bluuebunny/crossref_metadata_2025 huggingface dataset:
Replication of Genome-Wide Association Studies of Type 2 Diabetes Susceptibility in Japan
Authors: Horikawa Yukio , Miyake Kazuaki , Yasuda Kazuki , Enya Mayumi , Hirota Yushi , Yamagata Kazuya , Hinokio Yoshinori , Oka Yoshitomo , Iwasaki Naoko , Iwamoto Yasuhiko , Yamada Yuichiro , Seino Yutaka , Maegawa Hiroshi , Kashiwagi Atsunori , Yamamoto Ken , Tokunaga Katsushi , Takeda Jun , Kasuga Masato
Published: May 2008

Background: In Europeans and populations of European origin, several groups have recently identified novel type 2 diabetes susceptibility genes, including FTO, SLC30A8, HHEX, CDKAL1, CDKN2B, and IGF2BP2, none of which were in the list of functional candidates.

Objective and Design: The aim of this study was to replicate in a Japanese population previously identified associations of single nucleotide polymorphisms (SNPs) within 10 candidate loci with type 2 diabetes using a relatively large sample size: 1921 subjects with type 2 diabetes and 1622 normal controls.

Results: A total of 15 SNPs were genotyped. Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [odds ratio (OR) = 1.16 (95% confidence interval (CI) 1.05–1.27); P = 4.5 × 10−3] in SLC30A8; rs1111875 [OR = 1.27 (95% CI 1.14–1.40); P = 1.4 × 10−5] and rs7923837 [OR = 1.27 (95% CI 1.13–1.43); P = 1.0 × 10−4] in HHEX; rs10811661 [OR = 1.27 (95% CI 1.15–1.40); P = 1.9 × 10−6] in CDKN2B; rs4402960 [OR = 1.23 (95% CI 1.11–1.36); P = 8.1 × 10−5] and rs1470579 [OR = 1.18 (95% CI 1.07–1.31); P = 8.3 × 10−4] in IGF2BP2; and rs7754840 [OR = 1.28 (95% CI 1.17–1.41); P = 4.5 × 10−7] and rs7756992 [OR = 1.27 (95% CI 1.15–1.40); P = 9.8 × 10−7] in CDKAL1. The first and second strongest associations were found at variants in CDKAL1 and CDKN2B, both of which are involved in the regenerative capacity of pancreatic β-cells.

Conclusion: Some of these variants represent common type 2 diabetes-susceptibility genes in both Japanese and Europeans.
Tumour and dendrimers: a review on drug delivery aspects
Authors: Agarwal Abhinav , Asthana Abhay , Gupta Umesh , Jain Narendra K
Published: May 2008

Tumour is a morbid state, characterized by spontaneous outgrowth of an abnormal mass of cells. The evolution of tumours is random, disorganized, a condition of numerous mutations. The properties are biased and incompletely comprehended. It is a malignant or benign condition that encompasses its own rules of morphogenesis, an immortal state that elucidates different physiology. It is a pathological crisis that still haunts the minds of scientists, physicians and patients, a complete cure of which is still a dream to be realized. The unpredictable microenvironment of cancerous cells in all of its existing forms i.e. leukaemic cells, solid tumours and sarcomas is well documented. This phenomenon expressed by cancerous sites in the body poses various obstacles towards drug efficacy. Thus, it has become necessary to address briefly the issues relating to tumour physiology, its vasculature and angiogenesis. The information could provide insight towards the development of tumour-targeted drug delivery. The salient features regarding these have been discussed.
Pharmacokinetic evaluation of LASSBio-579: anN-phenylpiperazine antipsychotic prototype
Authors: Conrado Daniela J , Verli Hugo , Neves Gilda , Fraga Carlos Alberto Manssour , Barreiro Eliezer J , Rates Stela Maris Kuze , Costa Teresa Dalla
Published: May 2008

This work aimed to investigate the pharmacokinetics of the N-phenylpiperazine antipsychotic prototype LASSBio-579 and to compare the results with those described for its bioisosteric derivative LASSBio-581. LASSBio-579 was administered to male Wistar rats as a 10 mg kg−1 intravenous bolus and 30 and 60 mg kg−1 intraperitoneal and 60 mg kg−1 oral doses, and plasma concentrations were determined by a validated LC-MS/MS method. Individual plasma concentration-time profiles were evaluated by non-compartmental and compartmental analysis, using WinNonlin. LASSBio-579 plasma protein binding was 93 ± 4%. After intravenous administration of 10 mg kg−1, the Vdss (0.6 ± 0.2 L kg−1) and the t1/2 (5.2 ± 1.1 h) determined were smaller than those obtained after extravascular routes, but the CLtot (0.23 ± 0.05 Lh−1 kg−1) was statistically similar (α = 0.05). The intraperitoneal and oral bioavailability was around 1.7% and 0.6%, respectively. The plasma profiles obtained after intravenous and intraperitoneal administration of the compound were best fitted to a three-compartment and two-compartment lag-time open model, respectively. Brain tissue showed low penetration (6.3%) and t1/2 of 1.1 h. Both the limited bioavailability and the lower brain penetration of LASSBio-579, in comparison with the LASSBio-581, suggest that its CNS activity may be due to a high receptor binding affinity or to a specific distribution into brain structures.
Identification of metabolites of tectoridin in-vivo and in-vitro by liquid chromatography-tandem mass spectrometry
Authors: Chen Yong , Song Wei , Peng Zhi H , Ge Bao Y , Han Feng M
Published: May 2008

In this work, liquid chromatography-electrospray ionization tandem ion-trap mass spectrometry (LC-MSn) was used to investigate the in-vivo and in-vitro metabolism of tectoridin. After oral administration of a single dose (100 mg kg−1) of tectoridin to healthy rats, faeces and urine samples were collected for 0–48 h and 0–24 h, respectively. Tectoridin was also incubated with rat intestinal flora and rat liver microsomes. Samples from in-vivo and in-vitro metabolism studies were purified using a C18 solid-phase extraction cartridge, then separated using a reverse-phase C18 column with methanol/water (30:70, v/v, adjusted to pH 10.0 with ammonia water) as mobile phase and detected by an on-line MSn system. The structure of the metabolites was elucidated by comparing their molecular weights, retention times and full-scan MSn spectra with those of the parent drug. The results revealed six metabolites of tectoridin in urine (tectorigenin, hydrogenated tectorigenin, mono-hydroxylated tectorigenin, di-hydroxylated tectorigenin, glucuronide-conjugated tectorigenin and sulfate-conjugated tectorigenin); three metabolites in faeces (tectorigenin, di-hydroxylated tectorigenin and sulfate-conjugated tectorigenin); one metabolite in the intestinal flora incubation mixture (tectorigenin), and four in the liver microsomal incubation mixture (tectorigenin, hydrogenated tectorigenin, mono-hydroxylated tectorigenin and di-hydroxylated tectorigenin). Except for tectorigenin, all other metabolites of tectoridin are reported for the first time.
Zearalenone induces immunotoxicity in mice: possible protective effects of radish extract (Raphanus sativus)
Authors: Salah-Abbès Jalila Ben , Abbès Samir , Houas Zohra , Abdel-Wahhab Mosaad A , Oueslati Ridha
Published: May 2008

Radish (Raphanus sativus) has been extensively studied for its preventive effects against different degenerative diseases. Zearalenone (ZEN) is a mycotoxin produced by Fusarium spp and is frequently implicated in immunological disorders and occasionally in hyperoestrogenic syndromes contributing to the increased risk of cancer and other diseases. The aims of this study were, firstly, to quantitatively evaluate the Tunisian radish extract (TRE) for its total flavonoids, isothiocyanates and antioxidant activity and, secondly, to investigate the protective role of TRE against immune system disorders in Balb/c mice treated with ZEN for two weeks. The results indicated that mice treated with ZEN (40 mg kg−1) alone showed a significant decrease in lymphocytes of the total white blood cells, immunoglobulin profile (IgG and IgM), B cells, T-cell sub-types (CD3+, CD4+ and CD8+) and natural killer and pro-inflammatory cytokines. Mice treated with TRE (5, 10 or 15 mg kg−1) for 7 days before, during or after ZEN treatment, however, showed a significant improvement in lymphocyte, immunoglobulin profile, T-cell sub-types, B cells and pro-inflammatory cytokines. Moreover, treatment with the highest dose of TRE (15 mgkg−1) enhanced the release of tumour necrosis factor-α and interleukin-1β but the other parameters were comparable with those of the control. It could be concluded that TRE was effective in protecting against ZEN-induced immunological disorders. These results supported our hypothesis that TRE contains several compounds that are able to prevent or inhibit ZEN toxicity.
Antinociceptive and anti-inflammatory effects of the essential oil from Eremanthus erythropappus leaves
Authors: Sousa Orlando V , Silvério Marcelo S , Del-Vechio-Vieira Glauciemar , Matheus Filipe C , Yamamoto Célia H , Alves Maria S
Published: May 2008

The chemical composition of the essential oil from air-dried leaves of Eremanthus erythropappus was studied. The main compounds were β-pinene (23.24%), β-caryophyllene (22.92%), β-myrcene (10.03%) and germacrene D (9.40%). The essential oil had an LD50 of 2.90 gkg−1 in mice. Doses of 200 and 400 mgkg−1 inhibited 10.69% and 27.06% of acetic-acid-induced writhing in mice, respectively. In the formalin-induced nociception test in mice, the essential oil inhibited the first phase of paw licking by 29.13% (400 mgkg−1) and the second phase by 32.74% (200 mgkg−1) and 37.55% (400 mgkg−1). In the hot-plate test in mice, doses of 200 mgkg−1 and 400 mgkg−1 significantly increased the reaction time after 30, 60 and 90 min of treatment. Doses of 200 and 400 mgkg−1 inhibited carrageenan-induced paw oedema in rats by 15.18% and 36.61%, respectively. Doses of 200 and 400 mgkg−1 administered 4 h before intra-pleural injection of carrageenan significantly reduced exudate volume (by 20.20% and 48.70%, respectively) and leucocyte mobilization (by 5.88% and 17.29%, respectively). These results demonstrate that E. erythropappus has analgesic and anti-inflammatory properties, supporting the use of this plant in folk medicine.
Anti-angiogenic, antinociceptive and anti-inflammatory activities ofLonicera japonicaextract
Authors: Yoo Hye-Jung , Kang Hyun-Jung , Song Yun Seon , Park Eun-Hee , Lim Chang-Jin
Published: May 2008

This study aimed to elucidate some novel pharmacological activities of Lonicera japonica (Caprifoliaceae), which is widely used in Oriental folk medicine. The ethanolic extract of L. japonica (LJ) dose dependently inhibited chick chorioallantoic membrane angiogenesis. The antinociceptive activity of LJ was assessed using the acetic acid-induced constriction model in mice. LJ showed anti-inflammatory activity in two in-vivo models: the vascular permeability and air pouch models. LJ suppressed the production of nitric oxide via down-regulation of inducible nitric oxide synthase in lipopolysaccharide-stimulated RAW264.7 macrophage cells. However, LJ was unable to suppress induction of cyclooxygenase-2 in the stimulated macrophage cells. LJ decreased the reactive oxygen species level in the stimulated macrophage cells. In brief, the flowers of L. japonica possess potent anti-angiogenic and antinociceptive activities, in addition to anti-inflammatory activity, which partly supports its therapeutic efficacy.
Beneficial influence of capsaicin on lipid peroxidation, membrane-bound enzymes and glycoprotein profile during experimental lung carcinogenesis
Authors: Anandakumar P , Jagan S , Kamaraj S , Ramakrishnan G , Titto A A , Devaki T
Published: May 2008

This study was designed to examine the impact of a principal component of hot red peppers and chilli peppers, capsaicin, on alterations in lipid peroxidation, membrane-bound enzyme profiles and glycoprotein levels during benzo(a)pyrene (BP)-induced lung cancer in Swiss albino mice. BP (50 mgkg−1) induced deleterious changes that were revealed by alterations in lipid peroxidation, membrane-bound enzyme (Na+/K+ATPase, Ca2+ATPase and Mg2+ATPase) activity, levels of total protein and protein-bound carbohydrate components (sialic acid, hexose, hexosamine, hexuronic acid and fucose). Pre-co-treatment with capsaicin (10 mgkg−1) restored the detrimental effects induced by BP, indicating its protective role in BP-induced lung cancer.
The R246S hot-spot p53 mutant exerts dominant-negative effects in embryonic stem cells in vitro and in vivo
Authors: Lee Ming Kei , Sabapathy Kanaga
Published: May 2008

p53 is the most frequently mutated tumour-suppressor gene in human cancers. Mutant p53 is thought to contribute to carcinogenesis by the acquisition of gain-of-function properties or through the exertion of dominant-negative (DN) effects over the remaining wild-type protein. However, the context in which the DN effects are observed is not well understood. We have therefore generated `knock-in' mouse embryonic stem (ES) cells to investigate the effects of expressing a commonly found hot-spot p53 mutant, R246S – the mouse equivalent of human R249S, which is associated with hepatocellular carcinomas. We demonstrate here that R246S mutant p53 exhibits DN effects with respect to target gene expression, cell survival and cell cycle arrest both in cells that are in the undifferentiated state and upon differentiation. The knock-in cells contain higher levels of p53 that localizes to the nucleus even in the absence of genotoxic stress and yet remains non-functional, reminiscent of mutant p53 found in human tumours. In a model based on carbon-tetrachloride-induced liver injury, these cells were consistently highly tumorigenic in vivo, similar to p53–/– cells and in contrast to both p53+/+ and p53+/– ES cells. These data therefore indicate that the DN effects of mutant p53 are evident in the stem-cell context, in which its expression is relatively high compared with terminally differentiated cells.
Reduction of Crk and CrkL expression blocks reelin-induced dendritogenesis
Authors: Matsuki Tohru , Pramatarova Albéna , Howell Brian W.
Published: May 2008

The reelin signaling pathway regulates nervous system function after birth, in addition to its role in regulating neuronal positioning during embryogenesis. The receptor-dependent, reelin-induced tyrosine phosphorylation of the Dab1 docking protein is an established prerequisite for biological responses to this ligand. Here we show that the inactivation of a conditional Dab1 allele reduces process complexity in correctly positioned neurons in the CA1 region of the mouse hippocampus after birth. Reelin stimulation of cultured hippocampal neurons enhances dendritogenesis by approximately twofold and in a manner dependent on Src family kinases. This enhancement is blocked by reducing expression of Crk family proteins, adaptor molecules that interact with Dab1 in a tyrosine phosphorylation-dependent manner. Retrovirally expressed inhibitory RNAs used to reduce Crk and CrkL expression did not block BDNF-enhanced dendritogenesis or influence axonogenesis. Together, this demonstrates that the Crk family proteins are important downstream components of the reelin signaling pathway in the regulation of postnatal hippocampal dendritogenesis.
Interactions with titin and myomesin target obscurin and obscurin-like 1 to the M-band – implications for hereditary myopathies
Authors: Fukuzawa Atsushi , Lange Stephan , Holt Mark , Vihola Anna , Carmignac Virginie , Ferreiro Ana , Udd Bjarne , Gautel Mathias
Published: May 2008

Obscurin, a giant modular muscle protein implicated in G-protein and protein-kinase signalling, can localize to both sarcomeric Z-disks and M-bands. Interaction of obscurin with the Z-disk is mediated by Z-disk titin. Here, we unravel the molecular basis for the unusual localization of obscurin, a Z-disk-associated protein, to the M-band, where its invertebrate analogue UNC-89 is also localized. The first three domains of the N-terminus of obscurin bind to the most C-terminal domain of M-band titin, as well as to the M-band protein myomesin. Both proteins also interact with the N-terminal domains of obscurin-like 1 (Obsl1), a small homologue of obscurin. Downregulation of myomesin by siRNA interference disrupts obscurin–M-band integration in neonatal cardiomyocytes, as does overexpression of the binding sites on either myomesin, obscurin or Obsl1. Furthermore, all titin mutations that have been linked to limb-girdle muscular dystrophy 2J (LGMD2J) or Salih myopathy weaken or abrogate titin-obscurin and titin-Obsl1 binding, and lead to obscurin mislocalization, suggesting that interference with the interaction of these proteins might be of pathogenic relevance for human disease.
Novel self-association of the APC molecule affects APC clusters and cell migration
Authors: Li Zhuoyu , Kroboth Karin , Newton Ian P. , Näthke Inke S.
Published: May 2008

Truncation mutations in the adenomatous polyposis coli (APC) gene are responsible for familial and sporadic colorectal cancer. APC is a multifunctional protein involved in cell migration, proliferation and differentiation. The APC protein forms specific clusters in the cell periphery that correlate with sites of active cell migration. Little is known about the molecular mechanisms that govern these clusters. Here, we identify a novel interaction of an N-terminal region of APC with the extreme C-terminal 300 amino acids of APC and also with itself. The latter interaction is phospho-sensitive and is enhanced by 14-3-3 (YWHA) protein. These interactions modulate the clustering of APC at the ends of membrane protrusions. Overexpressing this domain or inhibiting 14-3-3 proteins disperses APC clusters and leads to decreased cell migration. Moreover, deleting this domain from full-length APC results in less-dynamic clusters compared with wild-type APC. Our data indicate that this newly identified regions in the N-terminal third of APC contributes to the regulation of APC clusters, thus providing a molecular clue for how locally regulated phosphorylation events could mediate the dynamics of APC clusters and contribute to cell migration.
Scratch test method: Energy dissipation and crack morphology
Authors: Krenn S , Badisch E , Pauschitz A
Published: May 2008

Abrasive wear is one of the most dominant wear mechanisms in industrial applications. Abrasive particles groove the metallic surface under various tribological interactions. Different wear mechanisms show a major influence on the abrasive wear behaviour, e.g. depending on the kinematic properties of abrasive particles. The scratch test method can be used to investigate a two-body-abrasion on a lab-scale and is defined as an ideal single tribological contact. Depending on the material behaviour, a certain amount of elastic and plastic deformation occurs during the scratch test. Especially, the characteristics of plastic deformation can give important information about the wear behaviour of the material investigated.

The objective of this work is the characterization of selected material properties by the use of a standard scratch tester (Millennium 100, TRIBOtechnic) in combination with special analysis methods, e.g. SEM, confocal white light microscope, and Matlab©. The main focus is laid on the characterization of plastic deformation behaviour correlated with energy dissipation during grooving. Furthermore, a detailed study on the interface properties of multi-phase materials is done.

Tests were carried out on single-phase materials with hardness in the range between 270–1100 HV5. The selected single-phase materials can be divided into brass materials, martensitic chromium steels, and complex high-alloyed Fe-based materials. Further investigations were done on multi-phase materials with Ni-based matrix and high content of synthetically added tungsten carbide (WC) with focus on crack initiation and direction of crack propagation. The influence of matrix hardness as well as carbide properties (e.g. shape, content, and orientation) are related to the crack behaviour of the composite material investigated. Results showed a strong correlation between crack morphology and matrix hardness. A soft metallic matrix (450 HV) tends to stop carbide-cracks in the interface, whereas a hard metallic matrix (600 HV) provides less resistance against crack propagation.
Catalytic Radical Cyclization of Oximes Induced by One-Electron Transfer
Authors: Kitamura Mitsuru , Narasaka Koichi
Published: May 2008

Anion radicals generated by one-electron reduction of oxime derivatives act as iminyl radical equivalents. That is, the intramolecular C–N bond formation of γ,δ-unsaturated or β-aryl oximes is induced by one-electron reduction to give various aza-heterocycles. The catalytic electron transfer processes are developed by using hydroquinones or copper reagents as electron donors. Photo-induced electron transfer is also utilized to transform of γ,δ-unsaturated oximes to dihydropyrroles. Total synthesis of peduncularine was achieved by applying the catalytic radical cyclization of oximes as a key step.
Palladium-Catalyzed CH Arylation and Dehydrogenative Homocoupling of Heteroaromatic Compounds and Application to the Design of Advanced Organic Materials
Authors: Mori Atsunori , Sugie Atsushi
Published: May 2008

CH arylation of five-membered heteroaromatic compounds such as thiazoles and thiophenes recently developed by the authors is reviewed. The reaction of thiazole with aryl iodides in the presence of a palladium/copper catalyst system and tetrabutylammonium fluoride causes CH arylation at the 2-position of thiazole. The reaction of 2-arylthiazole with aryl iodide by the catalysis of a palladium complex with silver(I) fluoride induces CH arylation at the 5-position. The reactions allow preparation of a variety of 2,5-diarylthiazoles in a facile manner. Spectroscopic, thermal, and electrochemical characteristics of 2,5-diarylthiazole are summarized. Introduction of the 2,5-diarylthiazole moiety, which exhibits photoluminescent and liquid crystalline characteristics, into the side chain of polymethacrylate is also described. CH arylation of thiophene derivatives are described to occur similarly to the case of thiazole. CH homocoupling of thiophene leading to bithiophene, in which the carbon–bromine bond on the thiophene ring is completely intact in the palladium-catalyzed reaction, is also described. Mechanistic studies on the reactions of thiophene are shown with a stoichiometric use of arylpalladium(II) halide complex and thiophene to undergo electrophilic substitution at the thiphene ring toward the palladium atom and the following reductive elimination of the thus obtained aryl(thienyl)palladium complex.
Acid-Catalyzed Reactions of Sarcophytoxide, a Marine Cembranoid: An Apparently Enantio-Directive Reaction, Unusual Products and Stereochemical Reconsideration of Epoxide–Ketone Rearrangement
Authors: Nii Keiji , Tagami Keiko , Kijima Masaru , Munakata Tatsuo , Ooi Takashi , Kusumi Takenori
Published: May 2008

Perchloric acid treatment of sarcophytoxide, a marine cembranoid possessing an epoxide, brought about epoxide–ketone rearrangement affording ketones. When the reaction time was long (22 h), a minor ketone that was antipodal to the ketone obtained in a short-time (10 min) reaction was formed. These puzzling findings, considering that the starting epoxide had three asymmetric carbons, were interpreted by surveying the structures of other ketonic products. The stereochemistry of a major ketone, which had been wrongly assigned, was corrected by extensive analyses of NMR spectra. The correct stereochemistry indicated that the epoxide–ketone rearrangement took a course via a cationic intermediate.
Effects of an Axial Amino Ligand on the Spectroscopic and Electrochemical Properties of Amino(methoxo)(tetraphenylporphyrinato)antimony(V) Complexes
Authors: Tsunami Shin-ichiro , Tanaka Kousuke , Matsumoto Jin , Shiragami Tsutomu , Yasuda Masahide
Published: May 2008

We investigated the effects of an axial amino ligand on the spectroscopic and electrochemical properties of alkylamino(methoxo)(tetraphenylporphyrinato)antimony(V) bromide 1 and anilino(methoxo)(tetraphenylporphyrinato)antimony(V) bromide 2. Fluorescence measurements of 1 and 2 showed that their fluorescence quantum yields were lower than that of dihydroxo(tetraphenylporphyrinato)antimony(V) bromide (3) due to intramolecular electron transfer (ET) from the axial amino ligand to the excited porphyrin ring. Fluorescence was enhanced by the addition of a proton, which was caused by the protonation of the axial nitrogen atom, thereby preventing ET. From the titration curves of fluorescence quantum yield (Φf) versus proton concentration, we estimated the acid dissociation constants (pKa) for the conjugate acid of the axial amino ligand of 1 to be 4.41–5.03. The reduction potentials (E1⁄2red) of 2 depended strongly on the electronic effect of the p-substituents (X) on the axial aniline group whereas the E1⁄2red of methoxo(p-substituted-phenoxo)(tetraphenylporphyrinato)antimony(V) bromide was little affected by the p-substituents on the phenoxo ligand. These observations were interpreted as reflecting the participation of the axial amino ligand in the LUMO, calculated for 2 by the PM3 method.
Synthesis, Structures, and Magnetic Properties of Doubly Face-Sharing Heterotrinuclear NiII–LnIII–NiII (Ln = Eu, Gd, Tb, and Dy) Complexes
Authors: Yamaguchi Tomoka , Sunatsuki Yukinari , Ishida Hiroyuki , Kojima Masaaki , Akashi Haruo , Re Nazzareno , Matsumoto Naohide , Pochaba Andrzej , Mrozinski Jerzy
Published: May 2008

Heterotrinuclear [(NiIIL)2LnIII(NO3)] complexes (where H3L = 1,1,1-tris[(salicylideneamino)methyl]ethane and Ln = Gd (1), Eu (2), Tb (3), and Dy (4)) were prepared by treating [Ni(H1.5L)]Cl0.5 with Ln(NO3)3·6H2O in the presence of triethylamine. Complexes 1·2CH3OH, 3·2CH3OH, and 4·C2H5OH·0.5H2O crystallized in the triclinic space group,Z=2, while 2·CH3OH·0.5H2O crystallized in the tetragonal space group, I41⁄a (No. 88), with Z=8. All the complexes had very similar structures. Each complex was a doubly face-sharing trinuclear molecule. The NiII ion is coordinated by the L3− ligand in an N3O3 coordination sphere, and the three phenolate oxygen atoms coordinate to an LnIII ion as bridging atoms. The LnIII ion is eight coordinate with six phenolate oxygen atoms of the two L3− ligands and two oxygen atoms of NO3−. Coordination of the NO3− group entails a bending of the Ni···Ln···Ni angle (ca. 140°). All the complexes involve π–π and CH–π interactions between the neighboring molecules to form a three-dimensional structure. Temperature-dependent magnetic susceptibility and field-dependent magnetization measurements on 1 showed a ferromagnetic interaction between the NiII and GdIII atoms. A ferromagnetic interaction was also suggested for NiII–TbIII (3) and NiII–DyIII (4).(No. 2), with
A Great Improvement of the Enantioselectivity of Lipase-Catalyzed Hydrolysis and Esterification Using Co-Solvents as an Additive
Authors: Nishigaki Tomohiro , Yasufuku Yoshitaka , Murakami Sayuri , Ebara Yasuhito , Ueji Shin-ichi
Published: May 2008

Addition of co-solvents such as tetrahydrofuran resulted in a great improvement of the enantioselectivity of lipase-catalyzed hydrolysis of butyl 2-(4-substituted phenoxy)propanoates in an aqueous buffer solution. On the other hand, lipase lyophilized from an aqueous solution containing the co-solvents catalyzed highly enantioselective esterification of 2-(4-substituted phenoxy)propionic acids, 2-(4-isobutylphenyl)propionic acid (ibuprofen), and 2-(6-methoxy-2-naphthyl)propionic acid (naproxen) in an organic solvent. An increase in the E value up to two orders of magnitude was observed for some substrates. The origin of the enantioselectivity enhancement caused by the co-solvent addition was mainly attributed to a significant deceleration in the initial reaction rate for the incorrectly binding enantiomer, as compared with that for the correctly binding enantiomer. From the results of FT-IR, CD, and ESR spectra, the co-solvent addition was also found to bring about a partial destruction of the tertiary structure of lipase.
Inflammation in Chronic Heart Failure
Authors: Parish Roy C , Evans Jeffery D
Published: May 2008

Objective:

To summarize findings regarding the association of inflammatory processes with chronic heart failure (HF).

Data Sources:

We conducted PubMed/MEDLINE searches (1966–January 2006) of primary literature using the following key words: ACE inhibitors, allopurinol, angiotensin-receptor antagonists, cardiomyopathy, chemokines, cytokines, diuretics, heart failure, Inflammation, interleukins, HMG-CoA reductase inhibitors, immunotherapy, medications used In heart failure, thalidomide, tumor necrosis (actor, and uric acid.

Study Selection and Data Extraction:

All articles that appeared to be relevant were read; of 305 articles examined, 87 were selected for discussion. Articles were selected if they were written in English and focused on any of the key words or appeared to have substantial content addressing inflammation in HF.

Data Synthesis:

Cytokines, uric acid, and other inflammatory mediators are associated with physiologic effects that are also prominent features of HF (eg, reduced contractility and cardiac output, endothelial dysfunction, hypercoagulability, autonomic dysfunction as evidenced by reduced resting heart rate variability, insulin resistance). With the exception of elevated tumor necrosis factor-α as a cause of insulin resistance, it is not clear whether elevated inflammatory mediators directly cause HF signs and symptoms or whether they are incidental markers. Awareness of these associations has occurred relatively recently; there have been few clinical studies of efforts to directly modify inflammatory mediators. Most currently accepted drug therapies of HF reduce concentrations of circulating cytokines, but the significance of these findings awaits directed study.

Conclusions:

Loss of myocardial function, autonomic dysfunction, and glucose intolerance are interrelated and linked by underlying chronic low-grade inflammation. Drug therapy with statins, pentoxifylline, and perhaps urate-lowering agents, in addition to current therapies, holds promise for treatment of HF.
Therapeutic Controversies: Aspirin, Clopidogrel, and Warfarin: Is the Combination Appropriate and Effective or Inappropriate and Too Dangerous?
Authors: Hermosillo A Janelle , Spinier Sarah A
Published: May 2008

Objective:

To review the rationale, clinical practice guideline recommendations, and clinical trial data describing bleeding and clinical outcomes associated with the use of the combination of aspirin, a thienopyridine, and warfarin.

Data Sources:

An English-language literature search was conducted using MEDLINE (1966–March 2008) and the search terms aspirin, clopidogrel, ticlopidine, thienopyridine, warfarin, antiplatelet, anticoagulant, myocardial infarction, atrial fibrillation, and percutaneous coronary intervention (PCI). Additional references were identified by reviewing reference citations of articles retrieved.

Study Selection and Data Extraction:

Applicable data were extracted from published reports and studies that included either clinical outcomes or adverse events.

Data Synthesis:

Clinical guidelines recommend the combination of antiplatelets and anticoagulants based largely on writing committee consensus. To date, only one randomized clinical trial has evaluated the safety and efficacy of adding warfarin to dual antiplatelet therapy (ie, triple antithrombotic therapy). Other published data are from case series, observational studies, and case-controlled studies primarily of patients undergoing PCI with intracoronary stent placement. Four of 12 studies reported no increased risk of major bleeding events. In the other 8 studies, a 3- to 6-fold increase in bleeding events was reported with triple antithrombotic therapy. Ischemic events were reported in only 6 of the studies. Only 2 studies observed an additional benefit in the reduction of ischemic events, and 1 study reported worsened ischemic outcomes with the triple antithrombotic regimen compared with dual antithrombotic therapy.

Conclusions:

Available guidelines pertaining to the concomitant administration of aspirin, a thienopyridine, and warfarin are based on limited trial data and consensus judgment. Overall, selection of triple antithrombotic therapy for patients with vascular disease is considered a matter of clinical judgment for an individual patient based on the prescriber's perceived balance between the patient's risk for recurrent ischemic events, expected duration of treatment, and patient's risk for bleeding.
Role of Metformin for Weight Management in Patients Without Type 2 Diabetes
Authors: Desilets Alicia R , Dhakal-Karki Sushmita , Dunican Kaelen C
Published: May 2008

Objective:

To evaluate the efficacy and safety of metformin for weight management in overweight and obese patients without type 2 diabetes.

Data Sources:

Literature was obtained through MEDLINE Ovid (1950–February week 3, 2008), EMBASE (all years), and a bibliographic review of relevant articles. Key words included metformin, obesity, overweight, and weight loss.

Study Selection/Data Extraction:

All studies published in the English language that evaluated the effects of metformin on weight in obese or overweight individuals were critically analyzed. Relevant articles were selected for inclusion in this review.

Data Synthesis:

Metformin is first-line pharmacotherapy in the treatment of overweight or obese patients with type 2 diabetes, with beneficial effects on weight in this population. Multiple trials have evaluated the effect of metformin on weight and other metabolic parameters in adults and adolescents without diabetes. Five of 12 trials in adults evaluated weight loss as a primary endpoint. Significant weight reduction was found in 4 of these studies; however, the trials were small and of weak design. Weight reduction was significant in 5 of the 6 adolescent trials; similarly, these studies were limited by weak study design and small patient population. Metabolic parameters (blood pressure, waist circumference, cholesterol parameters, insulin/glucose levels) often showed varying results. Metformin was well tolerated; gastrointestinal effects were the most frequently reported adverse effects.

Conclusions:

The weight loss effects of metformin in overweight or obese adults and adolescents without diabetes appear promising; however, trials have been limited by small patient populations and weak design. Metformin may also have a positive effect on metabolic parameters such as waist circumference, fasting insulin and glucose levels, and triglycerides. Further research involving large-scale trials that evaluate weight loss as a primary outcome is necessary to firmly establish the role of metformin in this population.
Reward-Dependent Modulation of Neuronal Activity in the Primate Dorsal Raphe Nucleus
Authors: Nakamura Kae , Matsumoto Masayuki , Hikosaka Okihide
Published: May 2008

The dopamine system has been thought to play a central role in guiding behavior based on rewards. Recent pharmacological studies suggest that another monoamine neurotransmitter, serotonin, is also involved in reward processing. To elucidate the functional relationship between serotonin neurons and dopamine neurons, we performed single-unit recording in the dorsal raphe nucleus (DRN), a major source of serotonin, and the substantia nigra pars compacta, a major source of dopamine, while monkeys performed saccade tasks in which the position of the target indicated the size of an upcoming reward. After target onset, but before reward delivery, the activity of many DRN neurons was modulated tonically by the expected reward size with either large- or small-reward preference, whereas putative dopamine neurons had phasic responses and only preferred large rewards. After reward delivery, the activity of DRN neurons was modulated tonically by the received reward size with either large- or small-reward preference, whereas the activity of dopamine neurons was not modulated except after the unexpected reversal of the position–reward contingency. Thus, DRN neurons encode the expected and received rewards, whereas dopamine neurons encode the difference between the expected and received rewards. These results suggest that the DRN, probably including serotonin neurons, signals the reward value associated with the current behavior.
Cytoskeletal Requirements in Axonal Transport of Slow Component-b
Authors: Roy Subhojit , Winton Matthew J. , Black Mark M. , Trojanowski John Q. , Lee Virginia M.-Y.
Published: May 2008

Slow component-b (SCb) translocates ∼200 diverse proteins from the cell body to the axon and axon tip at average rates of ∼2–8 mm/d. Several studies suggest that SCb proteins are cotransported as one or more macromolecular complexes, but the basis for this cotransport is unknown. The identification of actin and myosin in SCb led to the proposal that actin filaments function as a scaffold for the binding of other SCb proteins and that transport of these complexes is powered by myosin: the “microfilament-complex” model. Later, several SCb proteins were also found to bind F-actin, supporting the idea, but despite this, the model has never been directly tested. Here, we test this model by disrupting the cytoskeleton in a live-cell model system wherein we directly visualize transport of SCb cargoes. We focused on three SCb proteins that we previously showed were cotransported in our system: α-synuclein, synapsin-I, and glyceraldehyde-3-phosphate dehydrogenase. Disruption of actin filaments with latrunculin had no effect on the velocity or frequency of transport of these three proteins. Furthermore, cotransport of these three SCb proteins continued in actin-depleted axons. We conclude that actin filaments do not function as a scaffold to organize and transport these and possibly other SCb proteins. In contrast, depletion of microtubules led to a dramatic inhibition of vectorial transport of SCb cargoes. These findings do not support the microfilament-complex model, but instead indicate that the transport of protein complexes in SCb is powered by microtubule motors.
Spoken Word Memory Traces within the Human Auditory Cortex Revealed by Repetition Priming and Functional Magnetic Resonance Imaging
Authors: Gagnepain Pierre , Chételat Gael , Landeau Brigitte , Dayan Jacques , Eustache Francis , Lebreton Karine
Published: May 2008

Previous neuroimaging studies in the visual domain have shown that neurons along the perceptual processing pathway retain the physical properties of written words, faces, and objects. The aim of this study was to reveal the existence of similar neuronal properties within the human auditory cortex. Brain activity was measured using functional magnetic resonance imaging during a repetition priming paradigm, with words and pseudowords heard in an acoustically degraded format. Both the amplitude and peak latency of the hemodynamic response (HR) were assessed to determine the nature of the neuronal signature of spoken word priming. A statistically significant stimulus type by repetition interaction was found in various bilateral auditory cortical areas, demonstrating either HR suppression and enhancement for repeated spoken words and pseudowords, respectively, or word-specific repetition suppression without any significant effects for pseudowords. Repetition latency shift only occurred with word-specific repetition suppression in the right middle/posterior superior temporal sulcus. In this region, both repetition suppression and latency shift were related to behavioral priming. Our findings highlight for the first time the existence of long-term spoken word memory traces within the human auditory cortex. The timescale of auditory information integration and the neuronal mechanisms underlying priming both appear to differ according to the level of representations coded by neurons. Repetition may “sharpen” word-nonspecific representations coding short temporal variations, whereas a complex interaction between the activation strength and temporal integration of neuronal activity may occur in neuronal populations coding word-specific representations within longer temporal windows.
Circuit and Plasticity Defects in the Developing Somatosensory Cortex ofFmr1Knock-Out Mice
Authors: Bureau Ingrid , Shepherd Gordon M. G. , Svoboda Karel
Published: May 2008

Silencing of theFmr1gene causes fragile X syndrome. Although defects in synaptic plasticity in the cerebral cortex have been linked to cognitive impairments inFmr1 knock-out(ko) mice, the specific cortical circuits affected in the syndrome are unknown. Here, we investigated the development of excitatory projections in the barrel cortex ofFmr1 komice. In 2-week-oldFmr1 komice, a major ascending projection connecting layer 4 (L4) to L3 (L4→L3), was defective in multiple and independent ways: its strength was reduced, caused by a lower connection probability; the axonal arbors of L4 cells were spatially diffuse in L2/3; the L4→L3 projection did not show experience-dependent plasticity. By 3 weeks, the strength of the L4→L3 projection was similar to that of wild type. Our data indicate thatFmr1shapes sensory cortical circuits during a developmental critical period.
Cytokine Mechanisms of Central Sensitization: Distinct and Overlapping Role of Interleukin-1β, Interleukin-6, and Tumor Necrosis Factor-α in Regulating Synaptic and Neuronal Activity in the Superficial Spinal Cord
Authors: Kawasaki Yasuhiko , Zhang Ling , Cheng Jen-Kun , Ji Ru-Rong
Published: May 2008

Central sensitization, increased sensitivity in spinal cord dorsal horn neurons after injuries, plays an essential role in the induction and maintenance of chronic pain. However, synaptic mechanisms underlying central sensitization are incompletely known. Growing evidence suggests that proinflammatory cytokines (PICs), such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), are induced in the spinal cord under various injury conditions and contribute to pain hypersensitivity. Using patch-clamp recordings in lamina II neurons of isolated spinal cord slices, we compared the effects of IL-1β, IL-6, and TNFα on excitatory and inhibitory synaptic transmission. Whereas TNFα enhanced the frequency of spontaneous EPSCs (sEPSCs), IL-6 reduced the frequency of spontaneous IPSCs (sIPSCs). Notably, IL-1β both enhanced the frequency and amplitude of sEPSCs and reduced the frequency and amplitude of sIPSCs. Consistently, TNFα and IL-1β enhanced AMPA- or NMDA-induced currents, and IL-1β and IL-6 suppressed GABA- and glycine-induced currents. Furthermore, all the PICs increased cAMP response element-binding protein (CREB) phosphorylation in superficial dorsal horn neurons and produced heat hyperalgesia after spinal injection. Surprisingly, soluble IL-6 receptor (sIL-6R) produced initial decrease of sEPSCs, followed by increase of sEPSCs and CREB phosphorylation. Spinal injection of sIL-6R also induced heat hyperalgesia that was potentiated by coadministration with IL-6. Together, our data have demonstrated that PICs induce central sensitization and hyperalgesia via distinct and overlapping synaptic mechanisms in superficial dorsal horn neurons either by increasing excitatory synaptic transmission or by decreasing inhibitory synaptic transmission. PICs may further induce long-term synaptic plasticity through CREB-mediated gene transcription. Blockade of PIC signaling could be an effective way to suppress central sensitization and alleviate chronic pain.
Tumor Necrosis Factor α Mediates Lipopolysaccharide-Induced Microglial Toxicity to Developing Oligodendrocytes When Astrocytes Are Present
Authors: Li Jianrong , Ramenaden E. Radhika , Peng Jie , Koito Hisami , Volpe Joseph J. , Rosenberg Paul A.
Published: May 2008

Reactive microglia and astrocytes are present in lesions of white matter disorders, such as periventricular leukomalacia and multiple sclerosis. However, it is not clear whether they are actively involved in the pathogenesis of these disorders. Previous studies demonstrated that microglia, but not astrocytes, are required for lipopolysaccharide (LPS)-induced selective killing of developing oligodendrocytes (preOLs) and that the toxicity is mediated by microglia-derived peroxynitrite. Here we report that, when astrocytes are present, the LPS-induced, microglia-dependent toxicity to preOLs is no longer mediated by peroxynitrite but instead by a mechanism dependent on tumor necrosis factor-α (TNFα) signaling. Blocking peroxynitrite formation with nitric oxide synthase (NOS) inhibitors or a decomposition catalyst did not prevent LPS-induced loss of preOLs in mixed glial cultures. PreOLs were highly vulnerable to peroxynitrite; however, the presence of astrocytes prevented the toxicity. Whereas LPS failed to kill preOLs in cocultures of microglia and preOLs deficient in inducible NOS (iNOS) or gp91phox, the catalytic subunit of the superoxide-generating NADPH oxidase, LPS caused a similar degree of preOL death in mixed glial cultures of wild-type,iNOS−/−, andgp91phox−/−mice. TNFα neutralizing antibody inhibited LPS toxicity, and addition of TNFα induced selective preOL injury in mixed glial cultures. Furthermore, disrupting the genes encoding TNFα or its receptors TNFR1/2 completely abolished the deleterious effect of LPS. Our results reveal that TNFα signaling, rather than peroxynitrite, is essential in LPS-triggered preOL death in an environment containing all major glial cell types and underscore the importance of intercellular communication in determining the mechanism underlying inflammatory preOL death.
Phosphorylation of Homer3 by Calcium/Calmodulin-Dependent Kinase II Regulates a Coupling State of Its Target Molecules in Purkinje Cells
Authors: Mizutani Akihiro , Kuroda Yukiko , Futatsugi Akira , Furuichi Teiichi , Mikoshiba Katsuhiko
Published: May 2008

Homer proteins are components of postsynaptic density (PSD) and play a crucial role in coupling diverse target molecules. However, the regulatory aspect of Homer-mediated coupling has been addressed only about a dominant-negative effect of Homer1a, which requiresde novogene expression. Here, we present evidence that Homer-mediated coupling is regulated by its phosphorylation state. We found that Homer3, the predominant isoform in Purkinje cells, is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) bothin vitroandin vivo. Biochemical fractionation with phosphor-specific antibodies revealed the presence of phosphorylated Homer3 in the cytosolic fraction in contrast to high levels of nonphosphorylated Homer3 in PSD. In P/Q-type voltage-gated-Ca2+channel knock-out mice, in which CaMKII activation was reduced, the levels of Homer3 phosphorylation and the soluble form of Homer 3 were markedly lower. Furthermore, both robust phosphorylation of Homer3 and its dissociation from metabotropic glutamate receptor 1α (mGluR1α) were triggered by depolarization in primary cultured Purkinje cells, and these events were inhibited by CaMKII inhibitor. Anin vitrobinding kinetic analysis revealed that these phosphorylation-dependent events were attributable to a decrease in the affinity of phosphorylated Homer3 for its ligand. In a heterologous system, the Ca2+signaling pattern induced by mGluR1α activation was modulated by the Homer3 phosphorylation state. Together, these findings suggested that Homer3 in Purkinje cells might function as a reversible coupler regulated by CaMKII phosphorylation and that the phosphorylation is capable of regulating the postsynaptic molecular architecture in response to synaptic activity.