John Wiley & Sons, Ltd.