bluuebunny/crossref_metadata_2025 huggingface dataset:
Increase in efficiency of media utilization for recombinant protein production in Chinese hamster ovary culture through dilution
Authors: Thombre Shreya , Gadgil Mugdha
Published: April 2011

Animal cells are extensively used for the large‐scale production of recombinant proteins. Processes and genetically engineered cell lines have been developed to enhance longevity of the culture and increase protein productivity. In this study, we tested the effect of diluting a culture of Chinese hamster ovary (CHO) cells with phosphate‐buffered saline (PBS) on cell growth and efficiency of media utilization. An immunoglobulin G‐expressing CHO cell line was cultured in CD CHO media followed by dilution of the culture with PBS after the end of the exponential phase. A 28% and 61% increase in protein yield per milliliter of media was observed in the diluted culture in the batch and fed‐batch mode with glucose and protein hydrolysate feeding, respectively. To aid in analyzing the potential causes of this observed increase, an unstructured mathematical model was constructed using previously reported kinetics to simulate cell growth, nutrient utilization, and protein production. The model predicts an increase in recombinant protein yield per milliliter of media in PBS diluted cultures under both batch and fed‐batch conditions, and suggests that this observed increase could at least partly be due to a decrease in inhibitor concentration in the diluted culture.
Zur Zukunft der Sicherheitskonzepte im Bauwesen
Authors: Proske Dirk
Published: April 2011

Zu Beginn des Artikels werden die rechtlichen Sicherheitsanforderungen an die Errichtung von Bauwerken erläutert und diese Anforderungen mit den statistisch beobachteten Risiken für Bauwerkseinstürze verglichen. Daran schließt sich eine kurze Darstellung der Geschichte der numerischen Sicherheitskonzepte im Bauwesen und eine Erläuterung des aktuellen semi‐probabilistischen Sicherheitskonzeptes an. Weiterhin werden die Annahmen zur Berücksichtigung von Unsicherheiten im numerischen Sicherheitskonzept für den Entwurf von Bauwerken mit den beobachteten Ursachen für Bauwerksversagen verglichen. Es zeigt sich, dass menschliche Fehler einen signifikanten Beitrag zum katastrophalen Versagen von Bauwerken haben, sie aber in den aktuellen Baunormen praktisch ausgeschlossen werden. Diese Beobachtung gilt auch für die Anwendung von Software. Die Integration menschlicher Fehler und Softwarefehler in das probabilistische Sicherheitskonzept steht aus, da sich ihre Modellierung mit den Mitteln der Stochastik schwierig gestaltet. Deshalb bemüht man sich um eine Erweiterung der probabilistischen Sicherheitskonzepte durch Einbeziehung anderer mathematischer Verfahren zum Umgang mit Unsicherheit. Die Frage der Konsequenz auf die juristischen Anforderungen bleibt jedoch noch unbeantwortet.

The Future of Safety Concepts in Structural Engineering. In the beginning the paper discusses the legal safety requirements for design and construction of civil engineering structures and the observed risks from structural failures. The paper is continued by a short description of the history of safety concepts in structural engineering. This section is finished by some details of the current semi‐probabilistic safety concept. Furthermore the assumptions about uncertainty in the numerical safety concept are compared with observed causes of structural failures and damages. It can be seen, that human failures contribute significantly to the catastrophic collapses of structures. However, currently they are excluded in the design codes of practice. This result is also valid for software failures. The integration of human failures and software failures in the probabilistic safety concept yields to major problems since human failures and software failures are not random. Therefore an extension of the probabilistic safety concept with advanced mathematical techniques to deal with uncertainty is currently under way. However, the legal consequences of this extension are not yet investigated.
Simulation der Boden‐Bauwerk‐Interaktion unter Berücksichtigung eines elastisch‐plastischen Materialverhaltens des Baugrundes
Authors: Bransch Martin , Lehmann Lutz
Published: April 2011

In dem Beitrag wird eine neue Methode zur Berechnung der elastisch‐plastischen Baugrundverformungen und des Baugrundversagens unter Einbezug der Wellenausbreitung im Baugrund vorgestellt. Die hybride Methode basiert auf einer nichtlinearen Berechnung mittels der Finite‐Elemente‐Methode (FEM), einem nichtlinearen HHT‐α‐Zeitschrittverfahren und der “Scaled Boundary Finite Element Method” (SBFEM). Der Schwerpunkt der Arbeit liegt in der Erstellung eines praxisorientierten Berechnungsverfahrens, welches die genannten nicht‐lineare Effekte berücksichtigt. Um dieses Ziel zu erreichen, wird ein nichtlineares HHT‐α‐Verfahren mit voller Newton‐Raphson‐Iteration implementiert. Die Anwendbarkeit wird anhand von Beispielen mit unterschiedlicher Komplexität gezeigt. Die Beispiele beziehen sich auf Flachgründungen, allerdings ist die Methode auch auf Tiefgründungen, Baugruben oder Erdbebenberechnungen übertragbar.

Simulation of soil‐structure‐interaction with consideration of elastic‐plastic soil behaviour. This article presents a new method for the calculation of elastic‐plastic building ground deformations and failure including dynamic effects, like wave propagation. The presented procedure is a hybrid method, based on several common calculation methods. Included is the nonlinear calculation with the finite element method (FEM), a nonlinear HHT‐α method and the scaled boundary finite element method (SBFEM). Focuses are the implementation of an elastic‐plastic soil model with isotropic hardening, the derivation and implementation of a nonlinear HHT‐α method with full Newton‐Raphson iteration, and the implementation of these methods and the SBFEM in a nonlinear overall calculation scheme. The applicability of the developed method is given in several examples in different complexity. The examples are related to shallow foundations. But the method is also portable to pile foundations, building pits or earthquake calculations.
Ertüchtigung des Versorgungstunnels unter der Kieler Förde
Authors: Buba Richard , Stickler Martin , Uth Robert
Published: April 2011

In den Jahren 2008 bis 2010 wurde der 1368 m lange Versorgungstunnel unter der Kieler Förde ertüchtigt. Die Ertüchtigung erfolgte durch Einschieben einer neuen Innenschale aus Vortriebsrohren über die gesamte Tunnellänge. Durch dieses Verfahren konnten die vorhandenen Versorgungsleitungen während der Ertüchtigungs maßnahme im Tunnel verbleiben und die Demontage und Montage der Leitungen entfallen. Die Bauzeit und die Zeit der Unterbrechung der Fernwärmeversorgung wurden somit erheblich verkürzt. Der Verschub von 452 Rohren mit je 32 t Gewicht unter extrem beengten Verhältnissen stellte eine besondere Herausforderung dar. Durch die zielorientierte und sachlich‐fachkompetente Zusammenarbeit aller Projektbeteiligten konnte das Bauvorhaben erfolg reich verwirklicht werden.
Planung von Turbinenfundamenten in Erdbebengebieten
Authors: Basu Ashish Kumar , Nawrotzki Peter , Siepe Daniel
Published: April 2011

Dieser Beitrag stellt grundsätzliche Prinzipien elastisch gelagerter Systeme und Anwendungen im Bereich der Kraftwerksausrüstung und von Gebäuden in mittleren und hohen Erdbebenzonen dar. Kombinierte Feder‐Dämpferelemente mit speziellen Steifigkeitseigenschaften werden eingesetzt, um die seismischen Beschleunigungswerte der Turbinenkomponenten und weiteren sicherheits‐ oder nicht‐sicherheits relevanten Strukturen zu reduzieren. Für Turbinengebäude kann die Integration der Unterkonstruktion des Turbinendecks in das Maschinenhaus zusätzlich sowohl die relative Verschiebung zwischen den beiden Strukturen als auch den Spannungslevel in allen Bauteilen reduzieren.

Design of Turbine Foundations in Seismic Zones — Earthquake Protection Strategies. This contribution reveals basic principles of elastic support systems and applications on power plant equipment and buildings in medium and high seismic areas. Spring‐damper combinations with special stiffness properties are used to reduce seismic acceleration levels of turbine components and other safety or non‐safety related structures. For turbine buildings, the integration of the turbine substructure into the machine building can additionally reduce the relative displacement between both the structures as well as the stress levels in all structural members.
Effects of prepartum ingestion of Ipomoea carnea on postpartum maternal and neonate behavior in goats
Authors: Gotardo Andre T. , Pfister James A. , Ferreira Marcos Barbosa , Górniak Silvana Lima
Published: April 2011

Ipomoea carnea is a toxic plant that grows in tropical areas, and is readily consumed by grazing goats. The plant contains the alkaloids swainsonine and calystegines, which inhibit cellular enzymes and cause systematic cell death. This study evaluated the behavioral effects on dams and kids of prenatal ingestion of this plant. Freshly harvested leaves of I. carnea (10 g/kg body weight) were fed daily to nine pregnant goats from the fifth to the 16th week of gestation; five pregnant goats were controls. Dam and kid behavior were evaluated during 2‐hr postpartum. Further evaluation of the offspring was performed using various tests after birth: (1) reaching and discriminating their dam from an alien doe (two tests at 12‐hr postpartum), and (2) navigating a progressive maze (2, 4, and 6 days postpartum). Postnatal (n = 2) and fetal (n = 2) mortality were observed in the treated group. Intoxicated kids had difficulty in standing at birth, and only one was able to suckle within 2 hr of birth. Treated kids were slower than controls to arrive at their dam in the discrimination test; treated kids often (seven of nine completed tests) incorrectly chose the alien dam (controls: 0/10 tests). During some runs on days 2, 4, and 6 postpartum, treated kids were slower to leave the starting point of the maze, and were slower to arrive at the dam on all test days. This study suggests that the offspring of pregnant goats given I. carnea during gestation have significant behavioral alterations and developmental delays. Birth Defects Res (Part B) 92:131–138, 2011.  © 2011 Wiley‐Liss, Inc.
Sortilin: An unusual suspect in cholesterol metabolism
Authors: Dubé Joseph B. , Johansen Christopher T. , Hegele Robert A.
Published: April 2011

The concentration of low‐density lipoprotein (LDL) cholesterol (C) in plasma is a key determinant of cardiovascular disease risk and human genetic studies have long endeavoured to elucidate the pathways that regulate LDL metabolism. Massive genome‐wide association studies (GWASs) of common genetic variation associated with LDL‐C in the population have implicated SORT1 in LDL metabolism. Using experimental paradigms and standards appropriate for understanding the mechanisms by which common variants alter phenotypic expression, three recent publications have presented divergent and even contradictory findings. Interestingly, although these reports each linked SORT1 to LDL metabolism, they did not agree on a mechanism to explain the association. Here, we review recent mechanistic studies of SORT1 – the first gene identified by GWAS as a determinant of plasma LDL‐C to be evaluated mechanistically.
Silver nanoparticles assemblies mediated by functionalized biomimetic oligomers
Authors: Maayan Galia , Liu Li‐Kai
Published: April 2011

The interaction between biopolymers and metal nanoparticles (AgNPs) is a key element in the development of biomimetic nanomaterials with applications in catalysis, delivery, and recognition. Here we report a facile method for the functionalization of AgNPs by N‐substituted glycine oligomers, “peptoids.” Based on the established affinity between phenanthroline ligand and Ag(0), we synthesized a peptoid bearing 1,10‐phenanthroline at the N‐terminus (PHP). Treatment of AgNPs that were pre‐stabilized by citrate ions, with PHP, leads to the formation of aggregates as suggested by UV–vis spectroscopy. Transmission electron microscopy (TEM) revealed that the replacement of citrate ions by PHP yields spherical assemblies of AgNPs. These peptoids/AgNPs hybrids, as well as the ability of functional biomimetic oligomers to mediate the assembly of metal nanoparticles, hold potential for applications in sensor materials, biology, and catalysis. © 2011 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 96: 679–687, 2011.
Meta-analysis of neoadjuvant treatment modalities and definitive non-surgical therapy for oesophageal squamous cell cancer
Authors: Kranzfelder M , Schuster T , Geinitz H , Friess H , Büchler P
Published: April 2011

Background

The standard treatment for resectable oesophageal squamous cell carcinoma (OSCC) is surgical resection with adequate lymphadenectomy. Most Western patients receive neoadjuvant chemotherapy or chemoradiotherapy (CRT). In recent years some patients have received CRT alone (definitive CRT, dCRT). This meta-analysis sought to clarify the benefits of neoadjuvant and definitive treatment for OSCC.

Methods

Eligible randomized controlled trials (RCTs) were identified using the Cochrane database, MEDLINE and Embase. Only RCTs with intention-to-treat analysis, and published hazard ratios (HRs) or estimates from survival data, were included.

Results

Nine RCTs involving neoadjuvant CRT versus surgery, eight involving neoadjuvant chemotherapy versus surgery, and three involving neoadjuvant treatment followed by surgery or surgery alone versus dCRT were identified. The HR for overall survival was 0·81 (95 per cent confidence interval 0·70 to 0·95; P = 0·008) after neoadjuvant CRT and 0·93 (0·81 to 1·08; P = 0·368) after neoadjuvant chemotherapy. The likelihood of R0 resection was significantly higher after neoadjuvant treatment (CRT: HR 1·15, P = 0·043; chemotherapy: HR 1·16, P = 0·006). Morbidity rates were not increased after neoadjuvant CRT (HR 0·94, P = 0·363) but 30-day mortality was non-significantly higher with combined treatment. Morbidity (HR 1·03, P = 0·638) and mortality (HR 1·04, P = 0·810) rates after neoadjuvant chemotherapy and surgery did not differ from those after surgery alone. None of the RCTs reporting outcome after dCRT demonstrated a significant survival benefit, but treatment-related mortality rates were lower (HR 7·60, P = 0·007) than with neoadjuvant treatment followed by surgery or surgery alone.

Conclusion

For patients with resectable OSCC, a significant survival benefit for neoadjuvant CRT was evident, with no increase in morbidity rate. dCRT did not demonstrate any survival benefit over other curative strategies.
Hydrodesulfurization‐Supported Catalysts: Effect of the Preparation Method
Authors: Moradi P. , Parvari M.
Published: April 2011

Hydrodesulfurization (HDS) of dibenzothiophene in a batch reactor was performed at 5.5 MPa and 320 °C on CoMoS/Al2O3‐TiO2 using trans‐1,2‐cyclohexanediamine‐N,N,N′,N′‐tetraacetic acid (CYDTA) as a complexing agent for the preparation method. The effects of titania, concentration of CYDTA, and preparation procedure were investigated by using X‐ray diffraction, BET, Fourier transform infrared spectroscopy, and temperature‐programmed desorption of ammonia experiments. The catalyst prepared by impregnation with γ‐alumina and titanium isopropoxide as raw materials and a CYDTA/Co mole ratio of 1.2 provided an HDS activity (on a pseudo‐first‐order kinetic constant basis) value ∼3.8 times higher compared to that of a CoMo/Al2O3 catalyst.
Stability and Structure of Mixed‐Ligand Metal Ion Complexes That Contain Ni2+, Cu2+, or Zn2+, and Histamine, as well as Adenosine 5′‐Triphosphate (ATP4−) or Uridine 5′‐Triphosphate (UTP4−): An Intricate Network of Equilibria
Authors: Knobloch Bernd , Mucha Ariel , Operschall Bert P. , Sigel Helmut , Jeżowska‐Bojczuk Małgorzata , Kozłowski Henryk , Sigel Roland K. O.
Published: April 2011

With a view on protein–nucleic acid interactions in the presence of metal ions we studied the “simple” mixed‐ligand model systems containing histamine (Ha), the metal ions Ni2+, Cu2+, or Zn2+ (M2+), and the nucleotides adenosine 5′‐triphosphate (ATP4−) or uridine 5′‐triphosphate (UTP4−), which will both be referred to as nucleoside 5′‐triphosphate (NTP4−) . The stability constants of the ternary M(NTP)(Ha)2− complexes were determined in aqueous solution by potentiometric pH titrations. We show for both ternary‐complex types, M(ATP)(Ha)2− and M(UTP)(Ha)2−, that intramolecular stacking between the nucleobase and the imidazole residue occurs and that the stacking intensity is approximately the same for a given M2+ in both types of complexes: The formation degree of the intramolecular stacks is estimated to be 20 to 50 %. Consequently, in protein–nucleic acid interactions imidazole–nucleobase stacks may well be of relevance. Furthermore, the well‐known formation of macrochelates in binary M2+ complexes of purine nucleotides, that is, the phosphate‐coordinated M2+ interacts with N7, is confirmed for the M(ATP)2− complexes. It is concluded that upon formation of the mixed‐ligand complexes the M2+N7 bond is broken and the energy needed for this process corresponds to the stability differences determined for the M(UTP)(Ha)2− and M(ATP)(Ha)2− complexes. It is, therefore, possible to calculate from these stability differences of the ternary complexes the formation degrees of the binary macrochelates: The closed forms amount to (65±10) %, (75±8) %, and (31±14) % for Ni(ATP)2−, Cu(ATP)2−, and Zn(ATP)2−, respectively, and these percentages agree excellently with previous results obtained by different methods, confirming thus the internal validity of the data and the arguments used in the evaluation processes. Based on the overall results it is suggested that M(ATP)2− species, when bound to an enzyme, may exist in a closed macrochelated form only, if no enzyme groups coordinate directly to the metal ion.
Synthesis and Photoinduced Energy‐ and Electron‐Transfer Processes of C60–Oligothienylenevinylene–C70 Dumbbell Compounds
Authors: Urbani Maxence , Pelado Beatriz , de la Cruz Pilar , Yamanaka Ken‐ichi , Ito Osamu , Langa Fernando
Published: April 2011

Unsymmetric dumbbell molecules based on N‐methylpyrrolidine[60]fullerene, oligothienylenevinylenes (nTV; n=2, 4), and N‐methylpyrrolidine[70]fullerene, namely, C60‐nTV‐C70 were synthesized and their photophysical properties were studied. In nonpolar solvents, photoinduced energy‐transfer process predominantly takes place from the singlet excited state of nTV to C60 and C70, as was confirmed by time‐resolved emission and transient absorption spectroscopy. In polar solvent, charge‐separation processes take place instead of energy transfer. The generated charge‐separated radical‐ion pairs decay to the neutral molecules by a fast charge‐recombination process; for n=4, a rate constant of 2×107 s−1 and lifetime of 50 ns were evaluated.
Columnar Mesophases Based on Zinc Chlorophyll Derivatives Functionalized with Peripheral Dendron Wedges
Authors: Sengupta Sanchita , Uemura Shinobu , Patwardhan Sameer , Huber Valerie , Grozema Ferdinand C. , Siebbeles Laurens D. A. , Baumeister Ute , Würthner Frank
Published: April 2011

A chlorophyll derivative with a central zinc ion, a methoxy functionality at its 31‐position, and functionalized with a second‐generation dendron (3,4‐3,4,5)12G2‐CH2OH at its 172‐position was synthesized starting from natural chlorophyll a (Chl a). This compound exhibits liquid crystalline (LC) behavior and its mesomorphic properties have been characterized by differential scanning calorimetry (DSC), polarisation optical microscopy (POM), powder X‐ray diffraction (XRD), and scanning probe microscopy (SPM). A combination of powder XRD, high resolution scanning tunneling microscopy (STM), and atomic force microscopy (AFM) experiments revealed the formation of nano‐segregated well‐ordered columnar tubular superstructures consisting of about five molecules in the column stratum. These self‐assembled columns are further self‐organized into a two‐dimensional oblique unit cell lattice. Semiconducting behavior of this compound has been studied by pulse‐radiolysis time‐resolved microwave conductivity (PR‐TRMC) method and charge carrier mobility values of ∼10−2 cm2 V−1 s−1 are observed. Such organized columnar superstructures constructed from semisynthetic zinc chlorins are reminiscent of the tubular organization of the bacteriochlorophyll dyes in the light‐harvesting chlorosomal antennae of green sulphur bacteria.
Tuning Main Group Redox Chemistry through Steric Loading: Subvalent Group 13 Metal Complexes of Carbazolyl Ligands
Authors: Mansaray Hassanatu B. , Kelly Michael , Vidovic Dragoslav , Aldridge Simon
Published: April 2011

The ability of substituted carbazol‐9‐yl systems to ligate in σ fashion through the amido N‐donor, or to adopt alternative coordination modes through the π system of the central five‐membered ring, can be tuned by systematic variation in the steric demands of substituents in the 1‐ and 8‐positions. The differing affinities of the two modes of coordination for hard and soft metal centres can be shown to influence not only cation selectivity, but also the redox properties of the metal centre. Thus, the highly sterically sterically demanding 1,3,6,8‐tetra‐tert‐butylcarbazolyl ligand can be used to generate the structurally characterised amido‐indium(I) complex, [{(tBu4carb)In}n], (together with its isostructural thallium counterpart) in which the metal centre interacts with the central pyrrolyl ring in η3 fashion [d(InN)=2.679(3) Å; d(InC)=2.819(3), 2.899(3) Å]. By contrast, the smaller 3,6‐di‐tert‐butylcarbazolyl system is less able to restrict the metal centre from binding at the anionic nitrogen donor in the plane of the carbazolyl ligand (i.e. in σ fashion). Analogous chemistry with InI precursors therefore leads to disproportionation to the much harder InII [and In0], and the formation of the mixed‐valence product, [In2{In2(tBu2carb)6}], a homoleptic molecular [In4(NR2)6] system. This chemistry reveals a flexibility of ligation for carbazolyl systems that contrasts markedly with that of the similarly sterically encumbered terphenyl ligand family.
Targeted Cellular Uptake and siRNA Silencing by Quantum‐Dot Nanoparticles Coated with β‐Cyclodextrin Coupled to Amino Acids
Authors: Zhao Mei‐Xia , Li Jin‐Ming , Du Lingyan , Tan Cai‐Ping , Xia Qing , Mao Zong‐Wan , Ji Liang‐Nian
Published: April 2011

Quantum dots (QDs) have the potential to serve as photostable beacons to track siRNA delivery, which is fast becoming an attractive approach to probe gene function in cells. In this paper, we synthesized QD nanoparticles coated with β‐cyclodextrin (β‐CD) coupled to amino acids with different surface charges (positive, negative, and neutral) through direct ligand‐exchange reactions and used them to deliver siRNA. We found that these QDs are diffluent in biological buffer with high colloidal stability and have strong optical emission properties similar to those of tri‐n‐octylphosphine oxide (TOPO)‐coated QDs and also have a long fluorescence lifetime (12.5 ns for L‐His‐β‐CD‐coated CdSe/ZnSe QDs). The results of in vitro cytotoxicity and internalization of these modified QDs in normal and cancer cells showed that the β‐CD coupled to amino acid outlayers greatly improved the biocompatibility of QDs, and conferred with lower cytotoxicity even at very high concentration. In particular, the L‐His‐β‐CD‐coated CdSe/ZnSe QDs presented lower cytotoxicity to these cells (CC50 value is 180.6±3.4 μg mL−1 in ECV‐304 cells for 48 h). Transmission electron microscope (TEM) images showed that the QDs were localized in vesicles in the cytoplasm of the cells. Furthermore, compared with existing transfection agents, gene‐silencing efficiency of the modified QDs was slightly improved for HPV18 E6 gene in HeLa cells by gel electrophoresis analysis. Finally, the unique optical properties of QDs allow visible imaging of siRNA delivery in live cells. Taken together, our study not only provides new insights into the mechanisms of amino acid mediated delivery, but also greatly facilities the monitoring of gene‐silencing studies.
Benzyl and Naphthalene Methylphosphonic Acid Inhibitors of Autotaxin with Anti‐invasive and Anti‐metastatic Activity
Authors: Gupte Renuka , Patil Renukadevi , Liu Jianxiong , Wang Yaohong , Lee Sue C. , Fujiwara Yuko , Fells James , Bolen Alyssa L. , Emmons‐Thompson Karin , Yates C. Ryan , Siddam Anjaih , Panupinthu Nattapon , Pham Truc‐Chi T. , Baker Daniel L. , Parrill Abby L. , Mills Gordon B. , Tigyi Gabor , Miller Duane D.
Published: April 2011

Autotaxin (ATX, NPP2) is a member of the nucleotide pyrophosphate phosphodiesterase enzyme family. ATX catalyzes the hydrolytic cleavage of lysophosphatidylcholine (LPC) by lysophospholipase D activity, which leads to generation of the growth‐factor‐like lipid mediator lysophosphatidic acid (LPA). ATX is highly upregulated in metastatic and chemotherapy‐resistant carcinomas and represents a potential target to mediate cancer invasion and metastasis. Herein we report the synthesis and pharmacological characterization of ATX inhibitors based on the 4‐tetradecanoylaminobenzylphosphonic acid scaffold, which was previously found to lack sufficient stability in cellular systems. The new 4‐substituted benzylphosphonic acid and 6‐substituted naphthalen‐2‐ylmethylphosphonic acid analogues block ATX activity with Ki values in the low micromolar to nanomolar range against FS3, LPC, and nucleotide substrates through a mixed‐mode inhibition mechanism. None of the compounds tested inhibit the activity of related enzymes (NPP6 and NPP7). In addition, the compounds were evaluated as agonists or antagonists of seven LPA receptor (LPAR) subtypes. Analogues 22 and 30 b, the two most potent ATX inhibitors, inhibit the invasion of MM1 hepatoma cells across murine mesothelial and human vascular endothelial monolayers in vitro in a dose‐dependent manner. The average terminal half‐life for compound 22 is 10±5.4 h and it causes a long‐lasting decrease in plasma LPA levels. Compounds 22 and 30 b significantly decrease lung metastasis of B16‐F10 syngeneic mouse melanoma in a post‐inoculation treatment paradigm. The 4‐substituted benzylphosphonic acids and 6‐substituted naphthalen‐2‐ylmethylphosphonic acids described herein represent new lead compounds that effectively inhibit the ATX–LPA–LPAR axis both in vitro and in vivo.
Inhibition of Mycobacterium tuberculosis Methionine Aminopeptidases by Bengamide Derivatives
Authors: Lu Jing‐Ping , Yuan Xiu‐Hua , Yuan Hai , Wang Wen‐Long , Wan Baojie , Franzblau Scott G. , Ye Qi‐Zhuang
Published: April 2011

Methionine aminopeptidase (MetAP) carries out an essential function of protein N‐terminal processing in many bacteria and is a promising target for the development of novel antitubercular agents. Natural bengamides potently inhibit the proliferation of mammalian cells by targeting MetAP enzymes, and the X‐ray crystal structure of human type 2 MetAP in complex with a bengamide derivative reveals the key interactions at the active site. By preserving the interactions with the conserved residues inside the binding pocket while exploring the differences between bacterial and human MetAPs around the binding pocket, seven bengamide derivatives were synthesized and evaluated for inhibition of MtMetAP1a and MtMetAP1c in different metalloforms, inhibition of M. tuberculosis growth in replicating and non‐replicating states, and inhibition of human K562 cell growth. Potent inhibition of MtMetAP1a and MtMetAP1c and modest growth inhibition of M. tuberculosis were observed for some of these derivatives. Crystal structures of MtMetAP1c in complex with two of the derivatives provided valuable structural information for improvement of these inhibitors for potency and selectivity.
Early detection of ovarian cancer
Authors: Bell Jeffrey G.
Published: April 2011

Primary care physicians are recognizing the symptoms of ovarian cancer and ordering the appropriate diagnostic tests. On the basis of the diverse behavior of epithelial cancers, the goal of screening technology should shift from diagnosing early stage to diagnosing low‐volume disease.
Soft tissue sarcoma diagnosed subsequent to lymphoma is associated with prior radiotherapy and decreased survival
Authors: Katz Steven C. , Baldwin Keith , Karakousis Giorgos , Moraco Nicole , Buglino Anthony , Singer Samuel , Brennan Murray F.
Published: April 2011

BACKGROUND:

Cancer survivors are at increased risk for second malignancies, and vigilance is thus required. The authors sought to determine whether there was an association among lymphoma, sarcoma, and the associated treatments for these diseases.

METHODS:

From the authors' prospective soft tissue sarcoma (STS) database of 8240 patients, they identified 112 patients with STS and lymphoma treated from 1982 to 2009 who had complete follow‐up data. They examined the importance of the initial diagnosis in patients with both STS and lymphoma, in addition to determining the role of radiation therapy, a known inducer of sarcoma.

RESULTS:

Review of their sarcoma, gastric, urology, breast, and gynecology databases revealed that lymphoma (95%) or leukemia (5%) occurred in 1.6% of STS patients in comparison to 0.5% of patients in the other databases (P < .01; odds ratio, 3.1; 95% confidence interval, 2.6‐3.8). Patients diagnosed with STS only were more likely to die of disease at 10 years compared with those with STS and lymphoma (P = .006), but this difference was not significant when patients presenting with recurrence or metastases were excluded. Among patients with lymphoma and STS, lymphoma was the first diagnosis in 71% of patients. Median survival after STS diagnosis was shorter when lymphoma was the initial diagnosis (67 vs 170 months, P = .002), and these patients were more likely to have radiation‐associated STS (44% vs 3%, P < .001).

CONCLUSIONS:

There was a 3‐fold higher incidence of lymphoma in STS patients compared with other solid tumors. The poor prognosis of those diagnosed with both STS and lymphoma was most likely a consequence of prior irradiation. Cancer 2011. © 2011 American Cancer Society.
Using myc genes to search for stem cells in the ciliary margin of the Xenopus retina
Authors: Xue Xiao Yan , Harris William A.
Published: April 2011

The ciliary marginal zone (CMZ) of fish and frog retinas contains cells that proliferate throughout postembryonic development as the retina grows with increasing body size, indicating the presence of stem cells in this region. However, neither the location nor the molecular identity of retinal stem cells has been identified. Here, we show in Xenopus that c‐myc and n‐myc are sequentially expressed both during development and in the post‐embryonic retina. The c‐myc+/n‐myc− cells near the extreme periphery of the CMZ cycle more slowly and preferentially retain DNA label compared to their more central cmyc+/n‐myc+ neighbors which cycle rapidly and preferentially dilute DNA label. During retinal development c‐myc is functionally required earlier than n‐myc, and n‐myc expression depends on earlier c‐myc expression. The expression of c‐myc but not n‐myc in the CMZ depends on growth factor signaling. Our results suggest that c‐myc+/n‐myc− cells in the far peripheral CMZ are candidates for a niche‐dependent population of retinal stem cells that give rise to more centrally located and rapidly dividing n‐myc+ progenitors of more limited proliferative potential. Analysis of homologues of these genes in the zebrafish CMZ suggests that the transition from c‐myc to n‐myc expression might be conserved in other lower vertebrates whose retinas growth throughout life. © 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 475–490, 2012
Zebrafish as a genomics model for human neurological and polygenic disorders
Authors: Becker Thomas S. , Rinkwitz Silke
Published: April 2011

Whole exome sequencing and, to a lesser extent, genome‐wide association studies, have provided unprecedented advances in identifying genes and candidate genomic regions involved in the development of human disease. Further progress will come from sequencing the entire genome of multiple patients and normal controls to evaluate overall mutational burden and disease risk. A major challenge will be the interpretation of the resulting data and distinguishing true pathogenic mutations from rare benign variants. While in model organisms such as the zebrafish, mutants are sought that disrupt the function of individual genes, human mutations that cause, or are associated with, the development of disease, are often not acting in a Mendelian fashion, are frequently of small effect size, are late onset, and may reside in noncoding parts of the genome. The zebrafish model is uniquely poised for understanding human coding‐ and noncoding variants because of its sequenced genome, a large body of knowledge on gene expression and function, rapid generation time, and easy access to embryos. A critical advantage is the ease of zebrafish transgenesis, both for the testing of human regulatory DNA driving expression of fluorescent reporter proteins, and the expression of mutated disease‐associated human proteins in specific neurons to rapidly model aspects of neurological disorders. The zebrafish affords progress both through its model genome and it is rapidly developing transparent model vertebrate embryo. © 2011 Wiley Periodicals, Inc. Develop Neurobiol 72: 415–428, 2012
Detection of isoform‐specific fibroblast growth factor receptors by whole‐mount in situ hybridization in early chick embryos
Authors: Nishita Junko , Ohta Sho , Bleyl Steven B. , Schoenwolf Gary C.
Published: April 2011

We have developed “b” and “c” isoform‐specific chicken fibroblast growth factor (FGF) receptor 1–3 probes for in situ hybridization. We rigorously demonstrate the specificity of these probes by using both dot blot hybridization and whole‐mount in situ hybridization during neurulation and early postneurulation stages, and we compare expression patterns of each of the three isoform‐specific probes to one another and to generic probes to each of the three (non–isoform‐specific) FGF receptors. We show that the expression pattern of each receptor is represented by the collective expression of each of its two isoforms, with the expression of each FGF receptor being most similar to that of its “c” isoform at two of the three stages studied, and that tissue and stage differences exist in the patterns of expression of the six isoforms. We demonstrate the usefulness of these probes for defining the differential tissue expression of FGF receptor 1–3 isoforms. Developmental Dynamics 240:1537–1547, 2011. © 2011 Wiley‐Liss, Inc.
The chicken polydactyly (Po) locus causes allelic imbalance and ectopic expression of Shh during limb development
Authors: Dunn Ian C. , Paton I. Robert , Clelland Allyson K. , Sebastian Sujith , Johnson Edward J. , McTeir Lynn , Windsor Dawn , Sherman Adrian , Sang Helen , Burt Dave W. , Tickle Cheryll , Davey Megan G.
Published: April 2011

Point mutations in the intronic ZRS region of Lmbr1, a limb specific cis‐regulatory element of Sonic hedgehog (Shh), are associated with polydactyly in humans, cats, and mice. We and others have recently mapped the dominant preaxial polydactyly (Po) locus in Silkie chickens to a single nucleotide polymorphism (SNP) in the ZRS region. Using polymorphisms in the chicken Shh sequence, we confirm that the ZRS region directly regulates Shh expression in the developing limb causing ectopic Shh expression in the anterior leg, prolonged Shh expression in the posterior limb, and allelic imbalance between wt and Slk Shh alleles in heterozygote limbs. Using Silkie legs, we have explored the consequences of increased Shh expression in the posterior leg on the patterning of the toes, and the induction of preaxial polydactyly. Developmental Dynamics 240:1163–1172, 2011. © 2011 Wiley‐Liss, Inc.
Non‐canonical wnt signals antagonize and canonical wnt signals promote cell proliferation in early kidney development
Authors: McCoy Kyle E. , Zhou Xiaolan , Vize Peter D.
Published: April 2011

Canonical and non‐canonical wnt signals often have opposed roles. In this report, we use developing Xenopus embryos to demonstrate a novel anti‐proliferative role for non‐canonical wnt signals in the very earliest stages of kidney development. Non‐canonical wnt signals were down‐regulated using PDZ domain mutants of dishevelled 2 and up‐regulated using wild‐type vang‐like 2, while canonical signals were manipulated using dominant‐negative forms of lef1 or treatment with lithium. When non‐canonical signals are down‐regulated in the developing Xenopus pronephros, cell proliferation rates increased and when canonical signals were shutdown the opposite occurred. Treatment with lithium chloride has a powerful pro‐proliferative effect on the forming nephric primordium. Together these data show that in addition to previously documented antagonisms between these distinct wnt signaling pathways, they also have opposing effects on cell division. Developmental Dynamics 240:1558–1566, 2011. © 2011 Wiley‐Liss, Inc.
Pleiotropic patterning response to activation of Shh signaling in the limb apical ectodermal ridge
Authors: Wang Chi‐Kuang Leo , Tsugane Mizuyo H. , Scranton Victoria , Kosher Robert A. , Pierro Louis J. , Upholt William B. , Dealy Caroline N.
Published: April 2011

Sonic hedgehog (Shh) signaling in the limb plays a central role in coordination of limb patterning and outgrowth. Shh expression in the limb is limited to the cells of the zone of polarizing activity (ZPA), located in posterior limb bud mesoderm. Shh is not expressed by limb ectoderm or apical ectodermal ridge (AER), but recent studies suggest a role for AER–Shh signaling in limb patterning. Here, we have examined the effects of activation of Shh signaling in the AER. We find that targeted expression of Shh in the AER activates constitutive Shh signaling throughout the AER and subjacent limb mesoderm, and causes a range of limb patterning defects with progressive severity from mild polydactyly, to polysyndactyly with proximal defects, to severe oligodactyly with phocomelia and partial limb ventralization. Our studies emphasize the importance of control of the timing, level and location of Shh pathway signaling for limb anterior–posterior, proximal–distal, and dorsal–ventral patterning. Developmental Dynamics 240:1289–1302, 2011. © 2011 Wiley‐Liss, Inc.
Development of the external genitalia: Conserved and divergent mechanisms of appendage patterning
Authors: Cohn Martin J.
Published: April 2011

Over the past decade, the genetics of external genital development have begun to be understood. Male and female external genitalia develop from the genital tubercle. The early tubercle has a superficial resemblance to the limb bud, but an important distinction is that the limb consists of only mesoderm and ectoderm, whereas the genital tubercle also has an endodermal component, the urethral epithelium. Urethral epithelium, which expresses Sonic hedgehog, acts as a signaling region that controls outgrowth and pattern formation, and ultimately differentiates into the urethral tube. While there are intriguing parallels between limb and genital development, recent studies have identified some key differences, including the role of Fgf signaling. Our understanding of the mechanisms of genital development still lags far behind the limb, and major questions remain to be answered, including the molecular nature of the signals that initiate genital budding, sustain outgrowth, induce tissue polarity and orchestrate urethral tubulogenesis. Developmental Dynamics 240:1108–1115, 2011. © 2011 Wiley‐Liss, Inc.
Guided self‐help as the first step for bulimic symptoms: Implementation of a stepped‐care model within specialized psychiatry
Authors: Ramklint Mia , Jeansson Mats , Holmgren Sven , Ghaderi Ata
Published: April 2011

Objective:

This study describes the implementation and effectiveness of the first step, guided self‐help (GSH), in a clinical setting, of a stepped‐care model of cognitive behavior therapy for patients with bulimic symptoms.

Method:

Eighty‐nine patients participated.

Results:

In the intent to‐treat analyses, the effect sizes were small to moderate (0.25–0.66). However, the effect sizes were substantially larger (0.44–1.66) for the patients who completed all the GSH sessions (45%). The majority of noncompleters stayed within psychiatric services. Supplementary treatments were mostly directed towards comorbid conditions, especially depression. Those discontinuing treatment in advance where characterized by more lifetime diagnoses and higher ratings on the restraint subscale of the EDE‐Q.

Discussion:

GSH within specialized psychiatry might be effective for about 30% of the patients. There is no indication of patients losing their confidence in psychiatric services by being offered GSH as the first treatment. © 2011 by Wiley Periodicals, Inc. (Int J Eat Disord 2012)
Synthesis and Luminescent Properties of Cerium‐, Terbium‐, or Dysprosium‐Doped Gd4Si2O7N2 Materials
Authors: Song Yanhua , Guo Ning , You Hongpeng
Published: April 2011

Gd4Si2O7N2, a new oxynitride, has been prepared and the luminescent properties of the Ce3+, Tb3+ or Dy3+ doped product have been studied. XRD results indicate that Gd4Si2O7N2 is isostructural with Tb4Si2N2O7 and belongs to the monoclinic system. The SEM image shows that the synthesized powder disperses well and the particle diameter is between 1.40–4.0 μm. Upon excitation at 350 nm, Gd4Si2O7N2:Ce3+ exhibits blue emission peaking at 445 nm, which may have potential application as a blue phosphor in the field of solid state lighting. The major mechanism for the concentration quenching of the Ce3+ emission in Gd4Si2O7N2:Ce3+ is dipole‐dipole interactions. The emission colour of Gd4Si2O7N2:Tb3+ can be tuned from blue to green by changing the Tb3+ concentration. The ratio of yellow to blue emission for Gd4Si2O7N2:Dy3+ grows higher with an increase in the Dy3+ concentration. Energy transfer from the Gd3+ ions to Tb3+ or Dy3+ ions in the Gd4Si2O7N2 host was also observed.
Enthalpy–Entropy Correlation for Hydrogen Adsorption on MOFs: Variable‐Temperature FTIR Study of Hydrogen Adsorption on MIL‐100(Cr) and MIL‐101(Cr) (Eur. J. Inorg. Chem. 11/2011)
Authors: Palomino Gemma Turnes , Cabello Carlos Palomino , Areán Carlos Otero
Published: April 2011

The cover picture shows an allegoric representation of the dawning hopes of a hydrogen energy transition, which would alleviate the foreseeable shortage of fossil fuels for the transportation sector. Metal‐organic frameworks (MOFs), represented by the honeycomb structure, have become a main focus in the current search for economically viable materials for hydrogen storage and delivery. The signpost at the left of the picture is a reminder that thermodynamics of the hydrogen uptake and delivery process is ruled by the corresponding enthalpy and entropy changes, which are shown to be interrelated. Both of these thermodynamic quantities have to be taken into account for intelligent design of hydrogen storage materials. Details are discussed in the article by C. O. Areán et al. on p. 1703 ff.
Diastereoselective Deprotonative Metalation of Sugar‐Derived Ferrocene Esters Using Mixed Lithium–Cadmium Combinations
Authors: Sreeshailam Aare , Dayaker Gandrath , Chevallier Floris , Roisnel Thierry , Krishna Palakodety Radha , Mongin Florence
Published: April 2011

The ability of a mixed lithium–cadmium amide to deproto‐metallate diastereoselectively several sugar‐derived ferrocene esters was studied. The ferrocenecarboxylates generated from α‐D‐glucofuranoses gave the best results, as evidenced after subsequent trapping with iodine. Good chemical yields and diastereoselectivities up to 82 % in favor of the SP stereoisomer were obtained. The use of a different chiral group favored the formation of the RP stereoisomer, isolated in 34 % yield and 98 % diastereoselectivity.
Autologistic models for binary data on a lattice
Authors: Hughes John , Haran Murali , Caragea Petruţa C.
Published: April 2011

The autologistic model is a Markov random field model for spatial binary data. Because it can account for both statistical dependence among the data and for the effects of potential covariates, the autologistic model is particularly suitable for problems in many fields, including ecology, where binary responses, indicating the presence or absence of a certain plant or animal species, are observed over a two‐dimensional lattice. We consider inference and computation for two models: the original autologistic model due to Besag, and the centered autologistic model proposed recently by Caragea and Kaiser. Parameter estimation and inference for these models is a notoriously difficult problem due to the complex form of the likelihood function. We study pseudolikelihood (PL), maximum likelihood (ML), and Bayesian approaches to inference and describe ways to optimize the efficiency of these algorithms and the perfect sampling algorithms upon which they depend, taking advantage of parallel computing when possible. We conduct a simulation study to investigate the effects of spatial dependence and lattice size on parameter inference, and find that inference for regression parameters in the centered model is reliable only for reasonably large lattices (n > 900) and no more than moderate spatial dependence. When the lattice is large enough, and the dependence small enough, to permit reliable inference, the three approaches perform comparably, and so we recommend the PL approach for its easier implementation and much faster execution. Copyright © 2011 John Wiley & Sons, Ltd.
The role of statistics in the analysis of ecosystem services
Authors: Smith R. I. , Dick J. McP. , Scott E. M.
Published: April 2011

Operationalising the holistic approach implicit in an ecosystem services assessment is a challenge, incorporating social and economic considerations alongside the physical, chemical and biological function of ecosystems. The paper considers the role of statistics within a range of frameworks proposed for the analysis of ecosystem services. The use of different statistical techniques within the component parts of an ecosystem services assessment framework are discussed, including (1) data availability and sampling strategies, (2) statistical data analysis, (3) geography and spatial models, (4) meta‐analysis, (5) environmental models, (6) societal models, (7) feedbacks and loop analysis, and (8) graphical models including Bayesian belief networks. Issues of value and the potential for a statistical contribution to multivariate non‐monetary valuation are considered. We argue that statistics has an underpinning role by providing tools to link together the component elements along with their uncertainties for a thorough ecosystem services assessment, and should be an integral part of this developing inter‐disciplinary research area. Copyright © 2011 John Wiley & Sons, Ltd.