bluuebunny/crossref_metadata_2025 huggingface dataset:
The Training and Transfer of Real-World Perceptual Expertise
Authors: Tanaka James W. , Curran Tim , Sheinberg David L.
Published: February 2005

A hallmark of perceptual expertise is that experts classify objects at a more specific, subordinate level of abstraction than novices. To what extent does subordinate-level learning contribute to the transfer of perceptual expertise to novel exemplars and novel categories? In this study, participants learned to classify 10 varieties of wading birds and 10 varieties of owls at either the subordinate, species (e.g., “great blue crown heron,” “eastern screech owl”) or the family (“wading bird,” “owl”) level of abstraction. During training, the amount of visual exposure was equated such that participants received an equal number of learning trials for wading birds and owls. Pre- and posttraining performance was measured in a same/different discrimination task in which participants judged whether pairs of bird stimuli belonged to the same or different species. Participants trained in species-level discrimination demonstrated greater transfer to novel exemplars and novel species categories than participants trained in family-level discrimination. These findings suggest that perceptual categorization, not perceptual exposure per se, is important for the development and generalization of visual expertise.
A constitutive PR‐1::luciferase expression screen identifies Arabidopsis mutants with differential disease resistance to both biotrophic and necrotrophic pathogens
Authors: MURRAY SHANE L. , ADAMS NICOLETTE , KLIEBENSTEIN DANIEL J. , LOAKE GARY J. , DENBY KATHERINE J.
Published: February 2005

A complex signal transduction network involving salicylic acid, jasmonic acid and ethylene underlies disease resistance in Arabidopsis. To understand this defence signalling network further, we identified mutants that expressed the marker gene PR‐1::luciferase in the absence of pathogen infection. These cir mutants all display constitutive expression of a suite of defence‐related genes but exhibit different disease resistance profiles to two biotrophic pathogens, Pseudomonas syringae pv. tomato and Peronospora parasitica NOCO2, and the necrotrophic pathogen Botrytis cinerea. We further characterized cir3, which displays enhanced resistance only to the necrotrophic pathogen. Cir3‐mediated resistance to B. cinerea is dependent on accumulated salicylic acid and a functional EIN2 protein.
Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective
Authors: Hough R. E. , Snowden J. A. , Wulffraat N. M.
Published: February 2005

The potential of haemopoietic stem cell transplantation (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serindipitous remissions of autoimmune disease observed in patients undergoing transplantation for haematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases. Phase III clinical trials are in progress for some diseases. This review provides a comprehensive update on the efficacy and toxicity of HSCT in severe autoimmune disease. Future directions in the context of other evolving therapies are discussed.
Less than half of patients aged 65 years or under with myeloma proceed to transplantation: results of a two region population‐based survey*
Authors: Morris T. C. M. , Velangi Mark , Jackson Graham , Marks David I , Ranaghan Lisa
Published: February 2005

In this population‐based survey covering two geographically distinct UK regions, we evaluated the number of myeloma patients aged ≤65 years who have not undergone transplantation. The combined data from both of these regions showed that 57% of age‐eligible patients were not transplanted. While early death and comorbidity accounted for nearly half of the non‐transplanted patients, we examined the other reasons for non‐transplantation within each region, assessed regional variations in reasons for non‐transplant and looked at possible strategies aimed at increasing the transplantation rate.
Human leucocyte antigen class I and killer immunoglobulin‐like receptor expression patterns in T‐cell large granular lymphocyte leukaemia
Authors: Nowakowski Grzegorz S. , Morice William G. , Phyliky Robert L. , Li Chin‐Yang , Tefferi Ayalew
Published: February 2005

T‐cell large granular lymphocyte leukaemia (T‐LGLL) is often associated with suppression of haematopoiesis through unknown mechanisms. Killer immunoglobulin‐like receptors (KIRs) binding human‐leucocyte antigen (HLA)‐I in an allele‐specific manner are frequently expressed by T‐LGLL cells. HLA‐I genotyping was performed in seven T‐LGLL cases in which the neoplastic cells were known to express a single KIR isoform (CD158a, CD158b or CD158e). Five cases showed absence of the cognate HLA‐I antigen for the expressed KIR isoform, resulting in KIR/HLA‐I ‘mismatch’. Cytopenias occurred in all five ‘mismatch’ patients but not in two patients with ‘match’, suggesting that KIR/HLA‐I mismatch may contribute to the suppression of haematopoiesis.
Unique gene expression and clinical characteristics are associated with the 11q23 deletion in chronic lymphocytic leukaemia
Authors: Dickinson John D. , Smith Lynette M. , Sanger Warren G. , Zhou Guimei , Townley Peter , Lynch James C. , Steven Pavletic Z. , Bierman Philip J. , Joshi Shantaram S.
Published: February 2005

Chromosome abnormalities influence prognosis and tumour progression in B‐cell Chronic Lymphocytic Leukaemia (CLL). This study sought to determine whether these different disease subgroups were associated with unique gene expression patterns. Thirty‐four cases of CLL were screened for the 11q23, 13q14, 17p13 deletions, and trisomy 12 by fluorescence in situ hybridization (FISH). Expression of 205 cell signalling and apoptosis genes were compared by cDNA array among cases with different chromosome abnormalities. A majority of the statistically differentially expressed genes were present in the 11q23 deletion group by hierarchical clustering. CDC2, a serine/threonine kinase, was overexpressed in the 11q23 deletion group (P = 0·0004) and confirmed by TaqmanTM real‐time polymerase chain reaction. Several other genes associated with cell signalling were overexpressed in the 11q23 deletion group. A strong overall correlation existed between the presence of different chromosome abnormalities and a number of prognostic factors including immunoglobulin heavy chain variable region mutation status (P = 0·011), time to treatment (P = 0·025) and lymphocyte doubling time (P = 0·034). This study confirmed the prognostic impact of chromosome abnormalities identified by FISH in CLL, particularly the 11q23 deletion and trisomy 12. In addition, the 11q23 deletion group was associated with a unique gene expression pattern involving cell signalling and apoptosis genes.
Platelet glycoprotein Ib alpha polymorphisms affect the interaction with von Willebrand factor under flow conditions
Authors: Matsubara Yumiko , Murata Mitsuru , Hayashi Tomohiro , Suzuki Keijiro , Okamura Yosuke , Handa Makoto , Ishihara Hiroaki , Shibano Toshiro , Ikeda Yasuo
Published: February 2005

Interaction of platelet glycoprotein (GP) Ibα with von Willebrand factor (VWF) is essential for thrombus formation, particularly under high shear conditions. Previous case–control studies indicated that two GPIbα polymorphisms, 145Thr/Met and/or variable number (1–4) tandem repeats of 13 amino‐acid sequences, are associated with arterial thrombosis. The 145Met‐allele and the 3R‐ or 4R‐allele is associated with increased risk. However, there is little clear experimental data to support this association. To elucidate the functional effects of these polymorphisms, we prepared recombinant GPIbα fragments and tested them in vitro. The dissociation constants of ristocetin‐induced 125I‐labelled VWF binding to two forms of soluble recombinant GPIbα [1His–302Ala, either 145Thr (145T) or 145Met (145M)] were not different. Four types of Chinese hamster ovary cells expressing full‐length GPIbαβ/IX, 145T with one repeat (T1R), 145M with one repeat (M1R), 145T with four repeats (T4R), and 145M with four repeats (M4R), were prepared, and cell interactions with immobilized‐VWF were examined under various shear conditions. The cell rolling velocity of M4R under a shear condition of 114/s was significantly slower than that of T1R. Intermediate values were obtained with M1R and T4R. The results suggest that M4R interacts more strongly with VWF under flow conditions.
Effect of IL‐6 promoter polymorphism on incidence and outcome in Hodgkin's lymphoma
Authors: Cordano Pablo , Lake Annette , Shield Lesley , Taylor G. M. , Alexander Freda E. , Taylor Penelope R. A. , White Jo , Jarrett Ruth F.
Published: February 2005

A single nucleotide polymorphism (SNP) is present at position ‐174 of the human interleukin‐6 gene. The risk of developing Hodgkin's lymphoma (HL) in young adults decreases with an increasing number of C alleles at this position. We analysed the effect of this SNP on incidence and outcome in HL. DNA samples from 408 cases and 349 controls were screened and analysed following stratification by age, histological subtype and Epstein–Barr virus status. Although the risk of classical HL in young adults decreased with increasing C alleles, case–control differences were not significant. An excess of G alleles was observed for nodular lymphocyte predominant HL in young adults (n = 21), which was significant.
Carbon limitation of soil respiration under winter snowpacks: potential feedbacks between growing season and winter carbon fluxes
Authors: Brooks Paul D. , McKnight Diane , Elder Kelly
Published: February 2005

A reduction in the length of the snow‐covered season in response to a warming of high‐latitude and high‐elevation ecosystems may increase soil carbon availability both through increased litter fall following longer growing seasons and by allowing early winter soil frosts that lyse plant and microbial cells. To evaluate how an increase in labile carbon during winter may affect ecosystem carbon balance we investigated the relationship between carbon availability and winter CO2 fluxes at several locations in the Colorado Rockies. Landscape‐scale surveys of winter CO2 fluxes from sites with different soil carbon content indicated that winter CO2 fluxes were positively related to carbon availability and experimental additions of glucose to soil confirmed that CO2 fluxes from snow‐covered soil at temperatures between 0 and −3°C were carbon limited. Glucose added to snow‐covered soil increased CO2 fluxes by 52–160% relative to control sites within 24 h and remained 62–70% higher after 30 days. Concurrently a shift in the δ13C values of emitted CO2 toward the glucose value indicated preferential utilization of the added carbon confirming the presence of active heterotrophic respiration in soils at temperatures below 0°C. The sensitivity of these winter fluxes to substrate availability, coupled with predicted changes in winter snow cover, suggests that feedbacks between growing season carbon uptake and winter heterotrophic activity may have unforeseen consequences for carbon and nutrient cycling in northern forests. For example, published winter CO2 fluxes indicate that on average 50% of growing season carbon uptake currently is respired during the winter; changes in winter CO2 flux in response to climate change have the potential to reduce substantially the net carbon sink in these ecosystems.
Comparing soil organic carbon dynamics in plantation and secondary forest in wet tropics in Puerto Rico
Authors: Li Yiqing , Xu Ming , Zou Xiaoming , Shi Peijun , Zhang Yaoqi
Published: February 2005

We compared the soil carbon dynamics between a pine plantation and a secondary forest, both of which originated from the same farmland abandoned in 1976 with the same cropping history and soil conditions, in the wet tropics in Puerto Rico from July 1996 to June 1997. We found that the secondary forest accumulated the heavy‐fraction organic carbon (HF‐OC) measured by the density fractionation technique, more efficiently than the tree plantation did. Although there was no significant difference in total soil organic carbon (SOC) between the plantation (5.59±0.09 kg m−2) and the secondary forest (5.68±0.16 kg m−2), the proportion of HF‐OC carbon to the total SOC was significantly higher in the secondary forest (61%) than in the plantation (45%) (P<0.05). Forest floor mass and aboveground litterfall in the plantation were 168% and 22.8% greater than those in the secondary forest, respectively, while the decomposition rate of leaf litter in the plantation was 23.3% lower than that in the secondary forest. The annual mean soil respirations in the plantation and the secondary forest were 2.32±0.15 and 2.65±0.18 g C m−2 day−1, respectively, with a consistently higher rate in the secondary forest than in the plantation throughout the year. Microbial biomass measured by fumigation–incubation method demonstrated a strong seasonal variation in the secondary forest with 804 mg kg−1in the wet season and 460 mg kg−1in the dry season. However, the seasonal change of microbial biomass in the plantation was less significant. Our results suggested that secondary forests could stock more long‐term SOC than the plantations in the wet tropics because the naturally generated secondary forest accumulated more HF‐OC than the managed plantation.
Analyzing the ecosystem carbon and hydrologic characteristics of forested wetland using a biogeochemical process model
Authors: Cui Jianbo , Li Changsheng , Trettin Carl
Published: February 2005

A comprehensive biogeochemical model, Wetland‐DNDC, was applied to analyze the carbon and hydrologic characteristics of forested wetland ecosystem at Minnesota (MN) and Florida (FL) sites. The model simulates the flows of carbon, energy, and water in forested wetlands. Modeled carbon dynamics depends on physiological plant factors, the size of plant pools, environmental factors, and the total amount and turnover rates of soil organic matter. The model realistically simulated water level fluctuation, forest production, carbon pools change, and CO2 and CH4 emission under natural variations in different environmental factors at two sites. Analyses were focused on parameters and inputs potentially cause the greatest uncertainty in calculated change in plant and soil C and water levels fluctuation and shows that it was important to obtain accurate input data for initial C content, climatic conditions, and allocation of net primary production to various forested wetland components. The magnitude of the forest responses was dependent not only on the rate of changes in environmental factors, but also on site‐specific conditions such as climate and soil. This paper explores the ability of using the biogeochemical process model Wetland‐DNDC to estimate the carbon and hydrologic dynamics of forested wetlands and shifts in these dynamics in response to changing environmental conditions.
Saprobic microfungi underLolium perenneandTrifolium repensat different fertilization intensities and elevated atmospheric CO2concentration
Authors: Řezáčová Veronika , Blum Herbert , Hršelová Hana , Gamper Hannes , Gryndler Milan
Published: February 2005

Anthropogenic increases in atmospheric CO2concentration and the connected deposition of organic matter into the soil influence the occurrence of decomposers who regulate carbon release back into the atmosphere. The effects of increased concentration of atmospheric carbon dioxide, plant species cover quality and nitrogen (N) fertilization on the coenosis composition of soil saprobic microfungi were studied under field conditions (Swiss Free Air Carbon Dioxide Enrichment experiment). In total, 42 species of microfungi were detected in examined soil. The most significant response of soil mycoflora was induced by the species identity of plant cover. Higher N fertilization significantly suppressed the abundance of soil microfungi at ambient CO2. The effect of increased CO2on colony‐forming units was not significant when taken as an independent treatment; however, this factor interacted significantly with N availability. Some species, e.g. theClonostachys rosea, were proven associated with the plant cover components, in this particular case withTrifolium repens. Therefore, we suggest the identity of plant species constituting plant cover as the most important factors affecting soil microfungi in agroecosystems.
The contribution of MvfR to Pseudomonas aeruginosa pathogenesis and quorum sensing circuitry regulation: multiple quorum sensing‐regulated genes are modulated without affecting lasRI, rhlRI or the production of N‐acyl‐ l‐homoserine lactones
Authors: Déziel Eric , Gopalan Suresh , Tampakaki Anastasia P. , Lépine François , Padfield Katie E. , Saucier Maude , Xiao Gaoping , Rahme Laurence G.
Published: February 2005

The transcriptional regulator MvfR is required for full Pseudomonas aeruginosa virulence, the function of multiple quorum sensing (QS)‐regulated virulence factors and the synthesis of 4‐hydroxy‐2‐alkylquinolines (HAQs), including the Pseudomonas quinolone signal (PQS). Here we investigate the role of MvfR in the QS circuitry and P. aeruginosa pathogenesis. We demonstrate using a combination of biochemical and molecular approaches, including transcription profiling, that MvfR is involved in the regulation of multiple P. aeruginosa QS‐controlled genes without altering the expression of lasRI/rhlRI or the production of N‐acyl‐ l‐homoserine lactone (AHL) signals. Dissection of how mvfR is interwoven into the P. aeruginosa QS circuitry reveals that the MvfR system, through the essential contribution of PqsE, positively regulates a subset of genes dependant on both LasR and RhlR. Animal studies show that MvfR contributes to P. aeruginosa virulence by controlling the transcription of genes not under RhlR regulation, and that reduced virulence of a mvfR mutant is caused by the loss of pqsE expression and not only a deficiency in HAQs/PQS production. This study provides novel insights into the unique role of the MvfR system in AHL‐mediated QS and further supports its importance in P. aeruginosa pathogenesis.
The stress‐responsive chaperone α‐crystallin 2 is required for pathogenesis of Mycobacterium tuberculosis
Authors: Stewart Graham R. , Newton Sandra M. , Wilkinson Katalin A. , Humphreys Ian R. , Murphy Helen N. , Robertson Brian D. , Wilkinson Robert J. , Young Douglas B.
Published: February 2005

Mycobacterium tuberculosis has two members of the α‐crystallin (Acr) family of molecular chaperones. Expression of Acr1 is induced by exposure to hypoxia or nitric oxide and is associated with bacterial persistence in a non‐replicating state. Expression of Acr2 is induced by heat shock, oxidative stress, and uptake by macrophages. We have shown that Acr2 continues to be expressed at a high level during both acute and chronic infection in the mouse model, with an increased ratio of acr2:acr1 mRNA in the persistent phase. Deletion of the acr2 gene resulted in a decrease in the resistance of M. tuberculosis to oxidative stress but did not impair growth in mouse bone marrow macrophages. There was no difference in bacterial load in mice infected with an acr2 deletion mutant, but a marked alteration in disease progression was evident from reduced weight loss over a prolonged infection. This correlated with reduced recruitment of T‐cells and macrophages to the lungs of mice infected with the acr2 mutant and reduced immune‐related pathology. These findings demonstrate that both α‐crystallins contribute to persistent infection with M. tuberculosis and suggest that manipulation of acr expression can influence the host response to infection.
Transcription activation of a UV‐inducible Clostridium perfringens bacteriocin gene by a novel σ factor
Authors: Dupuy Bruno , Mani Nagraj , Katayama Seiichi , Sonenshein Abraham L.
Published: February 2005

Expression of the plasmid‐encoded Clostridium perfringens gene for bacteriocin BCN5 was shown to depend in vivo and in vitro on the activity of UviA protein. UviA,  also  plasmid‐encoded,  proved  to  be an RNA polymerase σ factor and was also partly autoregulatory. The uviA gene has two promoters; one provided a UviA‐independent, basal level of gene expression while the stronger, UviA‐dependent promoter was only utilized after the cell experienced DNA damage. As a result, BCN5 synthesis is induced by treatment with UV light or mitomycin C. UviA is related to a special class of σ factors found to date only in Clostridium species and responsible for activating transcription of toxin genes in Clostridium difficile, Clostridium tetani, and Clostridium botulinum.
A potential novel mechanism for the insertion of a membrane protein revealed by a biochemical analysis of the Plasmodium falciparum cytoadherence molecule PfEMP‐1
Authors: Papakrivos Janni , Newbold Chris I. , Lingelbach Klaus
Published: February 2005

Plasmodium falciparum erythrocyte membrane protein‐1 (PfEMP‐1) is exposed on the surface of infected erythrocytes where it both acts as an important pathogenicity factor in malaria and undergoes antigenic variation as a means of immune evasion. Because the mammalian erythrocyte lacks a protein secretory machinery there has been much interest in elucidating the mechanism whereby this protein is transferred from its site of synthesis within the parasite to its final destination. Current opinion favours a mechanism whereby PfEMP‐1 becomes cotranslationally inserted into the endoplasmic reticulum of the parasite and is subsequently transported as an integral part of an erythrocyte cytoplasmic membrane system derived from the parasite. Here we show that the solubility characteristics of this protein during several stages of its transport pathway are inconsistent with this view. Instead we propose that the protein is synthesized as a peripheral membrane protein which only when it arrives at its final destination assumes a transmembrane topology. Even in this state, the extractability of the protein with urea suggest that it is anchored in the membrane by protein‐protein rather than by protein–lipid interaction.
Differing requirements for the Arabidopsis Rad51 paralogs in meiosis and DNA repair
Authors: Bleuyard Jean‐Yves , Gallego Maria E. , Savigny Florence , White Charles I.
Published: February 2005

In addition to the recombinase Rad51, vertebrates have five paralogs of Rad51, all members of the Rad51‐dependent recombination pathway. These paralogs form two complexes (Rad51C/Xrcc3 and Rad51B/C/D/Xrcc2), which play roles in somatic recombination, DNA repair and chromosome stability. However, little is known of their possible involvement in meiosis, due to the inviability of the corresponding knockout mice. We have recently reported that the Arabidopsis homolog of one of these Rad51 paralogs (AtXrcc3) is involved in DNA repair and meiotic recombination and present here Arabidopsis lines carrying mutations in three other Rad51 paralogs (AtRad51B, AtRad51C and AtXrcc2). Disruption of any one of these paralogs confers hypersensitivity to the DNA cross‐linking agent Mitomycin C, but not to γ‐irradiation. Moreover, the atrad51c‐1 mutant is the only one of these to show meiotic defects similar to those of the atxrcc3 mutant, and thus only the Rad51C/Xrcc3 complex is required to achieve meiosis. These results support conservation of functions of the Rad51 paralogs between vertebrates and plants and differing requirements for the Rad51 paralogs in meiosis and DNA repair.
Control of expression and autoregulation of AGL15, a member of the MADS‐box family
Authors: Zhu Cong , Perry Sharyn E.
Published: February 2005

AGL15 is an Arabidopsis thaliana MADS‐domain regulatory factor that not only preferentially accumulates during embryogenesis but is also expressed at lower levels after the completion of germination. To better understand the control of expression of AGL15, a series of 5′ and internal deletions within the regulatory regions of AGL15 was generated. Regions important for the level of expression, including a region involved in expression in response to auxin, were identified. Additionally, AGL15 expression was found to respond to AGL15 accumulation amounts and to altered forms of AGL15. This feedback loop is at least in part due to direct regulation, as assessed by in vivo and in vitro binding of AGL15 to its own regulatory regions and by site‐directed mutagenesis studies.
Functional distribution and dynamics of Arabidopsis SR splicing factors in living plant cells
Authors: Tillemans Vinciane , Dispa Laurence , Remacle Claire , Collinge Mélanie , Motte Patrick
Published: February 2005

Serine/arginine‐rich (SR) proteins constitute an important class of splicing regulators in higher eukaryotes that share a modular structure consisting of one or two N‐terminal RNA recognition motif (RRM) domains and a C‐terminal RS‐rich domain. Herein, we have investigated the in vivo functional distribution of Arabidopsis SR factors. Agrobacterium‐mediated transient transformation revealed nuclear speckled distribution and the overall colocalization of fluorescent protein (FP)‐tagged SR factors in both tobacco and Arabidopsis cells. Their overall colocalization in larger nucleoplasmic domains was further observed after transcriptional and phosphorylation/dephosphorylation inhibition, indicating a close functional association between SR factors, independent of their phosphorylation state. Furthermore, we demonstrated in vivo the conserved role of the RS and RRM domains in the efficient targeting of Arabidopsis SR proteins to nuclear speckles by using a series of structural domain‐deleted mutants of atRSp31 and atRSZp22. We suggest additional roles of RS domain such as the shuttling of atRSZp22 between nucleoplasm and nucleolus through its phosphorylation level. The coexpression of deletion mutants with wild‐type SR proteins revealed potential complex associations between them. Fluorescence recovery after photobleaching demonstrated similar dynamic properties of SR factors in both tobacco transiently expressing cells and Arabidopsis transgenics. Cell cycle phase‐dependent organization of FP‐tagged SR proteins was observed in living tobacco BY‐2 cells. We showed that atRSp31 is degraded at metaphase by fluorescence quantification. SR proteins also localized within small foci at anaphase. These results demonstrate interesting related features as well as potentially important differences between plant and animal SR proteins.
Impact of an easily reducible disulfide bond on the oxidative folding rate of multi‐disulfide‐containing proteins
Authors: Leung H.J. , Xu G. , Narayan M. , Scheraga H.A.
Published: February 2005

Abstract:  The burial of native disulfide bonds, formed within stable structure in the regeneration of multi‐disulfide‐containing proteins from their fully reduced states, is a key step in the folding process, as the burial greatly accelerates the oxidative folding rate of the protein by sequestering the native disulfide bonds from thiol‐disulfide exchange reactions. Nevertheless, several proteins retain solvent‐exposed disulfide bonds in their native structures. Here, we have examined the impact of an easily reducible native disulfide bond on the oxidative folding rate of a protein. Our studies reveal that the susceptibility of the (40–95) disulfide bond of Y92G bovine pancreatic ribonuclease A (RNase A) to reduction results in a reduced rate of oxidative regeneration, compared with wild‐type RNase A. In the native state of RNase A, Tyr 92 lies atop its (40–95) disulfide bond, effectively shielding this bond from the reducing agent, thereby promoting protein oxidative regeneration. Our work sheds light on the unique contribution of a local structural element in promoting the oxidative folding of a multi‐disulfide‐containing protein.
Proline residue‐modified polycationic analogs of gramicidin S with high antibacterial activity against both Gram‐positive and Gram‐negative bacteria and low hemolytic activity*
Authors: Kawai M. , Yamamura H. , Tanaka R. , Umemoto H. , Ohmizo C , Higuchi S. , Katsu T.
Published: February 2005

Abstract:  Novel polycationic analogs of the cyclic decapeptide antibiotic, gramicidin S, possessing NH2, d/l‐Phe‐NH or l‐Lys‐NH groups at the 4α‐ or 4β‐positions of the l‐Pro residues, were synthesized. While l‐Pro(4α/β‐NH2)‐containing analogs exhibited much weaker antibacterial activity, the d/l‐Phe and l‐Lys‐substituted analogs exhibited higher antibacterial activity against Gram‐negative bacteria than the parent gramicidin S. All of these additional amino group‐containing analogs showed substantially reduced toxicity against human blood cells.
A practical synthesis of N‐Fmoc‐l‐pyrazinylalanine via Schöllkopf's chiral auxiliary
Authors: Neelamkavil S. , Mowery B.P. , Thornton E.R. , Smith A.B. , Hirschmann R.
Published: February 2005

Abstract:  A practical, gram‐scale synthesis of l‐pyrazinylalanine (Paa) is described, utilizing Schöllkopf's d‐valine‐derived bis‐lactim ether chiral auxiliary.
Synthesis of bis‐ and tris‐branched COOH‐terminal pegylating reagents: conjugation to NH2‐terminal peptides
Authors: Felix A.M. , Bandaranayake R.M.
Published: February 2005

Abstract:  In previous studies we reported an orthogonal protection scheme that was developed for the solution‐phase synthesis of a family of bis‐ and tris‐pegylating reagents which contain a free NH2‐terminus. These pegylating reagents were coupled to the COOH‐terminus of a model peptide. In the present study we report on the solution synthesis of a novel family of bis‐ and tris‐pegylating reagents which contain a free COOH‐terminus. To illustrate their general utility, conditions were developed for the coupling of these novel pegylating reagents to the NH2‐function of a model pentapeptide. Taken together, our studies demonstrate that these pegylating reagents are well suited for conjugation to peptides and proteins that contain either free COOH‐ or NH2‐functions. These reagents may have general utility in therapeutic development as branched pegylation has been shown to provide more effective protection of proteins from proteolysis by shielding the protein surface from approaching macromolecules.
Comparison of standard phenotypic assays with a PCR method to discriminate Candida albicans and C. dubliniensis
Authors: Mähnß B. , Stehr F. , Schäfer W. , Neuber K.
Published: January 2005

In 1995, Candida dubliniensis was described as a new species in the genus Candida. Its close relationship to C. albicans has proved problematic in the identification of C. dubliniensis in clinical specimens. The objective of this study was to determine if reproducible differentiation between both species can be obtained by phenotypic assays. Therefore, 100 strains from 86 patients with the ability to produce chlamydospores were examined with different methods including API ID 32 C, colour development on CHROMagar, chlamydospore formation on Staib agar, growth at different temperatures and germ tube formation at 39 °C. Additionally, polymerase chain reaction (PCR) was used as gold standard. Six of the investigated strains were C. dubliniensis. The results suggest that there is still no single phenotypic method satisfactory to distinguish between C. albicans and C. dubliniensis.
Chromoblastomycosis
Authors: Vijaya D. , Kumar B. H.
Published: January 2005

A 70‐year‐old male agriculturist from a rural area presented with a history of a painless verrucous lesion over the medial aspect of the left leg for 1 year following abrasion by a branch of a coconut tree. KOH preparation of the skin biopsy showed evidence of fungal elements. Cladophilalospora sp. was isolated in culture. The case was diagnosed as chromoblastomycosis. As there was no response to itraconazole, complete surgical resection of the lesion was done. At follow‐up after 1 year there was clinical as well as mycological cure.
The pT1a and pT1b category subdivision in renal cell carcinoma: is it reflected by differences in tumour biology?
Authors: Langner Cord , Ratschek Manfred , Rehak Peter , Tsybrovskyy Oleksiy , Zigeuner Richard
Published: January 2005

OBJECTIVE

To assess systematically the possible differences in pathology between pT1a and pT1b renal cell carcinomas (RCCs), as the sixth edition of the Tumour‐Nodes‐Metastasis (TNM) system implemented a subdivision of category pT1 into pT1a (<4 cm) and pT1b (4–7 cm), based on clinical outcome analysis and the approach to therapy.

PATIENTS AND METHODS

Conventional histopathology and immunohistochemical expression of several biomarkers were analysed in 66 patients with pT1a and 29 with pT1b RCCs, using a tissue microarray technique.

RESULTS

After 2 years of follow‐up, none of the 66 patients with pT1a and three of the 29 with pT1b tumours developed progressive disease. The tumour was grade 3 in four (6%) pT1a and 11 (38%) pT1b RCCs. Immunohistochemically, pT1a RCCs were characterized by strong expression of p27 (79%), bcl‐2 (67%), MUC1 (87%), insulin‐like growth factor (IGF)‐I (71%) and CD10 (88%), as well as moderate expression of IGF‐I receptor (43%) and low expression of epidermal growth factor receptor (EGFR, 20%). During progression to category pT1b, expression of p27 significantly decreased (54%) and EGFR expression increased (38%). Moreover, membranous staining patterns of MUC1 and CD10 changed from apical to circumferential in clear cell RCCs. p53 (pT1a 23%, pT1b 28%), E‐cadherin (10% and 17%), MIB‐1 (1.2% and 1.5%) and Skp2 (2% and none) expression seemed to be of minor importance.

CONCLUSION

This is the first study to show that the subdivision of category pT1 implemented in the latest issue of the TNM system is reflected by differences in conventional histopathology and expression of biomarkers.
A prospective evaluation of efficacy and compliance with a multistep treatment approach for erectile dysfunction in patients after non‐nerve sparing radical prostatectomy
Authors: Gontero Paolo , Fontana Francesco , Zitella Andrea , Montorsi Francesco , Frea Bruno
Published: January 2005

Associate Editor

Michael G. Wyllie

Editorial Board

Ian Eardley, UK

Jean Fourcroy, USA

Sidney Glina, Brazil

Julia Heiman, USA

Chris McMahon, Australia

Bob Millar, UK

Alvaro Morales, Canada

Michael Perelman, USA

Marcel Waldinger, Netherlands

OBJECTIVE

To assess the response rate to different erectile aids in a consecutive series of patients treated with non‐nerve sparing radical prostatectomy (NNSRP).

PATIENTS AND METHODS

Ninety‐four potent men were counselled about the different treatment options to restore an assisted erection before they had NNSRP. They were invited to participate in a multiphase protocol involving the sequential use of different erectile aids which aimed at restoring erectile function after surgery. The first proposed treatment was oral apomorphine sublingual. Patients with a positive response to the 1‐item overall efficacy question and a minimum score of 3 in both question 3 and 4 of the International Index of Erectile Function were considered responders to oral pharmacotherapy. Treatment with sildenafil was then suggested to those not responding. If patients did not respond to oral pharmacotherapy a trial with a vacuum erectile device was offered; those not responding to this were then offered intracavernosal injection therapy with prostaglandin‐E alone as the first option, followed by a mixture of vasoactive agents if needed. In those in whom injections also failed, a penile implant was recommended. At the 1‐year follow‐up visit all patients were offered a second trial with oral therapy regardless of the treatment currently in use.

RESULTS

Seventy‐six patients entered the protocol; there was no response to apomorphine. Five of 59 (8%) patients responded to sildenafil when they first used it at a mean of 7 months after NNSRP, while there were three additional responders in 22 patients who tried it for a second time a year later. Of patients achieving at least a complete tumescence sufficient for vaginal penetration, 52% and 60% were considered responders to the vacuum device and intracavernosal injections, respectively. Overall, 44% of patients enrolled in the protocol chose to use an erectile aid for at‐home use. At the 1‐year follow‐up, only 20% of patients were still using an erectile aid, including two who had had a penile implant.

CONCLUSIONS

Up to 10% of patients may achieve a clinically significant erection with sildenafil after NNSRP, but 80% will not be using any erectile aid at 1 year after surgery. In the present study protocol the proposed erectile aids were largely inadequate for treating the permanent erectile dysfunction that follows NNSRP.
Risk factors in predicting a poor response to sildenafil citrate in elderly men with erectile dysfunction
Authors: Park Kwanjin , Ku Ja Hyun , Kim Soo Woong , Paick Jae‐Seung
Published: January 2005

OBJECTIVE

To assess the clinical efficacy of sildenafil and the potential predictors of poor response to sildenafil in elderly patients with erectile dysfunction (ED).

PATIENTS AND METHODS

The study included 162 patients (aged ≥ 60 years) treated with sildenafil for at least 8 weeks; all patients were evaluated with a history, physical examination, measurement of total testosterone and a pharmacological erection test. Sexual function before and 8 weeks after treatment was assessed using the self‐administered International Index of Erectile Function (IIEF). Treatment was considered successful when the patient attained a higher grade on the erectile function (EF) domain score, and an affirmative response to the overall assessment question. Factors influencing treatment outcome were evaluated by univariate and multivariate statistical analysis.

RESULTS

The overall efficacy with sildenafil was 47% (76/162). On univariate analysis, uncontrolled diabetes, current smoking, hypogonadism (<3 µg/L testosterone) and low pretreatment EF domain score (<17) were selected as predictors of a poor response. On multivariate logistic regression, a low pretreatment EF domain score was the strongest independent prognostic factor for a poor response (odds ratio 2.25, 95% confidence interval, 1.45–7.33), and this was followed by hypogonadism (1.89, 1.12–3.16) and current smoking (1.34, 1.04–3.52).

CONCLUSION

In a real clinical setting, sildenafil was effective for about half of the elderly men. The baseline EF domain score, hypogonadism and current smoking were significantly associated with failure of sildenafil. These results suggest that modifying reversible risk factors, e.g. stopping smoking and replacing testosterone, would be beneficial in augmenting the efficacy of sildenafil in elderly men.
Anti‐tumour activity of heat‐shock protein 60‐recognizing CD4+ T cells against syngeneic murine renal cell carcinoma
Authors: Eto Masatoshi , Harada Mamoru , Tatsugami Katsunori , Harano Masahiko , Koga Hirofumi , Matsuzaki Goro , Naito Seiji
Published: January 2005

OBJECTIVES

To determine whether heat‐shock protein (HSP) 60‐recognizing CD4+ T cells show antitumour activity against renal carcinoma (RENCA) cells, as HSP is highly expressed by tumour cells and induced in cells by various stresses, including transformation.

MATERIALS AND METHODS

RENCA, a renal cortical adenocarcinoma cell line of BALB/c origin, was used. Expression of major histocompatibility complex (MHC) class I, class II and HSP‐60 on RENCA tumour cells was analysed by flow cytometry. BASL1.1, an autoreactive T‐helper type 1 type CD4+ T cell clone established by us, and that recognises HSP‐60, was also used for a tumour‐neutralising assay.

RESULTS

The RENCA cells were negative for MHC class II, but expressed intracellular HSP‐60. In the tumour‐neutralising assay, BASL1.1 cells significantly suppressed the in vivo growth of RENCA cells. Three of five mice rejected RENCA cells when co‐inoculated with BASL1.1 cells.

CONCLUSIONS

These results indicate that HSP‐60‐recognizing CD4+ T cells have the potential to eliminate renal cell carcinoma in vivo and that the eliciting of an anti‐self T cell response at the tumour site can lead to regression of renal cancer.
Effects of mechanical irritation on the autonomic part of the median nerve
Authors: Orlin J. R. , Stranden E. , Slagsvold C.‐E.
Published: January 2005

The diagnosis of median nerve compression is generally based upon a prolonged nerve conduction velocity although this frequently is preceded by clinical symptoms for years. The present study was designed to identify indicators for early decompression of the median nerve in patients exhibiting symptoms compatible with carpal tunnel syndrome (CTS). Microvascular perfusion in finger tip skin and skin temperature were studied during dorsiflexion of the hand prior to and following a manual exercise test in control subjects and in patients with clinical symptoms and signs of CTS. Evaluation of the microcirculation was performed using photoplethysmography (PPG) and laser Doppler fluxmetry (LDF). Fingertip skin temperature was measured by thermography and was significantly reduced in patients after exercise (P < 0.001), whereas no significant change occurred in control subjects. During increasing degrees of dorsiflexion (0–75°) and after manual exercise, fingertip skin perfusion remained unchanged in both patients and control subjects. In conclusion, patients with low‐grade CTS experience skin temperature reduction, presumably caused by increased sweating as opposed to a generally suspected vasoconstriction. These autonomic median nerve dysfunctions provide the physiological basis for the use of thermography in confirming low‐grade CTS.
Transaction Costs, Agglomeration Economies, and Industrial Location*
Authors: WOOD GAVIN A. , PARR JOHN B.
Published: February 2005

ABSTRACT  Following an outline of the different types of agglomeration economy, consideration is given to transaction costs. Transaction costs may have a definite spatial dimension because institutional, commercial, cultural, and language characteristics are differentiated across the geographic space separating market agents. The concept of transaction space is introduced to represent the spatial differentiation of these characteristics, and this concept is used to cast light on how space can contribute to coordination and agency problems that raise transaction costs. Contractual agreements that are rearranged, so as to span a less heterogeneous transaction space, permit the reduction of transaction costs. Agglomeration can then be interpreted as an alternative to hierarchical structures within firms in economizing on transaction costs. The paper concludes with illustrations of how this framework may help to understand the spatial implications of corporate restructuring and new information technologies.
The Territorial Agglomerations of Firms: A Social Capital Perspective from the Spanish Tile Industry
Authors: MOLINA‐MORALES F. XAVIER
Published: February 2005

ABSTRACT  Using the Social Capital theoretical framework, territorial agglomerations of firms, such as in the industrial district, can be identified as dense strong‐tie networks and are thus suitable for exploiting activities. This paper addresses the possible exploring limitations of these clustered firms. Following alternative explanations, such as the structural holes and weak tie approaches, it is proposed that local institutions may play a role as intermediary agents between external disperse networks and internal dense networks, therefore enabling these firms to deal with the requirements of an ever‐changing environment. The paper also develops an empirical section where the Spanish ceramic tile industrial district is described in order to illustrate theoretical arguments. Findings suggested a number of ways in which local institutions may facilitate the creation of value for firms. Particularly, local institutions interact with many external firms and institutions and undertake research projects with local firms. In addition, some quantification of the participation of firms in the activities carried out by institutions is offered, suggesting explanations for the barriers that prevent firms from gaining direct access to external networks.
Ferulic acid ethyl ester protects neurons against amyloid β‐ peptide(1–42)‐induced oxidative stress and neurotoxicity: relationship to antioxidant activity
Authors: Sultana Rukhsana , Ravagna Agrippino , Mohmmad‐Abdul Hafiz , Calabrese Vittorio , Butterfield D. Allan
Published: February 2005

Alzheimer's disease (AD) is neuropathologically characterized by depositions of extracellular amyloid and intracellular neurofibrillary tangles, associated with loss of neurons in the brain. Amyloid β‐peptide (Aβ) is the major component of senile plaques and is considered to have a causal role in the development and progress of AD. Several lines of evidence suggest that enhanced oxidative stress and inflammation play important roles in the pathogenesis or progression of AD. The present study aimed to investigate the protective effects of ethyl‐4‐hydroxy‐3‐methoxycinnamic acid (FAEE), a phenolic compound which shows antioxidant and anti‐inflammatory activity, on Aβ(1–42)‐induced oxidative stress and neurotoxicity. We hypothesized that the structure of FAEE would facilitate radical scavenging and may induce protective proteins. Aβ(1–42) decreases cell viability, which was correlated with increased free radical formation, protein oxidation (protein carbonyl, 3‐nitrotyrosine), lipid peroxidation (4‐hydroxy‐2‐trans‐nonenal) and inducible nitric oxide synthase. Pre‐treatment of primary hippocampal cultures with FAEE significantly attenuated Aβ(1–42)‐induced cytotoxicity, intracellular reactive oxygen species accumulation, protein oxidation, lipid peroxidation and induction of inducible nitric oxide synthase. Treatment of neurons with Aβ(1–42) increases levels of heme oxygenase‐1 and heat shock protein 72. Consistent with a cellular stress response to the Aβ(1–42)‐induced oxidative stress, FAEE treatment increases the levels of heme oxygenase‐1 and heat shock protein 72, which may be regulated by oxidative stresses in a coordinated manner and play a pivotal role in the cytoprotection of neuronal cells against Aβ(1–42)‐induced toxicity. These results suggest that FAEE exerts protective effects against Aβ(1–42) toxicity by modulating oxidative stress directly and by inducing protective genes. These findings suggest that FAEE could potentially be of importance for the treatment of AD and other oxidative stress‐related diseases.
Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine
Authors: Thomas David M. , Kuhn Donald M.
Published: February 2005

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine‐induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low‐dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug‐induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug‐induced hyperthermia.