bluuebunny/crossref_metadata_2025 huggingface dataset:
Tuning the Au‐Free InSb Nanocrystal Morphologies Grown by Patterned Metal–Organic Chemical Vapor Deposition
Authors: Lin Andrew , Shapiro Joshua N. , Eisele Holger , Huffaker Diana L.
Published: April 2014

A thorough study of direct InSb nanocrystal formations on patterned InAs (111)B substrates is provided. These nanostructures are created without the use of Au catalysts or initial InAs segments. Under the growth conditions generally used for selective‐area, catalyst‐free epitaxy, a wide range of InSb nanocrystal morphologies are observed. This is because the low‐energy InSb surfaces, studied by first‐principles calculations, are the {111} facets as opposed to the {110} facets. By controlling the V/III ratio during growth, different InSb nanostructures can be achieved. Using low V/III growth conditions, In droplets start to form and InSb nucleation takes place at the droplet–semiconductor interface only, resulting in vertical, self‐catalyzed InSb nanopillars.
Highly Sensitive Non‐Classical Strain Gauge Using Organic Heptazole Thin‐Film Transistor Circuit on a Flexible Substrate
Authors: Nam Seung Hee , Jeon Pyo Jin , Min Sung Wook , Lee Young Tack , Park Eun Young , Im Seongil
Published: April 2014

A non‐classical organic strain gauge as a voltage signal sensor is reported, using an inverter‐type thin‐film transistor (TFT) circuit, which is able to sensitively measure a large quantity of elastic strain (up to ≈2.48%), which approaches an almost folding state. Novel heptazole‐based organic TFTs are chosen to be incorporated in this gauge circuit; organic solid heptazole has small domain size in general. While large crystal domain‐pentacene TFTs seldom show sufficient current variation upon mechanical bending for tensile strain, these heptazole TFTs demonstrate a significant variation for the same strain condition as applied to pentacene devices. In addition, the pentacene channel does not recover to its original electric state after bending but heptazole channels are very elastic and reversible, even after going through serious bending. More interesting is that the heptazole TFTs show only a little variation of signal current under horizontal direction strain, while they make a significant amount of current decrease under vertical direction strain. Utilizing the anisotropic response to the tensile bending strain, an ultrasensitive voltage output strain gauge composed of a horizontally and vertically oriented TFT couple is demonstrated.
Peptide Dendrimer–Doxorubicin Conjugate‐Based Nanoparticles as an Enzyme‐Responsive Drug Delivery System for Cancer Therapy
Authors: Zhang Chengyuan , Pan Dayi , Luo Kui , She Wenchuan , Guo Chunhua , Yang Yang , Gu Zhongwei
Published: April 2014

Peptide dendrimers have shown promise as an attractive platform for drug delivery. In this study, mPEGylated peptide dendrimer–doxorubicin (dendrimer–DOX) conjugate‐based nanoparticle is prepared and characterized as an enzyme‐responsive drug delivery vehicle. The drug DOX is conjugated to the periphery of dendrimer via an enzyme‐responsive tetra‐peptide linker Gly‐Phe‐Leu‐Gly (GFLG). The dendrimer–DOX conjugate can self‐assemble into nanoparticle, which is confirmed by dynamic light scattering, scanning electron microscopy, and transmission electron microscopy studies. At equal dose, mPEGylated dendrimer–DOX conjugate‐based nanoparticle results in significantly high antitumor activity, and induces apoptosis on the 4T1 breast tumor model due to the evidences from tumor growth curves, an immunohistochemical analysis, and a histological assessment. The in vivo toxicity evaluation demonstrates that nanoparticle substantially avoids DOX‐related toxicities and presents good biosafety without obvious side effects to normal organs of both tumor‐bearing and healthy mice as measured by body weight shift, blood routine test, and a histological analysis. Thus, the mPEGylated peptide dendrimer–DOX conjugate‐based nanoparticle may be a potential nanoscale drug delivery vehicle for the breast cancer therapy.
The Study of Spin‐Valley Coupling in Atomically Thin Group VI Transition Metal Dichalcogenides
Authors: Zhu Bairen , Zeng Hualing , Dai Junfeng , Cui Xiaodong
Published: April 2014

In the hunt for ultimately thin electronic devices, atomically thin layers of group VI transition metal dichalcogenides (TMDCs) are recognized as ideal 2D materials after the success of graphene. Monolayer TMDCs feature nonzero but contrasting Berry curvatures and valence‐band spin splitting with opposite sign at inequivalent K and K′ valleys located at the corners of the 1st Brillouin zone. These features raise the possibility of manipulating electrons' valley and spin degrees of freedom by optical and electric means, which subsequently makes monolayer TMDCs promising candidates for spintronics and valleytronics applications.
Three‐Dimensional Nanofabrication by Block Copolymer Self‐Assembly
Authors: Ross Caroline A. , Berggren Karl K. , Cheng Joy Y. , Jung Yeon Sik , Chang Jae‐Byum
Published: April 2014

Thin films of block copolymers are widely seen as enablers for nanoscale fabrication of semiconductor devices, membranes, and other structures, taking advantage of microphase separation to produce well‐organized nanostructures with periods of a few nm and above. However, the inherently three‐dimensional structure of block copolymer microdomains could enable them to make 3D devices and structures directly, which could lead to efficient fabrication of complex heterogeneous structures. This article reviews recent progress in developing 3D nanofabrication processes based on block copolymers.
Ruthenium‐Catalyzed Intramolecular Allylic Dearomatization/Migration Reaction of Indoles and Pyrroles
Authors: Yang Ze‐Peng , Zhuo Chun‐Xiang , You Shu‐Li
Published: April 2014

An efficient synthesis of polycyclic indole and pyrrole derivatives via a ruthenium‐catalyzed intramolecular allylic dearomatization/migration reaction has been developed. This method features wide substrate scope, mild reaction conditions, and an operationally simple procedure. The capture of the spiro intermediate provides solid evidence for the dearomatization/migration reaction pathway.

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Enantioselective Cascade Oxa‐Michael–Michael Reactions of 2‐Hydroxynitrostyrenes with Enones Using a Prolinol Thioether Catalyst
Authors: Xia Ai‐Bao , Wu Chao , Wang Tao , Zhang Yan‐Peng , Du Xiao‐Hua , Zhong Ai‐Guo , Xu Dan‐Qian , Xu Zhen‐Yuan
Published: April 2014

The efficient simultaneous activation of cyclohexenones or simple alkyl acyclic enones and 2‐hydroxynitrostyrenes was realized by using a prolinol thioether catalyst. Thus, a highly chemo‐, diastereo‐ and enantioselective synthesis of functionalized tetrahydroxanthenones and chromanes with up to three contiguous stereocenters was developed.

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Selective Palladium‐Catalyzed Direct CH Arylation of Unsubstituted N‐Protected Pyrazoles
Authors: Kumpulainen Esa T. T. , Pohjakallio Antti
Published: April 2014

A highly selective C‐5 arylation of N‐dimethylaminosulfamoyl‐protected pyrazole with aryl bromides is catalyzed by 2–5 mol% palladium in the presence of triphenylphosphine ligand and carboxylic acid additive. Selectivities up to 45:1 (C‐5:C‐4) can be achieved by running the reaction in non‐polar solvents. A thorough study of scope and limitations shows good general tolerance of aryl bromide substitution. However, limitations on tolerance of ortho‐subsitution and protic functional groups were established. Together with a telescoped deprotection step this method presents a viable alternative for the synthesis of C‐3 arylated pyrazole building blocks.

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Chiral Phosphoric Acid‐Catalyzed Enantioselective Three‐ Component Aza‐Diels–Alder Reactions of Aminopyrroles and Aminopyrazoles
Authors: Brioche Julien , Courant Thibaut , Alcaraz Lilian , Stocks Michael , Furber Mark , Zhu Jieping , Masson Géraldine
Published: April 2014

A highly stereoselective three‐component Povarov reaction, catalyzed by (R)‐ and (S)‐BINOL hydrogen phosphate, was achieved for the first time with aminopyrroles and aminopyrazoles as 2‐azadiene precursors. A variety of aldehydes, enecarbamates, amino‐substituted azines participated in the reaction to afford the tetrahydropyrrolopyridines and tetrahydropyrazolopyridines in good yields with excellent diatereo‐ and enantioselectivities. A stereochemical model is proposed to account for the observed absolute stereochemistry.

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Electrogenerated N‐Heterocyclic Carbene in Ionic Liquid: An Insight into the Mechanism of the Oxidative Esterification of Aromatic Aldehydes
Authors: Forte Gianpiero , Chiarotto Isabella , Inesi Achille , Loreto Maria Antonietta , Feroci Marta
Published: April 2014

An N‐heterocyclic carbene (NHC), generated by cathodic reduction of BMIm BF4, mediates the oxidative esterification of aromatic aldehydes with organic bromides in the corresponding ionic liquid as solvent. The product recovery by simple extractive work‐up with diethyl ether allowed the ionic liquid to be recycled up to 9 times for subsequent electrolyses, with no significant loss in the product yield. The isolation of an intermediate, whose structure was confirmed by synthesis and transformation into the ester, provided the key for a mechanistic insight into the reaction.

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Clinical profiles of multiple myeloma in Asia—An Asian Myeloma Network study
Authors: Kim Kihyun , Lee Jae Hoon , Kim Jin Seok , Min Chang Ki , Yoon Sung Soo , Shimizu Kazuyuki , Chou Takaaki , Kosugi Hiroshi , Suzuki Kenshi , Chen Wenming , Hou Jian , Lu Jin , Huang Xiao‐Jun , Huang Shang‐Yi , Chng Wee Joo , Tan Daryl , Teoh Gerrard , Chim Chor Sang , Nawarawong Weerasak , Siritanaratkul Noppadol , Durie Brian G.
Published: April 2014

The incidence of multiple myeloma (MM) is known to be variable according to ethnicity. However, the differences in clinical characteristics between ethnic groups are not well‐defined. In Asian countries, although the incidence of MM has been lower than that of Western countries, there is growing evidence that MM is increasing rapidly. The Asian Myeloma Network decided to initiate the first multinational project to describe the clinical characteristics of MM and the clinical practices in Asia. Data were retrospectively collected from 23 centers in 7 countries and regions. The clinical characteristics at diagnosis, survival rates and initial treatment of 3,405 symptomatic MM patients were described. Median age was 62 years (range, 19–106), with 55.6% of being male. Median overall survival (OS) was 47 months (95% CI 44.0–50.0). Stem cell transplantation was performed in 666 patients who showed better survival rates (79 vs. 41 months, P < 0.001). The first‐line treatments of 2,970 patients were analyzed. The overall response rate was 71% including very good partial response or better in 31% of the 2,660 patients those were able to be evaluated. New drugs including bortezomib, thalidomide, and lenalidomide were used in 36% of 2,970 patients and affected OS when used as a first‐line treatment. Am. J. Hematol. 89:751–756, 2014. © 2014 Wiley Periodicals, Inc.
A phase 1 study of ACE‐536, a regulator of erythroid differentiation, in healthy volunteers
Authors: Attie Kenneth M. , Allison Mark J. , McClure Ty , Boyd Ingrid E. , Wilson Dawn M. , Pearsall Amelia E. , Sherman Matthew L.
Published: April 2014

ACE‐536, a recombinant protein containing a modified activin receptor type IIB, is being developed for the treatment of anemias caused by ineffective erythropoiesis, such as thalassemias and myelodysplastic syndromes. ACE‐536 acts through a mechanism distinct from erythropoiesis‐stimulating agents to promote late‐stage erythroid differentiation by binding to transforming growth factor‐β superfamily ligands and inhibiting signaling through transcription factors Smad 2/3. The goal of this Phase 1 study was to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ascending dose levels of ACE‐536 in healthy volunteers. Thirty‐two postmenopausal women were randomized in sequential cohorts of eight subjects each to receive up to two doses of either ACE‐536 (0.0625–0.25 mg/kg) or placebo (3:1 randomization) given subcutaneously every 2 weeks. Mean baseline age was 59.4 years, and hemoglobin was 13.2 g/dL. ACE‐536 was well tolerated at dose levels up to 0.25 mg/kg over the 1‐month treatment period. There were no serious or severe adverse events, nor clinically meaningful changes in safety laboratory measures or vital signs. Mean ACE‐536 AUC0–14d and Cmax increased proportionally after first dose; mean t½ was 15–16 days. Dose‐dependent increases in hemoglobin concentration were observed, beginning 7 days after initiation of treatment and maintained for several weeks following treatment. The proportion of subjects with a hemoglobin increase ≥1.0 g/dL increased in a dose‐dependent manner to 83.3% of subjects in the highest dose group, 0.25 mg/kg. ACE‐536 was well tolerated and resulted in sustained increases in hemoglobin levels in healthy postmenopausal women. Am. J. Hematol. 89:766–770, 2014. © 2014 Wiley Periodicals, Inc.
Macrocerebellum, epilepsy, intellectual disability, and gut malrotation in a child with a 16q24.1–q24.2 contiguous gene deletion
Authors: Seeley Andrea H. , Durham Mark A. , Micale Mark A. , Wesolowski Jeffrey , Foerster Bradley R. , Martin Donna M.
Published: April 2014

Macrocerebellum is a rare condition characterized by enlargement of the cerebellum with conservation of the overall shape and cytoarchitecture. Here, we report on a child with a distinctive constellation of clinical features including macrocerebellum, epilepsy, apparent intellectual disability, dysautonomia, gut malrotation, and poor gut motility. Oligonucleotide chromosome microarray analysis identified a 16q24.1–q24.2 deletion that included four OMIM genes (FBXO31, MAP1LC3B, JPH3, and SLC7A5). Review of prior studies describing individuals with similar or overlapping16q24.1–q24.2 deletions identified no other reports of macrocerebellum. These observations highlight a potential genetic cause of this rare disorder and raise the possibility that one or more gene(s) in the 16q24.1–q24.2 interval regulate cerebellar development. © 2014 Wiley Periodicals, Inc.
The function of greetings in male Tonkean macaques
Authors: De Marco Arianna , Sanna Andrea , Cozzolino Roberto , Thierry Bernard
Published: April 2014

Males living in multi‐male groups are both strong rivals and potential allies. In several primate species they regularly interact through ritualized exchanges known as greetings. We studied five captive groups of Tonkean macaques (Macaca tonkeana) to test five hypotheses regarding the social function of greetings. We found that greetings were mostly reciprocal interactions, and that they often involved physical contact and facial displays. Although they were mostly initiated by the higher‐ranking individual in each dyad, subordinates could initiate approximately one‐third of greetings, which indicates that greetings do not serve as a formal acknowledgement of dominance relationships. Although greeting frequencies were negatively correlated to the frequency of supplantations and conflicts, they were not significantly influenced by age and dominance status, showing that greetings are not used to appease partners or decrease tension between males. Males most frequently greeted partners with whom they spent more time in proximity and body contact, and this is consistent with the hypothesis that greetings play a role in reinforcing social relationships. Lastly, greetings increased in frequency between individuals involved in challenges for rank, lending support to the hypothesis that males assess the state of their social relationships through greetings. Am. J. Primatol. 76:989–998, 2014. © 2014 Wiley Periodicals, Inc.
Regulated Incorporation of Two Different Metal Ions into Programmed Sites in a Duplex by DNA Polymerase Catalyzed Primer Extension
Authors: Funai Tatsuya , Nakamura Junko , Miyazaki Yuki , Kiriu Risa , Nakagawa Osamu , Wada Shun‐ichi , Ono Akira , Urata Hidehito
Published: April 2014

Metal‐mediated base pairs formed by the coordination of metal ions to natural or artificial bases impart unique chemical and physical properties to nucleic acids and have attracted considerable interest in the field of nanodevices. AgI ions were found to mediate DNA polymerase catalyzed primer extension through the formation of a C–AgI–T base pair, as well as the previously reported C–AgI–A base pair. The comparative susceptibility of dNTPs to AgI‐mediated enzymatic incorporation into the site opposite cytosine in the template was shown to be dATP>dTTP≫dCTP. Furthermore, two kinds of metal ions, AgI and HgII, selectively mediate the incorporation of thymidine 5′‐triphosphate into sites opposite cytosine and thymine in the template, respectively. In other words, the regulated incorporation of different metal ions into programmed sites in the duplex by DNA polymerase was successfully achieved.
Doubling the Capacity of Lithium Manganese Oxide Spinel by a Flexible Skinny Graphitic Layer
Authors: Noh Hyun Kuk , Park Han‐Saem , Jeong Hu Young , Lee Sang Uck , Song Hyun‐Kon
Published: April 2014

By coating nanoparticular lithium manganese oxide (LMO) spinel with a few layers of graphitic basal planes, the capacity of the material reached up to 220 mA h g−1 at a cutoff voltage of 2.5 V. The graphitic layers 1) provided a facile electron‐transfer highway without hindering ion access and, more interestingly, 2) stabilized the structural distortion at the 3 V region reaction. The gain was won by a simple method in which microsized LMO was ball‐milled in the presence of graphite with high energy. Vibratory ball milling pulverized the LMO into the nanoscale, exfoliated graphite of less than 10 layers and combined them together with an extremely intimate contact. Ab initio calculations show that the intrinsically very low electrical conductivity of the tetragonal phase of the LMO is responsible for the poor electrochemical performance in the 3 V region and could be overcome by the graphitic skin strategy proposed.
Palladium‐Catalyzed C(sp3)H Activation: A Facile Method for the Synthesis of 3,4‐Dihydroquinolinone Derivatives
Authors: Yan Jia‐Xuan , Li Hu , Liu Xiang‐Wei , Shi Jiang‐Ling , Wang Xin , Shi Zhang‐Jie
Published: April 2014

3,4‐Dihydroquinolinones were synthesized by the palladium‐catalyzed, oxidative‐addition‐initiated activation and arylation of inert C(sp3)H bonds. Pd(OAc)2 and P(o‐tol)3 were used as the catalyst and ligand, respectively, to improve the efficiency of the reaction. A further advantage of this reaction is that it could be performed in air. A relatively rare seven‐membered palladacycle was proposed as a key intermediate of the catalytic cycle.
Design of Monodisperse and Well‐Defined Polypeptide‐Based Polyvalent Inhibitors of Anthrax Toxin
Authors: Patke Sanket , Boggara Mohan , Maheshwari Ronak , Srivastava Sunit K. , Arha Manish , Douaisi Marc , Martin Jacob T. , Harvey Ian B. , Brier Matthew , Rosen Tania , Mogridge Jeremy , Kane Ravi S.
Published: April 2014

The design of polyvalent molecules, presenting multiple copies of a specific ligand, represents a promising strategy to inhibit pathogens and toxins. The ability to control independently the valency and the spacing between ligands would be valuable for elucidating structure–activity relationships and for designing potent polyvalent molecules. To that end, we designed monodisperse polypeptide‐based polyvalent inhibitors of anthrax toxin in which multiple copies of an inhibitory toxin‐binding peptide were separated by flexible peptide linkers. By tuning the valency and linker length, we designed polyvalent inhibitors that were over four orders of magnitude more potent than the corresponding monovalent ligands. This strategy for the rational design of monodisperse polyvalent molecules may not only be broadly applicable for the inhibition of toxins and pathogens, but also for controlling the nanoscale organization of cellular receptors to regulate signaling and the fate of stem cells.
Mechanistic Insights into Polycycle Formation by Reductive Cyclization in Ikarugamycin Biosynthesis
Authors: Zhang Guangtao , Zhang Wenjun , Zhang Qingbo , Shi Ting , Ma Liang , Zhu Yiguang , Li Sumei , Zhang Haibo , Zhao Yi‐Lei , Shi Rong , Zhang Changsheng
Published: April 2014

Ikarugamycin is a member of the polycyclic tetramate macrolactams (PTMs) family of natural products with diverse biological activities. The biochemical mechanisms for the formation of polycyclic ring systems in PTMs remain elusive. The enzymatic mechanism of constructing an inner five‐membered ring in ikarugamycin is reported. A three‐gene‐cassette ikaABC from the marine‐derived Streptomyces sp. ZJ306 is sufficient for conferring ikarugamycin production in a heterologous host. IkaC catalyzes a reductive cyclization reaction to form the inner five‐membered ring by a Michael addition‐like reaction. This study provides the first biochemical evidence for polycycle formation in PTMs and suggests a reductive cyclization strategy which may be potentially applicable in general to the corresponding ring formation in other PTMs.
Biocompatible and biodegradable alginate/poly(N‐isopropylacrylamide) hydrogels for sustained theophylline release
Authors: Dumitriu Raluca Petronela , Oprea Ana‐Maria , Natalia Cheaburu Catalina , Nistor Manuela‐Tatiana , Novac Ovidiu , Ghiciuc Cristina Mihaela , Profire Lenuta , Vasile Cornelia
Published: April 2014

Mixed‐interpenetrated polymeric networks based on sodium alginate (ALG) and poly(N‐isopropylacryl amide) (PNIPAAm) covalently cross‐linked with N,N'‐methylenebisacrylamide are studied for their biocompatibility, nontoxicity, and biodegradability aiming their application in drug delivery. The presence of drug‐polymeric matrix interactions and the distribution of the drug in the polymeric network for theophylline‐loaded ALG/PNIPAAm hydrogels are also investigated by spectroscopic and microscopic methods. The quantitative evaluation of theophylline loaded hydrogels performed by NIR‐CI technique shows a better drug entrapment and a higher homogeneity of the samples with increased alginate content. The thermal behavior of the hydrogels is significantly modified by theophylline presence. The application of the ALG/PNIPAAm hydrogels as carriers for sustained drug release formulations was assessed by the theophylline release tests performed both by in vitro and in vivo studies. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 40733.
cDNA CLONING AND HETEROLOGOUS EXPRESSION OF AN ENDO‐β‐1,4‐GLUCANASE FROM THE FUNGUS‐GROWING TERMITE Macrotermes barneyi
Authors: Ni Jinfeng , Wu Yan , Yun Chao , Yu Menglan , Shen Yulong
Published: April 2014

Major β‐glucosidase (BG) and endo‐β‐1,4‐glucanase (EG) activities were localized to the midgut of the fungus‐growing termite Macrotermes barneyi. Previously, we obtained the endogenous BG gene (MbmgBG1) from the midgut of M. barneyi. Here, we report the cDNA cloning of another endogenous cellulase, the EG protein MbEG1. This cellulase was partially purified from crude extract of the midgut of worker termites using zymogram analysis. Based on the N‐terminal amino acid sequence and using rapid amplification of cDNA ends (RACE), a full‐length cDNA of 1,843 base pairs was obtained. This encoded 448 amino acids and the sequence was similar to that of the members of glycoside hydrolase family 9. The MbEG1 transcript was detected primarily in the midgut using quantitative real‐time polymerase chain reaction (PCR). To confirm functional activity of MbEG1, heterologous expression was conducted in both Escherichia coli and Pichia pastoris expression systems. Results indicated that MbEG1 could be functionally expressed in P. pastoris. This study provides the information that may facilitate understanding of cellulolytic systems in fungus‐growing termites.
1‐Amino‐3‐(1H‐1,2,3‐triazol‐1‐yl)propylphosphonates as Acyclic Analogs of Nucleotides
Authors: Głowacka Iwona E. , Balzarini Jan , Piotrowska Dorota G.
Published: April 2014

A new series of 1‐amino‐3‐(1H‐1,2,3‐triazol‐1‐yl)propylphosphonates (R)‐ and (S)‐16 were obtained from enantiomerically pure (R)‐ and (S)‐1‐tert‐butoxycarbonyl (Boc)‐amino‐3‐azidopropylphosphonates and N‐propargylated nucleobases in good yields. All 1,2,3‐triazolylphosphonates (R)‐ and (S)‐16 were evaluated for their activities against a broad range of DNA and RNA viruses. Compound (R)‐16g (B = 3‐acetylindole) was moderately active against vesicular stomatitis virus in HeLa cell cultures (EC50 = 45 µM). In addition, (S)‐16c (B = adenine), (R)‐16f (B = N3‐Bz‐benzuracil), (R)‐16g (B = 3‐acetylindole), and (R)‐16h (B = 5,6‐dimethylbenzimidazole) were cytotoxic toward Crandell‐Rees feline kidney (CRFK) cells (CC50 = 2.9, 45, 72, and 96 µM, respectively). Compounds (R)‐16g, (S)‐16g, and (S)‐16h were slightly cytostatic to different tumor cell lines.
Peripheral Calcitonin Gene‐Related Peptide Receptor Activation and Mechanical Sensitization of the Joint in Rat Models of Osteoarthritis Pain
Authors: Bullock Craig M. , Wookey Peter , Bennett Andrew , Mobasheri Ali , Dickerson Ian , Kelly Sara
Published: April 2014

Objective

To investigate the role of the sensory neuropeptide calcitonin gene‐related peptide (CGRP) in peripheral sensitization in experimental models of osteoarthritis (OA) pain.

Methods

Experimental knee OA was induced in rats by intraarticular injection of monosodium iodoacetate (MIA) or by transection of the medial meniscus (MMT). Single‐unit recordings of joint‐innervating nociceptors were obtained in MIA‐ and saline‐treated rats following administration of CGRP or the CGRP receptor antagonist CGRP 8–37. Effects of CGRP 8–37 were also examined in rats that underwent MMT and sham operations. Protein and messenger RNA (mRNA) levels of CGRP receptor components in the L3–L4 dorsal root ganglion (DRG) were investigated following MIA treatment.

Results

In both the MIA and MMT groups, the mechanical sensitivity of joint nociceptors was enhanced compared to that in the control groups. Exogenous CGRP increased mechanical sensitivity in a greater proportion of joint nociceptors in the MIA‐treated rats than in the saline‐treated rats. Local blockade of endogenous CGRP by CGRP 8–37 reversed both the MIA‐ and MMT‐induced enhancement of joint nociceptor responses. Joint afferent cell bodies coexpressed the receptor for CGRP, called the calcitonin‐like receptor (CLR), and the intracellular accessory CGRP receptor component protein. MIA treatment increased the levels of mRNA for CLR in the L3–L4 DRG and the levels of CLR protein in medium and large joint afferent neurons.

Conclusion

Our findings provide new and compelling evidence implicating a role of CGRP in peripheral sensitization in experimental OA. Our novel finding of CGRP‐mediated control of joint nociceptor mechanosensitivity suggests that the CGRP receptor system may be an important target for the modulation of pain during OA. CGRP receptor antagonists recently developed for migraine pain should be investigated for their efficacy against pain in OA.
Induction of an Inflammatory and Prodegradative Phenotype in Autologous Fibroblast‐like Synoviocytes by the Infrapatellar Fat Pad From Patients With Knee Osteoarthritis
Authors: Eymard Florent , Pigenet Audrey , Citadelle Danièle , Flouzat‐Lachaniette Charles‐Henri , Poignard Alexandre , Benelli Chantal , Berenbaum Francis , Chevalier Xavier , Houard Xavier
Published: April 2014

Objective

The infrapatellar fat pad (IFP) of the knee joint has an inflammatory phenotype in osteoarthritis (OA). Its close proximity to the synovial membrane suggests that the IFP could be involved in the induction of OA synovitis. This study was undertaken to investigate the response of fibroblast‐like synoviocytes (FLS) to autologous IFP and subcutaneous adipose tissue (SCAT) from patients with severe knee OA.

Methods

Samples of IFP, SCAT, and autologous synovial membrane tissue close to the IFP were harvested during surgery from 28 patients with end‐stage knee OA. FLS from 14 patients were stimulated with autologous IFP‐ or SCAT‐conditioned medium, and levels of messenger RNA (mRNA) expression and protein release of interleukin‐6 (IL‐6), IL‐8, secretory phospholipase A2 (sPLA2), cytosolic PLA2, cyclooxygenase 2 (COX‐2), microsomal prostaglandin E synthase, prostaglandin E2 (PGE2), and matrix metalloproteinases (MMPs) 1, 3, 9, and 13 were evaluated. Both IFP‐ and SCAT‐conditioned medium were evaluated by enzyme‐linked immunosorbent assay for secretion of IL‐6, soluble IL‐6 receptor (sIL‐6R), IL‐8, tumor necrosis factor α (TNFα), PGE2, IL‐1β, and interferon‐γ. In addition, OA FLS were treated with PGE2 receptor antagonists to evaluate the contribution of IFP‐derived PGE2 to the inflammatory response of FLS to the IFP.

Results

Stimulation of OA FLS with IFP‐conditioned medium induced the mRNA expression and protein release of IL‐6, IL‐8, sPLA2, COX‐2, PGE2, and MMPs 1, 3, 9, and 13. The extent of stimulation was consistently stronger with IFP‐conditioned medium than with SCAT‐conditioned medium. Moreover, secretion of IL‐6, sIL‐6R, IL‐8, TNFα, and PGE2 was greater in IFP‐conditioned medium than in SCAT‐conditioned medium, especially PGE2, whose secretion was 75‐fold stronger in IFP‐conditioned medium (P < 0.0001). PGE2 receptor antagonists dose‐dependently inhibited the release of IL‐6, IL‐8, and PGE2 by IFP‐stimulated FLS.

Conclusion

This study showed that the IFP has a potential role in the induction of synovial inflammation in patients with severe knee OA. Furthermore, secretion of PGE2 by the IFP may be involved in the OA inflammatory process.
The Phosphoinositide 3‐Kinase Isoform PI3Kβ Regulates Osteoclast‐Mediated Bone Resorption in Humans and Mice
Authors: Győri Dávid , Csete Dániel , Benkő Szilvia , Kulkarni Suhasini , Mandl Péter , Dobó‐Nagy Csaba , Vanhaesebroeck Bart , Stephens Len , Hawkins Phillip T. , Mócsai Attila
Published: April 2014

Objective

While phosphoinositide 3‐kinases (PI3Ks) are involved in various intracellular signal transduction processes, the specific functions of the different PI3K isoforms are poorly understood. We have previously shown that the PI3Kβ isoform is required for arthritis development in the K/BxN serum–transfer model. Since osteoclasts play a critical role in pathologic bone loss during inflammatory arthritis and other diseases, we undertook this study to test the role of PI3Kβ in osteoclast development and function using a combined genetic and pharmacologic approach.

Methods

The role of PI3Kβ in primary human and murine osteoclast cultures was tested with the PI3Kβ‐selective inhibitor TGX221 and by using PI3Kβ−/− mice. The trabecular bone architecture of PI3Kβ−/− mice was evaluated using micro–computed tomography and histomorphometric analyses.

Results

The expression of PI3Kβ was strongly and specifically up‐regulated during in vitro osteoclast differentiation. In vitro development of large multinucleated osteoclasts from human or murine progenitors and their resorption capacity were strongly reduced by the PI3Kβ inhibitor TGX221 or by the genetic deficiency of PI3Kβ. This was likely due to defective cytoskeletal reorganization and vesicular trafficking, since PI3Kβ−/− mouse multinucleated cells failed to form actin rings and retained intracellular acidic vesicles and cathepsin K. In contrast, osteoclast‐specific gene expression and the survival and apoptosis of osteoclasts were not affected. PI3Kβ−/− mice had significantly increased trabecular bone volume and showed abnormal osteoclast morphology with defective resorption pit formation.

Conclusion

PI3Kβ plays an important role in osteoclast development and function and is required for in vivo bone homeostasis.
Dealing with structural patterns of XML documents
Authors: Di Iorio Angelo , Peroni Silvio , Poggi Francesco , Vitali Fabio
Published: April 2014

Evaluating collections of XML documents without paying attention to the schema they were written in may give interesting insights into the expected characteristics of a markup language, as well as any regularity that may span vocabularies and languages, and that are more fundamental and frequent than plain content models. In this paper we explore the idea of structural patterns in XML vocabularies, by examining the characteristics of elements as they are used, rather than as they are defined. We introduce from the ground up a formal theory of 8 plus 3 structural patterns for XML elements, and verify their identifiability in a number of different XML vocabularies. The results allowed the creation of visualization and content extraction tools that are completely independent of the schema and without any previous knowledge of the semantics and organization of the XML vocabulary of the documents.
Can a minimal replicating construct be identified as the embodiment of cancer?
Authors: Solé Ricard V. , Valverde Sergi , Rodriguez‐Caso Carlos , Sardanyés Josep
Published: April 2014

Genomic instability is a hallmark of cancer. Cancer cells that exhibit abnormal chromosomes are characteristic of most advanced tumours, despite the potential threat represented by accumulated genetic damage. Carcinogenesis involves a loss of key components of the genetic and signalling molecular networks; hence some authors have suggested that this is part of a trend of cancer cells to behave as simple, minimal replicators. In this study, we explore this conjecture and suggest that, in the case of cancer, genomic instability has an upper limit that is associated with a minimal cancer cell network. Such a network would include (for a given microenvironment) the basic molecular components that allow cells to replicate and respond to selective pressures. However, it would also exhibit internal fragilities that could be exploited by appropriate therapies targeting the DNA repair machinery. The implications of this hypothesis are discussed.
Stress‐induced cellular adaptive strategies: Ancient evolutionarily conserved programs as new anticancer therapeutic targets
Authors: Cipponi Arcadi , Thomas David M.
Published: April 2014

Despite the remarkable achievements of novel targeted anti‐cancer drugs, most therapies only produce remission for a limited time, resistance to treatment, and relapse, often being the ultimate outcome. Drug resistance is due to highly efficient adaptive strategies utilized by cancer cells. Exogenous and endogenous stress stimuli are known to induce first‐line responses, capable of re‐establishing cellular homeostasis and determining cell fate decisions. Cancer cells may also mount second‐line adaptive strategies, such as the mutator response. Hypermutable subpopulations of cells may expand under severe selective stress, thereby accelerating the emergence of adapted clones. As with first‐line protective responses, these strategies appear highly conserved, and are found in yeasts and bacteria. We hypothesize that evolutionarily conserved programs rheostatically regulate mutability in fluctuating environments, and contribute to drug resistance in cancer cells. Elucidating the conserved genetic and molecular mechanisms may present novel opportunities to increase the effectiveness of cancer therapies.
A 400,000‐year‐old mitochondrial genome questions phylogenetic relationships amongst archaic hominins
Authors: Orlando Ludovic
Published: April 2014

By combining state‐of‐the‐art approaches in ancient genomics, Meyer and co‐workers have reconstructed the mitochondrial sequence of an archaic hominin that lived at Sierra de Atapuerca, Spain about 400,000 years ago. This achievement follows recent advances in molecular anthropology that delivered the genome sequence of younger archaic hominins, such as Neanderthals and Denisovans. Molecular phylogenetic reconstructions placed the Atapuercan as a sister group to Denisovans, although its morphology suggested closer affinities with Neanderthals. In addition to possibly challenging our interpretation of the fossil record, this study confirms that genomic information can be recovered from extremely damaged DNA molecules, even in the presence of significant levels of human contamination. Together with the recent characterization of a 700,000‐year‐old horse genome, this study opens the Middle Pleistocene to genomics, thereby extending the scope of ancient DNA to the last million years.
A new light on DNA replication from the inactive X chromosome
Authors: Aladjem Mirit I. , Fu Haiqing
Published: April 2014

While large portions of the mammalian genome are known to replicate sequentially in a distinct, tissue‐specific order, recent studies suggest that the inactive X chromosome is duplicated rapidly via random, synchronous DNA synthesis at numerous adjacent regions. The rapid duplication of the inactive X chromosome was observed in high‐resolution studies visualizing DNA replication patterns in the nucleus, and by allele‐specific DNA sequencing studies measuring the extent of DNA synthesis. These studies conclude that inactive X chromosomes complete replication earlier than previously thought and suggest that the strict order of DNA replication detected in the majority of genomic regions is not preserved in non‐transcribed, “silent” chromatin. These observations alter current concepts about the regulation of DNA replication in non‐transcribed portions of the genome in general and in the inactive X‐chromosome in particular.
Fast Proton Exchange in Histidine: Measurement of Rate Constants through Indirect Detection by NMR Spectroscopy
Authors: Sehgal Akansha Ashvani , Duma Luminita , Bodenhausen Geoffrey , Pelupessy Philippe
Published: April 2014

Owing to its imidazole side chain, histidine participates in various processes such as enzyme catalysis, pH regulation, metal binding, and phosphorylation. The determination of exchange rates of labile protons for such a system is important for understanding its functions. However, these rates are too fast to be measured directly in an aqueous solution by using NMR spectroscopy. We have obtained the exchange rates of the NH3+ amino protons and the labile NHε2 and NHδ1 protons of the imidazole ring by indirect detection through nitrogen‐15 as a function of temperature (272 K<T<293 K) and pH (1.3<pH<4.9) of uniformly nitrogen‐15‐ and carbon‐13‐labeled L‐histidine⋅HCl⋅H2O. Exchange rates up to 8.5×104 s−1 could be determined (i.e., lifetimes as short as 12 μs). The three chemical shifts δHi of the invisible exchanging protons Hi and the three one‐bond scalar coupling constants 1J(N,Hi) could also be determined accurately.
Organization of the spinal trigeminal nucleus in star‐nosed moles
Authors: Sawyer Eva K. , Leitch Duncan B. , Catania Kenneth C.
Published: April 2014

Somatosensory inputs from the face project to multiple regions of the trigeminal nuclear complex in the brainstem. In mice and rats, three subdivisions contain visible representations of the mystacial vibrissae, the principal sensory nucleus, spinal trigeminal subnucleus interpolaris, and subnucleus caudalis. These regions are considered important for touch with high spatial acuity, active touch, and pain and temperature sensation, respectively. Like mice and rats, the star‐nosed mole (Condylura cristata) is a somatosensory specialist. Given the visible star pattern in preparations of the star‐nosed mole cortex and the principal sensory nucleus, we hypothesized there were star patterns in the spinal trigeminal nucleus subnuclei interpolaris and caudalis. In sections processed for cytochrome oxidase, we found star‐like segmentation consisting of lightly stained septa separating darkly stained patches in subnucleus interpolaris (juvenile tissue) and subnucleus caudalis (juvenile and adult tissue). Subnucleus caudalis represented the face in a three‐dimensional map, with the most anterior part of the face represented more rostrally than posterior parts of the face. Multiunit electrophysiological mapping was used to map the ipsilateral face. Ray‐specific receptive fields in adults matched the CO segmentation. The mean areas of multiunit receptive fields in subnucleus interpolaris and caudalis were larger than previously mapped receptive fields in the mole's principal sensory nucleus. The proportion of tissue devoted to each ray's representation differed between the subnucleus interpolaris and the principal sensory nucleus. Our finding that different trigeminal brainstem maps can exaggerate different parts of the face could provide new insights for the roles of these different somatosensory stations. J. Comp. Neurol. 522:3335–3350, 2014. © 2014 Wiley Periodicals, Inc.
Metabolic Engineering: The Ultimate Paradigm for Continuous Pharmaceutical Manufacturing
Authors: Yadav Vikramaditya G. , Stephanopoulos Gregory
Published: April 2014

Research and development (R & D) expenditures by pharmaceutical companies doubled over the past decade, yet candidate attrition rates and development times rose markedly during this period. Understandably, companies have begun downsizing their pipelines and diverting investments away from R & D in favor of manufacturing. It is estimated that transitioning to continuous manufacturing could enable companies to compete for a share in emerging markets. Accordingly, the model for continuous manufacturing that has emerged commences with the conversion of late‐stage intermediates into the active pharmaceutical ingredient (API) in a series of continuous flow reactors, followed by continuous solid processing to form finished tablets. The use of flow reactions for API synthesis will certainly generate purer products at higher yields in shorter times compared to equivalent batch reactions. However, transitioning from batch to flow configuration simply alleviates transport limitations within the reaction milieu. As the catalogue of reactions used in flow syntheses is a subset of batch‐based chemistries, molecules such as natural products will continue to evade drug prospectors. Also, it is uncertain whether flow synthesis can deliver improvements in the atom and energy economies of API production at the scales that would achieve the levels of revenue growth targeted by companies. Instead, it is argued that implementing metabolic engineering for the production of oxidized scaffolds as gateway molecules for flow‐based addition of electrophiles is a more effective and scalable strategy for accessing natural product chemical space. This new paradigm for manufacturing, with metabolic engineering as its engine, would also permit rapid optimization of production variables and allow facile scale‐up from gram to ton scale to meet material requirements for clinical trials, thus recasting manufacturing as a tool for discovery.
Production of Clean Pyrolytic Sugars for Fermentation
Authors: Rover Marjorie R. , Johnston Patrick A. , Jin Tao , Smith Ryan G. , Brown Robert C. , Jarboe Laura
Published: April 2014

This study explores the separate recovery of sugars and phenolic oligomers produced during fast pyrolysis with the effective removal of contaminants from the separated pyrolytic sugars to produce a substrate suitable for fermentation without hydrolysis. The first two stages from a unique recovery system capture “heavy ends”, mostly water‐soluble sugars and water‐insoluble phenolic oligomers. The differences in water solubility can be exploited to recover a sugar‐rich aqueous phase and a phenolic‐rich raffinate. Over 93 wt % of the sugars is removed in two water washes. These sugars contain contaminants such as low‐molecular‐weight acids, furans, and phenols that could inhibit successful fermentation. Detoxification methods were used to remove these contaminants from pyrolytic sugars. The optimal candidate is NaOH overliming, which results in maximum growth measurements with the use of ethanol‐producing Escherichia coli.
Detection and separation of overlapping cells based on contour concavity forLeishmaniaimages
Authors: Neves João C. , Castro Helena , Tomás Ana , Coimbra Miguel , Proença Hugo
Published: April 2014

Life scientists often must count cells in microscopy images, which is a tedious and time‐consuming task. Automatic approaches present a solution to this problem. Several procedures have been devised for this task, but the majority suffer from performance degradation in the case of cell overlap. In this article, we propose a method to determine the positions of macrophages and parasites in fluorescence images ofLeishmania‐infected macrophages. The proposed strategy is primarily based on blob detection, clustering, and separation using concave regions of the cells' contours. In comparison with the approaches of Nogueira (Master's thesis, Department of University of Porto Computer Science, 2011) and Leal et al. (Proceedings of the 9th international conference on Image Analysis and Recognition, Vol. II, ICIAR'12. Berlin, Heidelberg: Springer‐Verlag; 2012. pp. 432–439), which also addressed this type of image, we conclude that the proposed methodology achieves better performance in the automatic annotation ofLeishmaniainfections. © 2014 International Society for Advancement of Cytometry
A technique to improve network lifetime in mobile ad hoc networks
Authors: Ray Niranjan Kumar , Turuk Ashok Kumar
Published: April 2014

Energy is an important issue in mobile ad hoc networks (MANETs), and different energy‐aware routing mechanisms have been proposed to minimize the energy consumption in MANETs. Most of the energy‐aware routing schemes reported in the literature have considered only the residual battery capacity as the cost metric in computing a path. In this paper, we have proposed, an energy‐aware routing technique which considers the following parameters: (i) a cost metric, which is a function of residual battery power and energy consumption rate of participating nodes in path computation; (ii) a variable transmission power technique for transmitting data packets; and (iii) To minimize the over‐utilization of participating nodes, a limit is set on the number of paths that can be established to a destination through a participating node. The proposed scheme is simulated using Qualnet 4.5 simulator, and compared with Ad hoc On‐Demand Distance Vector (AODV) and Lifetime Enhancement Routing (LER). We observed that the proposed scheme performs better in terms of network lifetime and energy consumption. Copyright © 2014 John Wiley & Sons, Ltd.
Prolonged in vivo imaging of Xenopus laevis
Authors: Hamilton Paul W. , Henry Jonathan J.
Published: April 2014

Background: While live imaging of embryonic development over long periods of time is a well established method for embryos of the frog Xenopus laevis, once development has progressed to the swimming stages, continuous live imaging becomes more challenging because the tadpoles must be immobilized. Current imaging techniques for these advanced stages generally require bringing the tadpoles in and out of anesthesia for short imaging sessions at selected time points, severely limiting the resolution of the data. Results: Here we demonstrate that creating a constant flow of diluted tricaine methanesulfonate (MS‐222) over a tadpole greatly improves their survival under anesthesia. Based on this result, we describe a new method for imaging stage 48 to 65 X. laevis, by circulating the anesthetic using a peristaltic pump. This supports the animal during continuous live imaging sessions for at least 48 hr. The addition of a stable optical window allows for high quality imaging through the anesthetic solution. Conclusions: This automated imaging system provides for the first time a method for continuous observations of developmental and regenerative processes in advanced stages of Xenopus over 2 days. Developmental Dynamics 243:1011–1019, 2014. © 2014 Wiley Periodicals, Inc.