bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extra copies of c‐myc are more pronounced in nodular melanomas than in superficial spreading melanomas as revealed by fluorescence in situ hybridisation
Authors: Treszl Andrea , Ádány Róza , Rákosy Zsuzsa , Kardos László , Bégány Ágnes , Gilde Katalin , Balázs Margit 
Published: June 2004

AbstractBackgroundAmplification of c‐myc is a common genetic alteration and associated with a poor prognosis in a variety of cancers. Extra copies of the gene have been found in large numbers of melanoma metastases, but only few primary tumours have been studied. We investigated the c‐myc copy number alterations in two different subtypes of primary melanomas with different biological behaviours.MethodsFluorescence in situ hybridisation was performed using c‐myc and centromeric 8 (C8) probes on 68 lesions (28 nodular melanomas [NMs], 26 superficial spreading melanomas [SSMs], and 14 metastases). To assess the ploidy pattern, copy number distribution of seven different chromosomes was also investigated.ResultsAll tumours showed aneuploid populations for at least three chromosomes. Whereas 61% of the NMs exhibited extra c‐myc copies, only 27% of SSMs showed increased gene dosage. The c‐myc/C8 ratio exceeding 1.5 was significantly higher in NMs (P = 0.01). High level amplification was seen only in NMs. An elevated c‐myc/C8 ratio was higher than 1.5 in only four metastases.ConclusionOur data show that c‐myc copy number alterations differ in the two melanoma subtypes and are associated with the advanced stage of the disease. The less frequent amplification of the c‐myc gene in metastatic lesions indicates that it may play an important role in the development of an invasive potential rather than in the metastatic process. © 2004 Wiley‐Liss, Inc.
CD4–c‐kit–CD3ϵ–IL‐2Rα+ Peyer's patch cells are a novel cell subset which secrete IL‐5 in response to IL‐2: implications for their role in IgA production
Authors: Kuraoka Masayuki , Hashiguchi Masaaki , Hachimura Satoshi , Kaminogawa Shuichi 
Published: June 2004

AbstractIn this study, we examined which cell population contributes to IL‐5 production by Peyer's patch (PP) cells. Thy1.2– fraction of PP cells, but not those of splenocytes, secreted IL‐5 in response to IL‐2. We found that CD3ϵ–IL‐2Rα+ cells purified from the Thy1.2–B220– fraction of PP cells secreted IL‐5 when stimulated with IL‐2. CD3ϵ–IL‐2Rα+ cells were subdivided into CD4+ and CD4– populations or c‐kit+ and c‐kit– populations, and only the CD4– and c‐kit– CD3ϵ–IL‐2Rα+ cells secreted IL‐5 in response to IL‐2. CD3ϵ–IL‐2Rα+ cells did not express NK cell‐markers and exhibited a lymphoid morphology. We have therefore identified CD3ϵ–IL‐2Rα+ cells as a unique lymphoid population that are not classified into conventional IL‐5‐producing cell populations, such as T cells, mast cells and NK cells. Depletion of CD3ϵ–IL‐2Rα+ cells from PP resulted in reduced IL‐5 production. Furthermore, IgA secretion by B cells was increased when PP B cells were cocultured with CD3ϵ–IL‐2Rα+ cells. Taken together, these results suggest that the novel subset of CD4–c‐kit–CD3ϵ–IL‐2Rα+ PP cells are capable of secreting a high level of IL‐5 in response to IL‐2, contribute markedly to IL‐5 production and help IgA secretion by B cells.
Apoptosis via the B cell antigen receptor requires Bax translocation and involves mitochondrial depolarization, cytochrome C release, and caspase‐9 activation
Authors: Eldering Eric , Mackus Wendelina J. M. , Derks Ingrid A. M. , Evers Ludo M. , Beuling Esther , Teeling Peter , Lens Susanne M. A. , van Oers Marinus H. J. , van Lier René A. W. 
Published: June 2004

AbstractVarious routes to apoptosis can be active during B cell development. In a model system of mature B cells, differences in caspase‐3 processing have suggested that antigen receptor (BCR)‐mediated apoptosis may involve a zVAD‐insensitive initiator protease(s). In search of the events leading to caspase‐3 activation, we now establish that both CD95‐ and BCR‐mediated apoptosis depend on Bax activation and cytochrome C (cytC) release. Nevertheless, the timing and caspase‐dependence of mitochondrial membrane depolarization differed considerably after CD95‐ or BCR‐triggering. To delineate events subsequent to cytC release, we compared apoptosis induced via BCR triggering and via direct mitochondrial depolarization by CCCP. In both cases, partial processing of caspase‐3 was observed in the presence of zVAD. By expression in 293 cells we addressed the potential of candidate initiator caspases to function in the presence of zVAD, and found that caspase‐9 efficiently processed caspase‐3, while caspase‐2 or –8 were inactive. Finally, retroviral expression of dominant‐negative caspase‐9 inhibited both CD95‐ and BCR‐mediated apoptosis. In conclusion, we obtained no evidence for involvement of a BCR‐specific protease. Instead, our data show for the first time that the BCR‐signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release. Subsequent caspase‐9 activation can solely account for events further downstream.
The effects of endothelin‐1 on degranulation, cytokine, and growth factor production by skin‐derived mast cells
Authors: Matsushima Hironori , Yamada Nobuo , Matsue Hiroyuki , Shimada Shinji 
Published: June 2004

AbstractEndothelin‐1 (ET‐1), originally described as a vasoconstrictor, is now known to be involved in pathogenesis of various disorders including vascular, inflammatory, and fibrotic diseases. Recentstudies suggest that mast cells are also involved in the same pathological conditions. In this study, we tested a hypothesis that ET‐1 would affect mast cell functions and contribute to such disease conditions, using fetal skin‐derived cultured mast cells (FSMC) and bone marrow‐derived cultured mast cells (BMMC). FSMC expressed ET receptors (ETA and ETB) at mRNA and protein levels, whereas BMMC expressed lower levels of ETA, and little, if any, ETB. ET‐1 induced degranulation by FSMC, but not by BMMC through ETA‐mediated pathways. ET‐1 at different concentrations exerted the reciprocal effects on degranulation by IgE‐bound FSMC. Furthermore, ET‐1 induced TNF‐α and IL‐6 production by FSMC, but not by BMMC, and significantly enhanced VEGF production and TGF‐β1 mRNA expression by FSMC. Finally, ET‐1 was produced by FSMC, but not by BMMC in response to Toll‐like receptor ligands. These results indicate contrasting impacts of ET‐1 on distinct mast cell populations. We propose that ET‐1 may participate in pathological conditions of various disorders via its multi‐functional effects on mast cells under certain conditions.
HSP60 induces self‐tolerance to repeated HSP60 stimulation and cross‐tolerance to other pro‐inflammatory stimuli
Authors: Kilmartin Barry , Reen Denis J. 
Published: June 2004

AbstractIn addition to their primary function as intracellular chaperone proteins, the immunomodulatory properties of heat shock proteins (HSP), including their role as adjuvants for vaccines, have become a focus of intense research interest. Interestingly, the effect of chronic exposure to an endogenous immunomodulator and initiator of inflammation such as autologous HSP60 has as yet remained uncharacterized. In this study, we demonstrate that pretreatment of monocytes with human HSP60 results in a suppression of TNF‐α production on restimulation with HSP60. Furthermore, desensitization with HSP60 inhibits TNF‐α expression in these cells in response to LPS stimulation, thereby inducing "cross‐tolerance". In contrast to TNF‐α suppression, IL‐1β expression was augmented in HSP60‐pretreated monocytes on restimulation, while being suppressed in THP‐1 cells. Addition of an anti‐IL‐10 neutralizing antibody had no significant effect on HSP60‐ or LPS‐induced tolerance.HSP60 priming of monocytes also results in significant down‐regulation of HLA‐DR, CD86 and Toll‐like receptor 4 expression, but minimally up‐regulates CD80 expression, similar to that previously reported with LPS. By identifying a previously unrecognized "tolerizing" effect of extended exposure to autologous HSP60 on the innate immune system, as opposed to its recently identified pro‐inflammatory stimulatory capacity, this study highlights a further level of complexity of our understanding of the biological activities of HSP.
Effect of Substitution of Methyl Groups on the Luminescence Performance of IrIII Complexes: Preparation, Structures, Electrochemistry, Photophysical Properties and Their Applications in Organic Light‐Emitting Diodes (OLEDs)
Authors: Jung Sungouk , Kang Youngjin , Kim Hyung‐Sun , Kim Yun‐Hi , Lee Chang‐Lyoul , Kim Jang‐Joo , Lee Sung‐Koo , Kwon Soon‐Ki 
Published: June 2004

AbstractA series of dimethyl‐substituted tris(pyridylphenyl)iridium(III) derivatives [(n‐MePy−n′‐MePh)3Ir] [n = 3, n′ = 4 (1); n = 4, n′ = 4 (2); n = 4, n′ = 5 (3); n = 5, n′ = 4 (4); n = 5, n′ = 5 (5)] have been synthesized and characterized to investigate the effect of the substitution of methyl groups on the solid‐state structure and photo‐ and electroluminescence. The absorption, emission, cyclic voltammetry and electroluminescent performance of 1−5 have also been systematically evaluated. The structures of 2 and 4 have been determined by a single‐crystal X‐ray diffraction analysis. Under reflux (> 200 °C) in glycerol solution, fac‐type complexes with a distorted octahedral geometry are predominantly formed as the major components in all cases. Electrochemical studies showed much smaller oxidation potentials relative to Ir(ppy)3 (Hppy = 2‐phenylpyridine). All complexes exhibit intense green photoluminescence (PL), which has been attributed to metal‐to‐ligand charge transfer (MLCT) triplet emission. The maximum emission wavelengths of thin films of 1, 3, 4 and 5 at room temperature are in the range 529−536 nm, while 2 displays a blue‐shifted emission band (λmax = 512 nm) with a higher PL quantum efficiency (ΦPL = 0.52) than those of complexes 1 and 3−5; this is attributed to a decrease of the intermolecular interactions. Multilayered organic light‐emitting diodes (OLEDs) were fabricated by using three (2, 3 and 4) of these IrIII derivatives as dopant materials. The electroluminescence (EL) spectra of the devices, which have the maximum peaks at 509−522 nm, with shoulder peaks near 552 nm, are consistent with the PL spectra in solution at 298 K. The devices show operating voltages at 1 mA/cm2 of 4.9, 5.6, 5.1, and 4.6 V for Ir(ppy)3, 2, 3, and 4, respectively. In particular, the device with 2 shows a higher external quantum efficiency (ηext = 11% at 1 mA/cm2) and brightness (4543 cd/m2 at 20 mA/cm2) than Ir(ppy)3 (ηext = 6.0% at 1 mA/cm2; 3156 cd/m2 at 20 mA/cm2) and other Ir(dmppy)3 derivatives, (dmppy = dimethyl‐substituted ppy), under the same conditions. The methyl groups at the meta (Ph) and para (Py) positions to the Ir metal atom have a great influence on absorption, emission, redox potentials and electroluminescence. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Solution Synthesis of Two Orthogonally Protected Lactosides as Tetravalent Disaccharide‐Based Scaffolds
Authors: Castoldi Sergio , Cravini Massimiliano , Micheli Fabrizio , Piga Elisabetta , Russo Giovanni , Seneci Pierfausto , Lay Luigi 
Published: June 2004

AbstractTwo tetravalent lactosidic scaffolds have been synthesised in solution from commercial lactose. Careful manipulation of the protecting groups allowed us to orthogonally protect four OH groups for their use as diversity sites for the development of broad screening libraries of sugar mimics. The selective access to each of these hydroxy groups has been demonstrated on scaffold 2 by deprotection and functionalisation with p‐fluorophenyl isocyanate. Finally, the 6‐OH derivative of compound 2 was covalently attached to a polymeric support. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Reduction of Carbonyl Compounds by Lanthanide Metal/2‐Propanol: In‐situ Generation of Samarium Isopropyloxide for Stereoselective Meerwein−Ponndorf−Verley Reduction
Authors: Fukuzawa Shin‐ichi , Nakano Narihito , Saitoh Takahide 
Published: June 2004

AbstractThe reduction of ketones and aldehydes with lanthanide metals (La, Ce, Sm, Yb) and a catalytic amount of iodine (5 mol %) in iPrOH proceeded smoothly to produce the corresponding alcohols as the major products in good yield, while in THF, methanol, and ethanol the pinacols were mainly produced. The yields of alcohols were improved most effectively by the use of Sm metal, the amount of pinacol produced thus being minimized. The actual reducing agent may be samarium isopropyloxide, which mediates the Meerwein−Ponndorf−Verley‐type hydride‐transfer reaction, since the reaction can be carried out catalytically with respect to samarium. The stereoselectivities of the reductions of the 2‐ and 4‐substituted cyclohexanones with Sm/iPrOH were higher than those achieved with SmI2/iPrOH or Sm/H2O. The asymmetric reduction of acetophenone could be achieved to give the 1‐phenylethanol in up to 95% ee in the presence of the chiral ligand 7. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis of Free and Nα‐Fmoc‐/Nγ‐Boc‐Protected (2S,4S)‐ and (2S,4R)‐4‐Aminopipecolic Acids
Authors: Machetti Fabrizio , Cordero Franca M. , De Sarlo Francesco , Papini Anna M. , Alcaro Maria C. , Brandi Alberto 
Published: June 2004

AbstractThe preparation of (2S,4S)‐ and (2S,4R)‐4‐aminopipecolic acid, a conformationally constrained basic amino acid bearing orthogonal Nα/Nγ‐protection suitable for solid‐phase peptide synthesis, is reported. These amino acids were synthesised from enantiopure ethyl (2S)‐4‐oxo‐1‐(1‐phenylethyl)piperidine‐2‐carboxylate (1) with introduction of the side‐chain amino group by reductive amination, followed by protection/deprotection of the functional groups. A mixture of Fmoc‐Sly(Boc)‐OH 6 and 7 was used to establish their compatibility in solid‐phase peptide synthesis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Non‐Dipolar Behavior of Mesoionic Heterocycles: Synthesis and Tautomerism of 2‐Alkylthioisomünchnones
Authors: Ávalos Martín , Babiano Reyes , Cintas Pedro , Díaz Jesús , Jiménez José L. , López Ignacio , Palacios Juan C. 
Published: June 2004

AbstractThis paper describes a general preparation of a series of 1,3‐thiazolium‐4‐olates, each bearing an alkyl group at C‐2, through reactions between N‐arylthiocarboxamides and α‐haloacyl halides. Unlike the 2‐aryl‐substituted derivatives, such alkylated mesoionic compounds exist in equilibria with their non‐dipolar tautomers, the corresponding 2‐alkylidene‐1,3‐thiazolidin‐4‐ones. The unambiguous characterization of such tautomers and their relative stabilities have now been assessed by spectroscopic and computational studies. The presence of o,o′‐disubstituted aryl groups at N‐3 of the heterocyclic ring slows down free rotation around the N−Ar bond, thus opening access to a promising class of non‐biaryl atropisomers. Finally, treatment of N‐arylthioformamides with α‐haloacyl halides gives rise to N‐acylthioformamides instead of the corresponding mesoionic species. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
1,8‐Diazabicyclo[6.6.6]eicosane, 1,8‐Diazabicyclo[6.6.5]nonadecane and 1,8‐Diazabicyclo[6.6.4]octadecane and Their Diprotonated Forms
Authors: Pool Brett , Balalaie Saeed , Kunze Andreas , Schilling Gerhard , Bischof Peter , Gleiter Rolf 
Published: June 2004

AbstractThe preparation of the title compounds 9−11 was achieved by catalytic hydrogenation of 1,8‐diazabicyclo[6.6.6]eicosa‐4,11‐diyne (13), 1,8‐diazabicyclo[6.6.5]nonadeca‐4,11‐diyne (14), and 1,8‐diazabicyclo[6.6.4]octadeca‐4,11‐diyne (15), respectively. As catalyst we used Pd(OH)2 on carbon. NMR studies on 9−11 revealed an in/in conformation at the bridgehead positions. Treatment of 9−11 with an excess of trifluoroacetic acid yielded, in a kinetically controlled reaction, mixtures of the out/out and in/out diprotonated species [9·2H]2+, [10·2H]2+ and [11·2H]2+. The thermodynamically controlled species, the corresponding in/in conformers, are formed at higher temperatures and longer reaction times. The experimental observations are supported by AM1 calculations. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Highly Enantioselective Synthesis of No‐Carrier‐Added 6‐[18F]Fluoro‐L‐dopa by Chiral Phase‐Transfer Alkylation
Authors: Lemaire Christian , Gillet Steve , Guillouet Stéphane , Plenevaux Alain , Aerts Joël , Luxen André 
Published: June 2004

Abstract[18F]Fluoro‐L‐dopa, an important radiopharmaceutical for positron emission tomography (PET), has been synthesized using a phase‐transfer alkylation reaction. A chiral quaternary ammonium salt derived from a Cinchona alkaloid served as phase‐transfer catalyst for the enantioselective alkylation of a glycine derivative. The active methylene group of this Schiff‐base substrate was deprotonated with cesium hydroxide and rapidly alkylated by the 2‐[18F]fluoro‐4,5‐dimethoxybenzyl halide (X = Br, I). The reaction proceeded with high yield (> 90%) at 0 °C or room temperature in various solvents such as toluene or dichloromethane. Preparation of the [18F]alkylating agent on a solid support was developed. After labelling, the labeled [18F]fluoroveratraldehyde was trapped on a tC18 cartridge and then converted on the cartridge into the corresponding benzyl halide derivatives by addition of aqueous sodium borohydride and gaseous hydrobromic or ‐iodic acid. Hydrolysis and purification by preparative HPLC made 6‐[18F]fluoro‐L‐dopa ready for human injection in a 25−30% decay‐corrected radiochemical yield in a synthesis time of 100 min. The product was found to be chemically, radiochemically and enantiomerically pure (ee > 95%). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Telomerization of Butadiene withL‐Arabinose andD‐Xylose in DMF: Selective Formation of their Monooctadienyl Glycosides
Authors: Estrine Boris , Bouquillon Sandrine , Hénin Françoise , Muzart Jacques 
Published: June 2004

AbstractConditions to achieve the palladium‐catalysed telomerization of butadiene withL‐arabinose andD‐xylose as telogens have been identified. With DMF as solvent, optimised ratios of substrate, reactants and catalytic system allowed the selective grafting of one octadienyl chain onto the anomeric hydroxy group. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Transannular Reactions of Two Non‐Parallel 1,3‐Butadiyne Units − Syntheses, Structures and Protonation Reactions of 1‐Isopropyl‐1‐azacyclopentadeca‐3,5,11,13‐tetrayne and 1‐Isopropyl‐1‐azacyclohexadeca‐3,5,12,14‐tetrayne
Authors: Schmidt Erik M. , Gleiter Rolf , Rominger Frank 
Published: June 2004

AbstractThe syntheses of 1‐isopropyl‐1‐azacyclopentadeca‐3,5,11,13‐tetrayne (15a) and 1‐isopropyl‐1‐azacyclohexadeca‐3,5,12,14‐tetrayne (15b) were accomplished in a stepwise approach. The key intermediates were 1,14‐dibromotetradeca‐2,4,10,12‐tetrayne (14a) and 1,15‐dibromopentadeca‐2,4,11,13‐tetrayne (14b). The ring closure to 15a and 15b was achieved by reaction with isopropylamine. X‐ray investigations on single crystals of 15a and 15b revealed a non‐parallel orientation of the 1,3‐butadiyne units. The reaction of 15b with concd. HCl in ethanol yielded 5,12‐dichloro‐2‐isopropyl‐1,2,3,6,7,8,9,10‐octahydrocyclonona[e]isoindole (16c) and 5‐chloro‐2‐isopropyl‐2,3,6,7,8,9,10,11‐octahydrocyclonona[e]isoindol‐12(1H)‐one (17c). A mechanism for the reaction of 15b with HCl is proposed. The reaction of 15a with concd. HCl in ethanol gives 5‐chloro‐2‐isopropyl‐2,3,7,8,9,10‐hexahydrocycloocta[e]isoindol‐11(6H)‐one (24c). (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis of 3‐Substituted Dihydro‐1‐phenylamino‐1H‐pyrrolo[1,2‐a]imidazole‐2,5(3H,6H)‐diones from α‐Amino Acid Phenylhydrazides and Levulinic Acid
Authors: Verardo Giancarlo , Geatti Paola , Merli Marcello , Castellarin Elena E. 
Published: June 2004

Abstractα‐Amino acid phenylhydrazides 1 readily react with levulinic acid to produce the imidazolidin‐4‐one intermediates 4, which undergo a second ring closure to afford the dihydro‐1H‐pyrrolo[1,2‐a]imidazole‐2,5‐dione derivatives 5. It has been established that the solvent polarity has a great influence on the rate of the second condensation reaction, but not on the first. A mechanism, supported by experimental evidence, has been proposed to explain how the imidazolidin‐4‐one intermediates 4, obtained as expected as a mixture of two diastereoisomers, give a single isomer for the bicyclic derivatives 5; the absolute stereochemistry of these compounds has been determined by X‐ray crystallographic analysis. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Synthesis, Self‐Assembled Monolayers and Alkaline Earth Metal Ion Recognition of p‐tert‐Butylcalix[4]arene Derivatives
Authors: Zhang Sheng , Song Fayi , Echegoyen Luis 
Published: June 2004

AbstractThe synthesis and self‐assembled monolayer (SAM) formation of three conformational isomers of p‐tert‐butylcalix[4]crown‐6 derivatives 3a−3c and one p‐tert‐butylcalix[4]arene derivative (3d) are reported. The SAMs of these compounds were prepared and characterized by electrochemistry, reflection‐absorption infrared spectroscopy (RAIRS) and contact‐angle measurements. The recognition properties of these SAMs with metal cations were systematically investigated using electrochemical techniques and impedance spectroscopy. The monolayers exhibit selective binding and sensing abilities with alkaline earth metal cations such as Ca2+ and Ba2+ over alkali metal ions. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Nucleophilic Reactivities of Ketene Acetals
Authors: Tokuyasu Takahiro , Mayr Herbert 
Published: June 2004

AbstractThe kinetics of the reactions of ketene acetals with benzhydrylium ions have been followed photometrically. The reactions proceed with rate‐determining C−C bond formation that is considerably faster than expected for outer‐sphere electron transfer processes. Structure−reactivity relationships are discussed. The excellent correlations between the observed second‐order rate constants (log k2) and the previously reported electrophilicity parameters (E) of benzhydrylium ions suggest that several of the compounds investigated in this work can be used as reference nucleophiles for the development of electrophilicity scales. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)
Pyrrolizidine Alkaloids by Intramolecular Palladium‐Catalysed Allylic Alkylation: Synthesis of (±)‐Isoretronecanol
Authors: Lemaire Sébastien , Giambastiani Giuliano , Prestat Guillaume , Poli Giovanni 
Published: June 2004

AbstractAn efficient and stereoconvergent approach to 3‐substituted hexahydroindol‐2‐one derivatives by palladium‐catalysed intramolecular allylic alkylation has been developed. Subsequently, the straightforward conversion of the hexahydroindol‐2‐one 7d into the alkaloid (±)‐isoretronecanol has been performed. The synthesis entails 11 steps starting from 1,3‐cyclohexadiene, affording the final target in a 29% overall yield. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)