bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of the Nitrogen Transfer Pathway in the Arbuscular Mycorrhizal Symbiosis: Gene Characterization and the Coordination of Expression with Nitrogen Flux
Authors: Tian Chunjie , Kasiborski Beth , Koul Raman , Lammers Peter J. , Bücking Heike , Shachar-Hill Yair
Published: May 2010

The arbuscular mycorrhiza (AM) brings together the roots of over 80% of land plant species and fungi of the phylum Glomeromycota and greatly benefits plants through improved uptake of mineral nutrients. AM fungi can take up both nitrate and ammonium from the soil and transfer nitrogen (N) to host roots in nutritionally substantial quantities. The current model of N handling in the AM symbiosis includes the synthesis of arginine in the extraradical mycelium and the transfer of arginine to the intraradical mycelium, where it is broken down to release N for transfer to the host plant. To understand the mechanisms and regulation of N transfer from the fungus to the plant, 11 fungal genes putatively involved in the pathway were identified from Glomus intraradices, and for six of them the full-length coding sequence was functionally characterized by yeast complementation. Two glutamine synthetase isoforms were found to have different substrate affinities and expression patterns, suggesting different roles in N assimilation. The spatial and temporal expression of plant and fungal N metabolism genes were followed after nitrate was added to the extraradical mycelium under N-limited growth conditions using hairy root cultures. In parallel experiments with 15N, the levels and labeling of free amino acids were measured to follow transport and metabolism. The gene expression pattern and profiling of metabolites involved in the N pathway support the idea that the rapid uptake, translocation, and transfer of N by the fungus successively trigger metabolic gene expression responses in the extraradical mycelium, intraradical mycelium, and host plant.
Why do people with anxiety disorders become depressed? A prospective‐longitudinal community study
Authors: Wittchen H‐U. , Kessler R. C. , Pfister H. , Höfler M. , Lieb R.
Published: May 2010

Objective: To examine the temporal relationships of anxiety and depressive disorders, their risk factors and to explore why people with anxiety develop depression.

Method: Data from an original 4–5‐year prospective‐longitudinal community study (N=3021) of adolescents and young adults with DSM‐IV anxiety and depressive disorders identified with the Composite International Diagnostic Interview are used to examine risk factors, as well as course and outcome.

Results: (i) Anxiety disorders, except for panic disorder, are almost always primary conditions. (ii) Over the follow‐up period, rates of comorbid anxiety‐depression increased substantially and resulted in increased impairment and disabilities. (iii) Predictors for first onset of ‘pure’ depressive and ‘pure’ anxiety disorders revealed recognizable differences. (iv) Baseline clinical characteristics of anxiety disorders were significantly associated with an increased risk to develop major depression over the follow‐up period.

Conclusion: Findings suggest that most anxiety disorders are primary disorders that substantially increase the risk for secondary depression.
Development of the International Classification of Mental Health Care (ICMHC)
Authors: De Jong A.
Published: May 2010

Objective: Evaluations of the process of providing mental health care have been hampered because a tool to systematically describe the interventions actually provided by the services was lacking. In this paper the development of such a tool (the International Classification of Mental Health Care; ICMHC) is described.

Method: Subsequent versions of the ICMHC were developed, using comments from experts in 24 WHO field centres and results from a number of field trials. In the final version 10 Modalities of Care can be used to describe Modules of Care, using the Level of Specialization scale. The inter‐rater reliability of this version was evaluated by the Italian research team, using data from 43 services.

Results: Reliability ranged from excellent for nine modalities to reasonably good for the remaining modality.

Conclusion: In the context of evaluation studies, the ICMHC can be used to describe systematically mental health care interventions.
Mental health care in Piedmont: a description of its structure and components using a new technology for service assessment
Authors: Munizza C. , Tibaldi G. , Cesano S. , Dazzi R. , Fantini G. , Palazzi C. , Scala E. , Zuccolin M.
Published: May 2010

Objective: The northern‐Italian region of Piedmont has a total population of 4.3 million. The regional territory is currently divided into 22 local health services, each serving a population not exceeding 300 000 and incorporating a Department of Mental Health. The organization of psychiatric assistance can be described as relatively stable and conforms with the standards imposed by national regulations. Drawing upon previous research experience, and with the support of the relevant regional authorities, our survey implements the methodology developed by the EPCAT team and will eventually embrace about 80% of all local health service areas in this region.

Methods: The survey was preceded by a number of preliminary steps including the training of four researchers, inter‐rater reliability testing (particularly for the International Classification of Mental Health Care), and the adjustment of the methodology developed by the EPCAT team to facilitate understanding and use of the instrumentation by the psychiatric professionals involved in the data collection.

Results: This paper summarizes data on the structure and components of the mental health service in three areas of Piedmont, with special reference to structures funded by the National Health System.

Conclusion: Overlooking the imbalances affecting both the resources available for different populations, and the operational profiles of psychiatric agencies of the same type, our data allow an assessment of the descriptive and comparative capabilities of the proposed methodology.
The European Socio‐Demographic Schedule (ESDS): rationale, principles and development
Authors: Beecham J. , Johnson S. ,   EPCAT Group
Published: May 2010

Objective: To design an internationally valid and practical instrument on which data can be recorded for small areas that describes the sociodemographic characteristics known to be associated with psychiatric morbidity and service use.

Method: (1) Identification of a set of sociodemographic characteristics which, on the basis of currently available evidence, would be expected to influence needs for and provision of mental health care in different countries. (2) Selection of a subset of these for inclusion in the schedule based on likely degree of cross‐cultural validity and on the types and formats of the data routinely available in each country. (3) Revision of the schedule following a pilot by EPCAT members.

Results: The European Socio‐Demographic Schedule (ESDS) was successfully employed to collect sociodemographic data in seven catchment areas. Differences were found between the areas in terms of availability of data as well as in the resulting profiles.

Conclusion: The ESDS has been shown to be applicable in a number of European countries.
Assessment instruments: standardization of the European Service Mapping Schedule (ESMS) in Spain
Authors: Salvador‐Carulla L. , Romero C. , Martinez A. , Haro J. M. , Bustillo G. , Ferreira A. , Gaite L. , Johnson S. ,   EPCAT/PSICOST Group
Published: May 2010

Objective: To adapt the European Service Mapping Schedule (ESMS) for use in Spain and assess the quality of this schedule.

Method: Following linguistic and conceptual translation, 77 services in five Spanish catchment areas were described by independent local raters, including two experts in health services research. Feasibility (applica‐bility, acceptability and practicality), descriptive validity and overall percentage agreement were assessed.

Results: ESMS feasibility was considered adequate. The tree system facilitates reporting and comparison of data. Face, content and discriminant validity are adequate for almost all services. The overall reliability was high but completion of the service utilization section required expert supervision. The ESMS revealed large differences in service availability and utilization in the five different areas of Spain.

Conclusion: The ESMS has proved useful for describing mental health services in Spain, and facilitates comparisons between catchment areas.
Panbiogeographical analysis of the shark genus Rhizoprionodon (Chondrichthyes, Carcharhiniformes, Carcharhinidae)
Authors: Gallo V. , Cavalcanti M. J. , Da Silva R. F. L. , Da Silva H. M. A. , Pagnoncelli D.
Published: May 2010

The distributional patterns of the seven species of Rhizoprionodon were analysed using the panbiogeographical method of track analysis. The individual tracks of Rhizoprionodon suggest that the genus is mainly an Indian–Atlantic Ocean group. Five generalized tracks were found: (1) Caribbean, defined by R. porosus and R. terraenovae; (2) eastern coast of South America, defined by R. porosus and R. lalandei; (3) Indian Ocean, defined by R. acutus and R. oligolinx; (4) north‐western Australia, defined by R. acutus, R. oligolinx and R. taylori; (5) north‐north‐eastern Australia, defined by R. acutus and R. taylori. Only R. longurio was not included in any generalized track, and its distribution is restricted to the eastern Pacific Ocean. Two biogeographical nodes were found at the intersection of the generalized tracks 1 and 2 (Caribbean Sea) and generalized tracks 4 and 5 (north Australia). The generalized tracks overlap with those found in several unrelated marine taxa. Overall, the generalized tracks are associated with warm currents. The biogeographical nodes found (Caribbean and Australian) are coincident with the global distribution of mangroves.
Effect of wave exposure dynamics on gut content mass and growth of young‐of‐the‐year fishes in the littoral zone of lakes
Authors: Stoll S. , Hofmann H. , Fischer P.
Published: May 2010

Total length, body mass and gut content mass of young‐of‐the‐year (YOY) perch Perca fluviatilis, dace Leuciscus leuciscus and bleak Alburnus alburnus were recorded over the summer of 2006 at three littoral sites at Upper Lake Constance. In P. fluviatilis and L. leuciscus, gut content mass correlated positively with wave‐induced energy flux (EF) of the respective site and sampling day, while no correlation of gut content mass with EF was found in A. alburnus. It was assumed that benthivorous P. fluviatilis and L. leuciscus profited from suspended or uncovered benthic food items generated by wave action at sites and periods with high EF. Alburnus alburnus, in contrast, feeding mainly on zooplankton in upper parts of the water column, could not profit from increased EF. In P. fluviatilis, increased gut content mass during periods of high EF resulted in higher growth rates. For L. leuciscus, no real growth rates in local fish populations could be determined, as individuals were less sedentary, and when increased growth occurred at sites during the periods of high EF, migration of fish levelled out the resulting size differences within few days. The results of this study show that dynamic habitat variables affect site profitability in the littoral zone of lakes, especially in benthivorous fishes. Therefore, dynamic habitat variables should be considered in addition to fixed habitat properties in analyses of habitat choice of fishes in the littoral zone of lakes.
Effects of turbidity and prey density on the foraging success of age 0 year yellow perch Perca flavescens
Authors: Wellington C. G. , Mayer C. M. , Bossenbroek J. M. , Stroh N. A.
Published: May 2010

Laboratory experiments were conducted to determine how larval and juvenile yellow perch Perca flavescens respond to changes in prey density when exposed to different levels and types of turbidity (phytoplanktonic or sedimentary). Across prey densities, consumption by P. flavescens tended to be less in phytoplanktonic turbidity compared with sedimentary turbidity. For larvae, this effect was dependent on turbidity level (consumption differed between turbidity types only at high turbidity), while for juveniles the difference with turbidity type was equal across turbidity levels. These results suggest that phytoplankton blooms are detrimental to the ability of late season age 0 year P. flavescens to forage and support the need to control factors leading to excessive phytoplankton growth in lakes.
Effects of discharge and local density on the growth of juvenile Atlantic salmon Salmo salar
Authors: Teichert M. A. K. , Kvingedal E. , Forseth T. , Ugedal O. , Finstad A. G.
Published: May 2010

The study explored the combined effects of density, physical habitat and different discharge levels on the growth of juvenile Atlantic salmon Salmo salar in artificial streams, by manipulating flow during both summer and winter conditions. Growth was high during all four summer trials and increased linearly with discharge and mean velocity. Differences in fish densities (fish m−3) due to differences in stream volume explained a similar proportion of the variation in mean growth among discharge treatments. Within streams, the fish aggregated in areas of larger sediment size, where shelters were probably abundant, while growth decreased with increasing densities. Fish appeared to favour the availability of shelter over maximization of growth. Mean growth was negative during all winter trials and did not vary among discharge treatments. These results suggest that increased fish densities are a major cause of reduced summer growth at low discharge, and that habitat‐mediated density differences explain the majority of the growth variation across habitat conditions both during summer and winter.
The functional role of the caudal fin in the feeding ecology of the common thresher shark Alopias vulpinus
Authors: Aalbers S. A. , Bernal D. , Sepulveda C. A.
Published: May 2010

This study tests the hypothesis that the common thresher shark Alopias vulpinus uses its elongate caudal fin to both produce thrust and immobilize prey during feeding. Underwater video recorded in southern California from 2007 to 2009 revealed 34 feeding events, all of which were initiated with the upper lobe of the caudal fin.
Genetic support for random mating between left and right‐mouth morphs in the dimorphic scale‐eating cichlid fish Perissodus microlepis from Lake Tanganyika
Authors: Lee H. J. , Pittlik S. , Jones J. C. , Salzburger W. , Barluenga M. , Meyer A.
Published: May 2010

Population genetic analyses were conducted to investigate whether random mating occurs between left and right‐mouth morphs of the dimorphic scale‐eating cichlid fish Perissodus microlepis from two geographical sites in southern Lake Tanganyika. The mitochondrial and nuclear DNA markers (13 microsatellite loci) revealed no genetic differentiation between left and right morphs (i.e. widespread interbreeding). The observed lack of genetic divergence between the different morphs allowed for the exclusion of the possibility of assortative mating between same morph types. The microsatellite data showed no significant departures of heterozygosity from Hardy–Weinberg equilibrium, suggesting purely random mating between the morphs. Overall, this study indicated no genetic evidence for either assortative or disassortative mating, but it did provide support for the random mating hypothesis. Highly significant, albeit weak, spatial population structure was also found when samples of different morphs were pooled according to geographical sites. An additional analysis of two microsatellite loci that were recently suggested to be putatively linked to the genetic locus that determines the laterality of these mouth morphs did not show any such association.
Rediscovery and redescription of the unusual subterranean characiform Stygichthys typhlops, with notes on its life history
Authors: Moreira C. R. , Bichuette M. E. , Oyakawa O. T. , De Pinna M. C. C. , Trajano E.
Published: May 2010

The rediscovery of the enigmatic subterranean characiform Stygichthys typhlops is reported almost a half‐century after the collection of the holotype, the only specimen previously known. Thirty‐four specimens were collected in two shallow hand‐dug wells at the region of the type locality, c. 13 km south‐west of the town of Jaíba, Minas Gerais, Brazil. These specimens provide new information on the morphology of this species, and for the first time on its life history. The conservation status of S. typhlops is discussed. The species is severely threatened by habitat loss caused by exploitation of the aquifer.
Exposure of fish to high‐intensity sonar does not induce acute pathology
Authors: Kane A. S. , Song J. , Halvorsen M. B. , Miller D. L. , Salierno J. D. , Wysocki L. E. , Zeddies D. , Popper A. N.
Published: May 2010

This study investigated immediate effects of intense sound exposure associated with low‐frequency (170–320 Hz) or with mid‐frequency (2·8–3·8 kHz) sonars on caged rainbow trout Oncorhynchus mykiss, channel catfish Ictalurus punctatus and hybrid sunfish Lepomis sp. in Seneca Lake, New York, U.S.A. This study focused on potential effects on inner ear tissues using scanning electron microscopy and on non‐auditory tissues using gross and histopathology. Fishes were exposed to low‐frequency sounds for 324 or 628 s with a received peak signal level of 193 dB re 1 µPa (root mean square, rms) or to mid‐frequency sounds for 15 s with a received peak signal level of 210 dB re 1 µPa (rms). Although a variety of clinical observations from various tissues and organ systems were described, no exposure‐related pathologies were observed. This study represents the first investigation of the effects of high‐intensity sonar on fish tissues in vivo. Data from this study indicate that exposure to low and midfrequency sonars, as described in this report, might not have acute effects on fish tissues.
An easier method to identify the individual genomic composition of allopolyploid complexes
Authors: Inácio A. , Matos I. , Machado M. P. , Coelho M. M.
Published: May 2010

A new method for the fast identification of the genomic composition of the cyprinid Squalius alburnoides is presented. The method is based on a length polymorphism detected in the β‐actin gene, which serves as the basis for the development of a semi‐quantitative PCR.
Genetic heterogeneity and selection signature at the KIT gene in pigs showing different coat colours and patterns
Authors: Fontanesi L. , D’Alessandro E. , Scotti E. , Liotta L. , Crovetti A. , Chiofalo V. , Russo V.
Published: May 2010

Mutations in the porcine KIT gene (Dominant white locus) have been shown to affect coat colours and colour distribution in pigs. We analysed this gene in several pig breeds and populations (Sicilian black, completely black or with white patches; Cinta Senese; grey local population; Large White; Duroc; Hampshire; Pietrain; wild boar; Meishan) with different coat colours and patterns, genotyping a few polymorphisms. The 21 exons and parts of the intronic regions were sequenced in these pigs and 69 polymorphisms were identified. The grey‐roan coat colour observed in a local grey population was completely associated with a 4‐bp deletion of intron 18 in a single copy KIT gene, providing evidence that this mutation characterizes the Id allele described in the early genetic literature. The white patches observed in black Sicilian pigs were not completely associated with the presence of a duplicated KIT allele (Ip), suggesting that genetic heterogeneity is a possible cause of different coat colours in this breed. Selection signature was evident at the KIT gene in two different belted pig breeds, Hampshire and Cinta Senese. The same mutation(s) may cause the belted phenotype in these breeds that originated in the 18th–19th centuries from English pigs (Hampshire) and in Tuscany (Italy) in the 14th century (Cinta Senese). Phylogenetic relationships of 28 inferred KIT haplotypes indicated two clades: one of Asian origin that included Meishan and a few Sicilian black haplotypes and another of European origin.
AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders
Authors: Dawson Mark A. , Curry Jayne E. , Barber Kelly , Beer Philip A. , Graham Brent , Lyons John F. , Richardson Caroline J. , Scott Mike A. , Smyth Tomoko , Squires Matthew S. , Thompson Neil T. , Green Anthony R. , Wallis Nicola G.
Published: May 2010

Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi‐targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2‐dependent systems. AT9283 potently inhibited proliferation and Jak2‐related signalling in Jak2‐dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6‐JAK2 (TEL‐JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases.
Tolerance induction after specific immunotherapy with pollen allergoids adjuvanted by monophosphoryl lipid A in children
Authors: Rosewich M , Schulze J , Eickmeier O , Telles T , Rose M A , Schubert R , Zielen S
Published: May 2010

Specific immunotherapy (SIT) is a well-established and clinically effective treatment for allergic diseases. A pollen allergoid formulated with the T helper type 1 (Th1)-inducing adjuvant monophosphoryl lipid A (MPL) facilitates short-term SIT. Little is known about mechanisms of tolerance induction in this setting. In a prospective study, 34 patients allergic to grass pollen (25 male, nine female, median age 10·2 years) received a total of 44 SIT courses (20 in the first, 24 in the second) with MPL-adjuvanted pollen allergoids. Immunogenicity was measured by levels of specific immunoglobulin G (IgGgrass) and IgG4grass by antibody blocking properties on basophil activation, and by induction of CD4+, CD25+ and forkhead box P3 (FoxP3+) regulatory T cells (Treg). Specific IgG and IgG4 levels increased only slightly in the first year of SIT. In the second year these changes reached significance (P < 0·0001). In keeping with these findings, we were able to show an increase of Treg cells and a decreased release of leukotrienes after the second year of treatment. In the first year of treatment we found little evidence for immunological changes. A significant antibody induction was seen only after the second course of SIT. Short-course immunotherapy with pollen allergoids formulated with the Th1-inducing adjuvant MPL needs at least two courses to establish tolerance.
Mitigation of septic shock in mice and rhesus monkeys by human chorionic gonadotrophin-related oligopeptides
Authors: Khan N A , Vierboom M P M , Van Holten– Neelen C , Breedveld E , Zuiderwijk-Sick E , Khan A , Kondova I , Braskamp G , Savelkoul H F J , Dik W A , ‘t Hart B A , Benner R
Published: May 2010

The marked improvement of several immune-mediated inflammatory diseases during pregnancy has drawn attention to pregnancy hormones as potential therapeutics for such disorders. Low molecular weight fractions derived from the pregnancy hormone human chorionic gonadotrophin (hCG) have remarkable potent immunosuppressive effects in mouse models of diabetes and septic shock. Based on these data we have designed a set of oligopeptides related to the primary structure of hCG and tested these in models of septic shock in mice and rhesus monkeys. We demonstrate that mice exposed to lipopolysaccharide (LPS) and treated subsequently with selected tri-, tetra-, penta- and hepta-meric oligopeptides (i.e. MTR, VVC, MTRV, LQGV, AQGV, VLPALP, VLPALPQ) are protected against fatal LPS-induced septic shock. Moreover, administration of a cocktail of three selected oligopeptides (LQGV, AQGV and VLPALP) improved the pathological features markedly and nearly improved haemodynamic parameters associated with intravenous Escherichia coli-induced septic shock in rhesus monkeys. These data indicate that the designed hCG-related oligopeptides may present a potential treatment for the initial hyperdynamic phase of septic shock in humans.
Cyclophilin–CD147 interactions: a new target for anti-inflammatory therapeutics
Authors: Yurchenko V , Constant S , Eisenmesser E , Bukrinsky M
Published: May 2010

CD147 is a widely expressed plasma membrane protein that has been implicated in a variety of physiological and pathological activities. It is best known for its ability to function as extracellular matrix metalloproteinase inducer (hence the other name for this protein, EMMPRIN), but has also been shown to regulate lymphocyte responsiveness, monocarboxylate transporter expression and spermatogenesis. These functions reflect multiple interacting partners of CD147. Among these CD147-interacting proteins cyclophilins represent a particularly interesting class, both in terms of structural considerations and potential medical implications. CD147 has been shown to function as a signalling receptor for extracellular cyclophilins A and B and to mediate chemotactic activity of cyclophilins towards a variety of immune cells. Recent studies using in vitro and in vivo models have demonstrated a role for cyclophilin–CD147 interactions in the regulation of inflammatory responses in a number of diseases, including acute lung inflammation, rheumatoid arthritis and cardiovascular disease. Agents targeting either CD147 or cyclophilin activity showed significant anti-inflammatory effects in experimental models, suggesting CD147–cyclophilin interactions may be a good target for new anti-inflammatory therapeutics. Here, we review the recent literature on different aspects of cyclophilin–CD147 interactions and their role in inflammatory diseases.
Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma
Authors: Kim S-H , Choi G-S , Ye Y-M , Jou I , Park H-S , Park S M
Published: May 2010

Diisocyanate is a leading cause of occupational asthma (OA). Diisocyanate-induced OA is an inflammatory disease of the airways that is associated with airway remodelling. Although the pathogenic mechanisms are unclear, oxidative stress may be related to the pathogenesis of diisocyanate-induced OA. In our previous report, we observed that the expression of ferritin light chain (FTL) was decreased in both of bronchoalveolar lavage fluid and serum of patients with diphenyl-methane diisocyanate (MDI)-induced OA compared to those of asymptomatic exposed controls and unexposed healthy controls. In this study of toluene diisocyanate (TDI)-OA, we found identical findings with increased transferrin and decreased ferritin levels in the serum of patients with TDI-OA. To elucidate whether diisocyanate suppresses FTL synthesis directly, we tested the effect of TDI on the FTL synthesis in A549 cells, a human airway epithelial cell line. We found that haem oxygenase-1 as well as FTL was suppressed by treatment with TDI in dose- and time-dependent manners. We also found that the synthesis of other anti-oxidant proteins such as thioredoxin-1, glutathione peroxidase, peroxiredoxin 1 and catalase were suppressed by TDI. Furthermore, TDI suppressed nuclear translocation of Nrf2 through suppressing the phosphorylation of mitogen-activated protein kinases (MAPKs); extracellular-regulated kinase 1/2 (ERK1/2); p38; and c-Jun N-terminal kinase (JNK). Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, 15-deoxy-Δ12,14-PGJ2 and rosiglitazone rescued the effect of TDI on HO-1/FTL expression. Collectively, our findings suggest that TDI suppressed HO-1/FTL expression through the MAPK–Nrf2 signalling pathway, which may be involved in the pathogenesis of TDI-induced OA. Therefore, elucidating these observations further should help to develop the therapeutic strategies of diisocyanate-induced OA.
Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis
Authors: Ablin J N , Entin-Meer M , Aloush V , Oren S , Elkayam O , George J , Barshack I
Published: May 2010

Eotaxin-2 is a potent chemoattractant for eosinophils, basophils and T helper type 2 (Th2) lymphocytes. The eotaxin-2/CCL24 receptor CCR3 is expressed in human brain, skin, endothelium and macrophages. The aim of the current study was to evaluate the protective effect of a monoclonal anti-eotaxin-2 antibody on the development of adjuvant-induced arthritis in rats (AIA). Adjuvant arthritis was induced in Lewis rats by intradermal injection of incomplete Freund's adjuvant +Mycobacterium tuberculosis. Rats were treated by intraperitoneal (i.p.) injection with three monoclonal antibodies against eotaxin-2 (G7, G8, D8) three times per week. Controls were treated with total mouse immunoglobulin G (IgG), methotrexate (MTX) or phosphate-buffered saline (PBS). Arthritis severity was evaluated by measuring ankle swelling, arthritic score, whole animal mobility and body weight. Sample joints were obtained for pathological evaluation and postmortem X-ray of ankle joints was performed to document erosions. Significant inhibition of arthritis was observed in rats treated with anti-eotaxin-2 antibodies compared to those treated with immunoglobulin or PBS. Inhibition was manifest in ankle diameter, arthritic score and mobility score. The antibody marked D8 showed the greatest efficacy. The effect was observed both in animals treated before the appearance of arthritis and in those where treatment was begun after development of joint inflammation. Combined treatment with D8 and MTX caused additional protection. Significant reduction of inflammation in D8-treated animals was also demonstrated in pathological and X-ray examinations. Inhibition of eotaxin-2 by monoclonal antibodies has a significant protective effect in adjuvant arthritis. These results may introduce a novel therapeutic target in rheumatoid arthritis and additional inflammatory joint disorders.
Selective effects of Lactobacillus casei Shirota on T cell activation, natural killer cell activity and cytokine production
Authors: Dong H , Rowland I , Tuohy K M , Thomas L V , Yaqoob P
Published: May 2010

Modulation of host immunity is an important potential mechanism by which probiotics confer health benefits. This study was designed to investigate the effects of a probiotic strain, Lactobacillus casei Shirota (LcS), on immune function using human peripheral blood mononuclear cells (PBMC) in vitro. In addition, the role of monocytes in LcS-induced immunity was also explored. LcS promoted natural killer (NK) cell activity and preferentially induced expression of CD69 and CD25 on CD8+ and CD56+ subsets in the absence of any other stimulus. LcS also induced production of interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α, IL-12 and IL-10 in the absence of lipopolysaccharide (LPS). In the presence of LPS, LcS enhanced IL-1β production but inhibited LPS-induced IL-10 and IL-6 production, and had no further effect on TNF-α and IL-12 production. Monocyte depletion reduced significantly the impact of LcS on lymphocyte activation, cytokine production and natural killer (NK) cell activity. In conclusion, LcS activated cytotoxic lymphocytes preferentially in both the innate and specific immune systems, which suggests that LcS could potentiate the destruction of infected cells in the body. LcS also induced both proinflammatory and anti-inflammatory cytokine production in the absence of LPS, but in some cases inhibited LPS-induced cytokine production. Monocytes play an important role in LcS-induced immunological responses.
The use of small molecule high-throughput screening to identify inhibitors of the proteinase 3-NB1 interaction
Authors: Choi M , Eulenberg C , Rolle S , Von Kries J P , Luft F C , Kettritz R
Published: May 2010

Anti-neutrophil cytoplasmic antibodies (ANCA) to proteinase 3 (PR3) are found in patients with small-vessel vasculitis. PR3-ANCA bind strongly to membrane PR3 (mPR3) that is presented by the NB1 receptor. We performed high-throughput screening using a small molecule library to identify compounds that inhibit PR3-NB1 binding. We established a human embryonic kidney (HEK293) cell-based system, where approximately 95 ± 2% of the NB1-transfected cells expressed the NB1 receptor on the cell surface. Addition of 0·1 µg/ml human PR3 to 104 NB1-expressing HEK293 cells resulted in PR3 binding that was detected by immunofluorescence using a fluorescence plate reader assay. We identified 13 of 20 000 molecules that inhibited PR3 binding by >70%. Seven of 13 substances showed reproducible inhibition in four additional validation experiments. Two selected compounds (27519 and 27549) demonstrated a dose-dependent inhibition over a range from 6·25 to 100 µM as measured by the plate reader assay. We used flow cytometry as a second assay, and found that both compounds reproducibly inhibited PR3 binding to NB1-transfected HEK293 cells at 50 µM (inhibition to 42 ± 4% with compound 27519 and to 47 ± 6% with compound 27549 compared to the dimethylsulphoxide control). Furthermore, compounds 27519 and 27549 also inhibited binding of exogenous PR3 to human neutrophils. In contrast, the compounds did not decrease mPR3 expression on resting neutrophils, but reduced the tumour necrosis factor-α-mediated mPR3 increase on NB1pos neutrophils when present continuously during the assay. The findings suggest that small inhibitory compounds provide a potential therapeutic tool to reduce mPR3 by preventing its binding to NB1.
Acute lung injury: apoptosis in effector and target cells of the upper and lower airway compartment
Authors: Z'graggen B Roth , Tornic J , Müller-Edenborn B , Reyes L , Booy C , Beck-Schimmer B
Published: May 2010

Apoptotic cell death has been considered an underlying mechanism in acute lung injury. To evaluate the evidence of this process, apoptosis rate was determined in effector cells (alveolar macrophages, neutrophils) and target cells (tracheobronchial and alveolar epithelial cells) of the respiratory compartment upon exposure to hypoxia and endotoxin stimulation in vitro. Cells were exposed to 5% oxygen or incubated with lipopolysaccharide (LPS) for 4, 8 and 24 h, and activity of caspase-3, -8 and -9 was determined. Caspase-3 of alveolar macrophages was increased at all three time-points upon LPS stimulation, while hypoxia did not affect apoptosis rate at early time-points. In neutrophils, apoptosis was decreased in an early phase of hypoxia at 4 h. However, enhanced expression of caspase-3 activity was seen at 8 and 24 h. In the presence of LPS a decreased apoptosis rate was observed at 8 h compared to controls, while it was increased at 24 h. Tracheobronchial as well as alveolar epithelial cells experienced an enhanced caspase-3 activity upon LPS stimulation with no change of apoptosis rate under hypoxia. While increased apoptosis rate is triggered through an intrinsic and extrinsic pathway in alveolar macrophages, intrinsic signalling is activated in tracheobronchial epithelial cells. The exact pathway pattern in neutrophils and alveolar epithelial cells could not be determined. These data clearly demonstrate that upon injury each cell type experiences its own apoptosis pattern. Further experiments need to be performed to determine the functional role of these apoptotic processes in acute lung injury.
Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus
Authors: Lenert P
Published: May 2010

Double-stranded (ds) DNA, DNA- or RNA-associated nucleoproteins are the primary autoimmune targets in SLE, yet their relative inability to trigger similar autoimmune responses in experimental animals has fascinated scientists for decades. While many cellular proteins bind non-specifically negatively charged nucleic acids, it was discovered only recently that several intracellular proteins are involved directly in innate recognition of exogenous DNA or RNA, or cytosol-residing DNA or RNA viruses. Thus, endosomal Toll-like receptors (TLR) mediate responses to double-stranded RNA (TLR-3), single-stranded RNA (TLR-7/8) or unmethylated bacterial cytosine (phosphodiester) guanine (CpG)-DNA (TLR-9), while DNA-dependent activator of IRFs/Z-DNA binding protein 1 (DAI/ZBP1), haematopoietic IFN-inducible nuclear protein-200 (p202), absent in melanoma 2 (AIM2), RNA polymerase III, retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5) mediate responses to cytosolic dsDNA or dsRNA, respectively. TLR-induced responses are more robust than those induced by cytosolic DNA- or RNA- sensors, the later usually being limited to interferon regulatory factor 3 (IRF3)-dependent type I interferon (IFN) induction and nuclear factor (NF)-κB activation. Interestingly, AIM2 is not capable of inducing type I IFN, but rather plays a role in caspase I activation. DNA- or RNA-like synthetic inhibitory oligonucleotides (INH-ODN) have been developed that antagonize TLR-7- and/or TLR-9-induced activation in autoimmune B cells and in type I IFN-producing dendritic cells at low nanomolar concentrations. It is not known whether these INH-ODNs have any agonistic or antagonistic effects on cytosolic DNA or RNA sensors. While this remains to be determined in the future, in vivo studies have already shown their potential for preventing spontaneous lupus in various animal models of lupus. Several groups are exploring the possibility of translating these INH-ODNs into human therapeutics for treating SLE and bacterial DNA-induced sepsis.
Investigating the role of proinflammatory CD16+ monocytes in the pathogenesis of inflammatory bowel disease
Authors: Koch S , Kucharzik T , Heidemann J , Nusrat A , Luegering A
Published: May 2010

Infiltrating monocytes and macrophages contribute to the initiation and perpetuation of mucosal inflammation characteristic for human inflammatory bowel disease (IBD). Peripheral blood monocytes expressing the low-affinity Fcγ receptor CD16 have been identified previously as a major proinflammatory cell population, based on their unique cytokine secretion profile. However, the contribution of these cells to the pathogenesis of inflammatory bowel disease remains to be elucidated. Thus, in this study we investigated whether the peripheral CD16+ monocyte count correlates with common IBD disease parameters, and whether these cells infiltrate the intestinal mucosa under inflammatory conditions. We observed that CD16+ peripheral blood monocytes are increased significantly in active Crohn's disease, particularly in patients with high Crohn's disease activity index and colonic involvement. Furthermore, we found that CD16+ cells are a major contributor to the inflammatory infiltrate in Crohn's disease mucosa, although their spontaneous migration through primary human intestinal endothelial cells is limited. Our data suggest that lamina propria, but not peripheral blood, CD16+ monocytes are a crucial proinflammatory cell population in IBD, and a potential target for anti-inflammatory therapy.
Immune modulation of co-transplantation mesenchymal stem cells with islet on T and dendritic cells
Authors: Li F R , Wang X G , Deng C Y , Qi H , Ren L L , Zhou H X
Published: May 2010

Allogeneic pancreatic islet transplantation theoretically represents a cure for type 1 diabetes. However, current immune suppressive therapies are often associated with undesired side effects. Given this problem, and the shortage of human islet donors, the majority of type 1 diabetes patients cannot currently be offered an islet transplant. However, it has been found that mesenchymal stem cells (MSCs) could exert unique immunosuppressive effects both in vitro and in vivo. Herein we transplanted allogeneic 200 islets alone or in combination with MSCs (3 × 106 cells) under the kidney capsules of diabetic C57LB/6 mouse. We found that the ratios of T helper type 1 (Th1) to Th2 and Tc1 to Tc2 were reduced, and the numbers of naive and memory T cells were down-regulated in peripheral blood after transplantation. In addition, the maturation, endocytosis and interleukin-12 secretion of dendritic cell (DCs)-derived bone marrow cells (BMCs) from receptor mice were suppressed. Rejection reaction was alleviated by MSCs which exerted suppressive effects through T lymphocyte subsets and DCs.
Peripartum nevirapine exposure and subsequent clinical outcomes among HIV‐infected women receiving antiretroviral therapy for at least 12 months
Authors: Chintu Namwinga , Giganti Mark J. , Putta Nande B. , Sinkala Moses , Sadoki Ebedy , Stringer Elizabeth M. , Stringer Jeffrey S. A. , Chi Benjamin H.
Published: May 2010

Objective  Prior exposure to intrapartum/neonatal nevirapine (NVP) is associated with compromised virologic treatment outcomes once non‐nucleoside reverse transcriptase inhibitor (NNRTI)–based antiretroviral therapy (ART) is initiated. We examined the longer‐term clinical outcomes in a programmatic setting.

Methods  We compared post‐12 month mortality and clinical treatment failure (defined by WHO clinical and immunologic criteria) among women with and without prior NVP exposure in Lusaka, Zambia.

Results  Between April 2004 and July 2006, 6740 women initiated an NNRTI‐containing regimen. At 12 months, 5172 (78%) remained active and were included in this analysis. Of these, 596 (12%) reported prior NVP exposure, whose time from exposure to ART initiation was: <6 months for 11%, 6–12 months for 13%, >12 months for 37%, unknown for 39%. Overall, women with prior NVP exposure trended towards increased survival (adjusted hazard ratio [AHR]: 0.53; 95% confidence interval [CI]: 0.27–1.06, P = 0.07) and towards increased hazard of clinical treatment failure (AHR: 1.18; 95% CI: 0.95–1.47, P = 0.14), particularly those with exposure for <6 months (AHR: 1.52; 95% CI: 0.94–2.45, P = 0.09).

Conclusions  Prior NVP exposure appeared to increase risk for clinical treatment failure after 12 months of follow‐up, but this finding did not reach statistical significance. With growing evidence linking recent NVP exposure to virologic failure, optimized monitoring algorithms should be considered for women with starting NNRTI‐based ART. The association between prior NVP exposure and improved survival has not been previously shown and may be a result of residual confounding around health‐seeking behaviours.
Comparative rates of lower jaw diversification in cichlid adaptive radiations
Authors: HULSEY C. D. , MIMS M. C. , PARNELL N. F. , STREELMAN J. T.
Published: May 2010

The lower jaw (LJ) provides an ideal trophic phenotype to compare rates and patterns of macroevolution among cichlid radiations. Using a novel phylogeny of four genes (ND2, dlx2, mitfb, and s7), we examined the evolutionary relationships among two of the most phylogenetically disparate cichlid radiations: (i) the Central America Heroines; and (ii) the East African Lake Malawi flock. To quantify jaw morphology, we measured two LJ lever systems in approximately 40 species from each lineage. Using geologic calibrations, we generated a chronogram for both groups and examined the rates of jaw evolution in the two radiations. The most rapidly evolving components of the LJ differed between the two radiations. However, the Lake Malawi flock exhibited a much faster rate of evolution in several components of the LJ. This rapid rate of divergence is consistent with natural selection, promoting unparalleled trophic diversification in Lake Malawi cichlids.
Hilltopping Behavior of Polistes commanchus navajoe (Hymenoptera: Vespidae)
Authors: Matthes‐Sears William , Alcock John
Published: May 2010

Males of the paper wasp Polistes commanchus aggregate in large numbers on hilltops in central and southeastern Arizona where individual males defend perch sites on shrubs, trees or rocks. Residents chase intruders away quickly and exhibit strong site fidelity at their perches. Takeovers are rare as are prolonged battles for possession of a site. Males have only weak preferences for peaktop perch sites as opposed to those lower on hillsides, and a similarly weak preference for perches in shrubs as opposed to those on rocks. Receptive females appear occasionally at the male aggregation sites to mate with perch holders. The relatively weak territoriality exhibited by P. commanchus may stem in part from the high density of males at peaktops and the correspondingly high rate of interactions. The evolution of hilltopping in a species whose reproductive females are clumped spatially at nest sites poses a puzzle for the ecological analysis of mating systems.
Sexual Monomorphism in Spotted Hyenas, Crocuta crocuta
Authors: III William J. Hamilton , Tilson Ronald L. , Frank Lawrence G.
Published: May 2010

Intersexual and intrasexual interactions by female spotted hyenas, (Crocuta crocuta), are correlated with the ability of the heavier and more aggressive females to dominate males at large carcasses, the principal food of spotted hyenas.

Female spotted hyenas have a modified clitoris closely resembling a penis. A slightly bilobed scrotum containing fat and connective tissue contributes to the male‐like appearance of the female sexual facies. Penile and pseudopenis erection by spotted hyenas occurs primarily during social encounters at carcasses and elsewhere.

Analyses here, based on interspecies comparisons of spotted hyena, brown hyena (Hyaena brunnea) and striped hyena (H. hyaena) morphology, behavior and ecology and interpopulation comparisons of spotted hyenas suggest possible gradualistic evolutionary interpretations of the pseudopenis.
Cumulative Effect of Male's Displays in the Sexual Behaviour of the Smooth Newt Triturus vulgaris (Urodela, Salamandridae)1
Authors: Teyssedre Claudine , Halliday Tim
Published: May 2010

The relevance of the temporal spacing of signals to the timing and nature of the receiver's response during a communicative process was studied in the sexual behaviour of the smooth newt Triturus vulgaris. The possibility that a high rate of stimulation allows an accumulation of the effects of successive signals was investigated by comparing sexual interactions leading and not leading to spermatophore deposition.

Results showed that the difference between the two types of interactions lay only in temporal features of the stimulation provided by the male to the female. Females, although in a comparable initial state of receptivity and exposed to comparable amounts of stimulation, performed the act triggering spermatophore deposition by the male only in some interactions. Display bouts, in which the male displayed at short intervals (less than 4 s), were longer in interactions where spermatophore deposition took place than in the others. This suggests that courtship was effective if accumulation of the effects of male displays could occur. This proposition was supported by the observation of a progressive change in the immediate female response to a given male display in the group where courtship bouts were longer.

Our results indicate the existence of a system of tonic communication (see Schleidt 1973) during the sexual behaviour of the smooth newt, in which the effects of the male displays accumulate over time until some critical threshold is reached in the female.