bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct recognition and lysis of leukemia cells by WT1-specific CD4+ T lymphocytes in an HLA class II-restricted manner
Authors: Guo Yun , Niiya Hironari , Azuma Taichi , Uchida Naoyuki , Yakushijin Yoshihiro , Sakai Ikuya , Hato Takaaki , Takahashi Masuhiro , Senju Satoru , Nishimura Yasuharu , Yasukawa Masaki
Published: April 2005

Wilms tumor gene 1 product (WT1) has been recognized as an attractive target antigen of immunotherapy for various malignancies including leukemia. Because tumor-associated antigen-specific CD4+ T lymphocytes undoubtedly play an important role in the induction of an antitumor immune response, we attempted to generate WT1-specific CD4+ T lymphocytes in vitro and examined their antileukemia functions. A CD4+ T-cell line, designated NIK-1, which proliferated and produced Th1 cytokines specifically in response to stimulation with the WT1-derived peptide, WT1337-347 LSHLQMHSRKH, in an HLA-DP5-restriced manner was established. NIK-1 exhibited cytotoxicity against HLA-DP5-positive, WT1-expressing leukemia cells but did not lyse HLA-DP5-negative, WT1-expressing leukemia cells or HLA-DP5-positive, WT1-negative cells. NIK-1 did not inhibit colony formation by normal bone marrow cells of HLA-DP5-positive individuals. This is the first report to describe WT1-specific and HLA class II-restricted CD4+ T lymphocytes possessing direct cytotoxic activity against leukemia cells. (Blood. 2005;106: 1415-1418)
Oligoclonal expansion of T lymphocytes with multiple second-site mutations leads to Omenn syndrome in a patient with RAG1-deficient severe combined immunodeficiency
Authors: Wada Taizo , Toma Tomoko , Okamoto Hiroyuki , Kasahara Yoshihito , Koizumi Shoichi , Agematsu Kazunaga , Kimura Hirokazu , Shimada Akira , Hayashi Yasuhide , Kato Masahiko , Yachie Akihiro
Published: April 2005

Omenn syndrome (OS) is a rare primary immunodeficiency characterized by the presence of activated/oligoclonal T cells, eosinophilia, and the absence of circulating B cells. OS patients carry leaky mutations of recombination activating genes (RAG1 or RAG2) resulting in partial V(D)J recombination activity, whereas null mutations cause severe combined immunodeficiency with absence of mature T and B cells (T-B- SCID). Here we describe somatic mosaicism due to multiple second-site mutations in a patient with RAG1 deficiency. We found that he is homozygous for a single base deletion in the RAG1 gene, which results in frameshift and likely abrogates the protein function. However, the patient showed typical OS features. Molecular analysis revealed that several second-site mutations, all of which restored the RAG1 reading frame and resulted in missense mutations, were demonstrated in his T cells. These findings suggest that his revertant T-cell mosaicism is responsible for OS phenotype switched from T-B- SCID. (Blood. 2005; 106:2099-2101)
Using co-occurrence network structure to extract synonymous gene and protein names from MEDLINE abstracts
Authors: Cohen AM , Hersh WR , Dubay C , Spackman K
Published: April 2005

Background

Text-mining can assist biomedical researchers in reducing information overload by extracting useful knowledge from large collections of text. We developed a novel text-mining method based on analyzing the network structure created by symbol co-occurrences as a way to extend the capabilities of knowledge extraction. The method was applied to the task of automatic gene and protein name synonym extraction.

Results

Performance was measured on a test set consisting of about 50,000 abstracts from one year of MEDLINE. Synonyms retrieved from curated genomics databases were used as a gold standard. The system obtained a maximum F-score of 22.21% (23.18% precision and 21.36% recall), with high efficiency in the use of seed pairs.

Conclusion

The method performs comparably with other studied methods, does not rely on sophisticated named-entity recognition, and requires little initial seed knowledge.
A method for the prediction of GPCRs coupling specificity to G-proteins using refined profile Hidden Markov Models
Authors: Sgourakis Nikolaos G , Bagos Pantelis G , Papasaikas Panagiotis K , Hamodrakas Stavros J
Published: April 2005

Background

G- Protein coupled receptors (GPCRs) comprise the largest group of eukaryotic cell surface receptors with great pharmacological interest. A broad range of native ligands interact and activate GPCRs, leading to signal transduction within cells. Most of these responses are mediated through the interaction of GPCRs with heterotrimeric GTP-binding proteins (G-proteins). Due to the information explosion in biological sequence databases, the development of software algorithms that could predict properties of GPCRs is important. Experimental data reported in the literature suggest that heterotrimeric G-proteins interact with parts of the activated receptor at the transmembrane helix-intracellular loop interface. Utilizing this information and membrane topology information, we have developed an intensive exploratory approach to generate a refined library of statistical models (Hidden Markov Models) that predict the coupling preference of GPCRs to heterotrimeric G-proteins. The method predicts the coupling preferences of GPCRs to Gs, Gi/o and Gq/11, but not G12/13 subfamilies.

Results

Using a dataset of 282 GPCR sequences of known coupling preference to G-proteins and adopting a five-fold cross-validation procedure, the method yielded an 89.7% correct classification rate. In a validation set comprised of all receptor sequences that are species homologues to GPCRs with known coupling preferences, excluding the sequences used to train the models, our method yields a correct classification rate of 91.0%. Furthermore, promiscuous coupling properties were correctly predicted for 6 of the 24 GPCRs that are known to interact with more than one subfamily of G-proteins.

Conclusion

Our method demonstrates high correct classification rate. Unlike previously published methods performing the same task, it does not require any transmembrane topology prediction in a preceding step. A web-server for the prediction of GPCRs coupling specificity to G-proteins available for non-commercial users is located at http://bioinformatics.biol.uoa.gr/PRED-COUPLE.
Crosstalk regulation among group 2- Sigma factors in Synechocystis PCC6803
Authors: Lemeille Sylvain , Geiselmann Johannes , Latifi Amel
Published: April 2005

Background

The cyanobacterium Synechocystis PCC6803 contains one group 1 (sigA) and four group 2 (sigB, sigC, sigD and sigE) sigma factors. The activity of these multiple sigma factors determines the transcriptional program of this bacterium. We wanted to study the role of the group 2 sigma factors in Synechocystis. We have therefore constructed mutants of each of the group 2 sigma factors and investigated their crosstalk.

Results

We used quantitative RT-PCR analysis to measure the relative abundance of the sig mRNAs in the four sigma mutants. Our data indicate that a network of mutual transcriptional regulation links the expression of the sigma genes. Accordingly, an environmental stress acting on only one of the sigma factors will indirectly modify the expression of most of the other sigma factors. This was confirmed by the transcriptional analysis of the sig mRNAs as a function of nitrogen starvation.

Conclusion

Taken together, our observations suggest that the crosstalk regulation between all group 1 and group 2 genes could be important for the adaptation of the bacterium to different environmental and physiological conditions.
Sequence determinants of protein aggregation: tools to increase protein solubility
Authors: Ventura Salvador
Published: April 2005

Escherichia coliis one of the most widely used hosts for the production of recombinant proteins. However, very often the target protein accumulates into insoluble aggregates in a misfolded and biologically inactive form. Bacterial inclusion bodies are major bottlenecks in protein production and are hampering the development of top priority research areas such structural genomics. Inclusion body formation was formerly considered to occur via non-specific association of hydrophobic surfaces in folding intermediates. Increasing evidence, however, indicates that protein aggregation in bacteria resembles to the well-studied process of amyloid fibril formation. Both processes appear to rely on the formation of specific, sequence-dependent, intermolecular interactions driving the formation of structured protein aggregates. This similarity in the mechanisms of aggregation will probably allow applying anti-aggregational strategies already tested in the amyloid context to the less explored area of protein aggregation inside bacteria. Specifically, new sequence-based approaches appear as promising tools to tune protein aggregation in biotechnological processes.
GIDEON: a comprehensive Web-based resource for geographic medicine
Authors: Berger Stephen A
Published: April 2005

GIDEON (Global Infectious Diseases and Epidemiology Network) is a web-based computer program designed for decision support and informatics in the field of Geographic Medicine. The first of four interactive modules generates a ranked differential diagnosis based on patient signs, symptoms, exposure history and country of disease acquisition. Additional options include syndromic disease surveillance capability and simulation of bioterrorism scenarios. The second module accesses detailed and current information regarding the status of 338 individual diseases in each of 220 countries. Over 50,000 disease images, maps and user-designed graphs may be downloaded for use in teaching and preparation of written materials. The third module is a comprehensive source on the use of 328 anti-infective drugs and vaccines, including a listing of over 9,500 international trade names. The fourth module can be used to characterize or identify any bacterium or yeast, based on laboratory phenotype. GIDEON is an up-to-date and comprehensive resource for Geographic Medicine.
Behavioral and neuroendocrine consequences of social subjugation across adolescence and adulthood
Authors: Ferris Craig F , Messenger Tara , Sullivan Ross
Published: April 2005

Background

Social subjugation is a very significant and natural stressor in the animal kingdom. Adult animals defeated and subjugated during establishment of dominance hierarchies or territorial encounters can be highly submissive in future agonistic interactions. While much is know about the biological and behavioral consequences of winning and losing fights in adulthood, little is known about adolescence; a developmental period noted for impulsivity and heightened agonistic behavior. The present studies were undertaken to determine if the behavioral and neuroendocrine consequences of social subjugation are comparable in adolescent versus adult Syrian golden hamsters (Mesocricetus auratus). Male siblings were studied from adolescence into adulthood following exposure to counterbalanced episodes of either a benign stressor, i.e., isolation in a novel cage, or the more severe stressor of social subjugation.

Results

As adults, hamsters with a history of social subjugation in adolescence show high levels of aggression toward intruders as compared to siblings subjugated in adulthood. Sibling controls subjugated in adulthood are highly submissive with little or no aggressive behavior. However, when subjugated in adulthood, hamsters with the earlier history of subjugation are no different than their sibling controls, i.e., adult subjugation promotes submissive behavior. Sexual motivation is high in adult hamsters with adolescent subjugation and testosterone levels remained stable over adulthood. In contrast, sibling controls subjugated in adulthood show lower levels of sexual motivation and reduced levels of testosterone. Release of cortisol during agonistic encounters is blunted in animals subjugated in adolescence but not adulthood. Measures of anxiety are reduced in hamsters with adolescent subjugation as compared to their sibling controls.

Conclusion

These data demonstrate a pronounced difference in behavior and neuroendocrinology between adolescent and adult hamsters in their response to social subjugation and suggest adolescence is a resilient period in development.
Globalization and Health
Authors: Martin Greg
Published: April 2005

This debut editorial of Globalization and Health introduces the journal, briefly delineating its goals and objectives and outlines its scope of subject matter. 'Open Access' publishing is expected to become an increasingly important format for peer reviewed academic journals and that Globalization and Health is 'Open Access' is appropriate. The rationale behind starting a journal dedicated to globalization and health is three fold:

Firstly: Globalization is reshaping the social geography within which we might strive to create health or prevent disease. The determinants of health – be they a SARS virus or a predilection for fatty foods – have joined us in our global mobility. Driven by economic liberalization and changing technologies, the phenomenon of 'access' is likely to dominate to an increasing extent the unfolding experience of human disease and wellbeing.

Secondly: Understanding globalization as a subject matter itself needs certain benchmarks and barometers of its successes and failings. Health is one such barometer. It is a marker of social infrastructure and social welfare and as such can be used to either sound an alarm or give a victory cheer as our interconnectedness hurts and heals the populations we serve.

And lastly: In as much as globalization can have an effect on health, it is also true that health and disease has an effect on globalization as exemplified by the existence of quarantine laws and the devastating economic effects of the AIDS pandemic.

A balanced view would propose that the effects of globalization on health (and health systems) are neither universally good nor bad, but rather context specific. If the dialogue pertaining to globalization is to be directed or biased in any direction, then it must be this: that we consider the poor first.
Globalization and Health: Exploring the opportunities and constraints for health arising from globalization
Authors: Yach Derek
Published: April 2005

The tremendous benefits which have been conferred to almost 5 billion people through improved technologies and knowledge highlights the concomitant challenge of bringing these changes to the 1 billion people living mostly in sub-Saharan Africa and South Asia who are yet to benefit. There is a growing awareness of the need to reduce human suffering and of the necessary participation of governments, non-government organizations and industry within this process. This awareness has recently translated into new funding mechanisms to address HIV/Aids and vaccines, a global push for debt relief and better trade opportunities for the poorest countries, and recognition of how global norms that address food safety, infectious diseases and tobacco benefit all. 'Globalization and Health' will encourage an exchange of views on how the global architecture for health governance needs to changes in the light of global threats and opportunities.
Trade related infections: farther, faster, quieter
Authors: Kimball Ann Marie , Arima Yuzo , Hodges Jill R
Published: April 2005

Modern global trading traffics large volumes of diverse products rapidly to a broad geographic area of the world. When emergent infections enter this system in traded products their transmission is amplified. With truly novel emergent infections with long incubation periods, such as Human Immunodeficiency Virus (HIV) or variant Creutzfeld Jacob Disease (vCJD), this transmission may silently disseminate infection to far distant populations prior to detection. We describe the chronology of two such "stealth infections," vCJD and HIV, and the production, processing, and distribution changes that coincided with their emergence. The concept of "vector products" is introduced. A brief case study of HIV incursion in Japan is presented in illustration. Careful "multisectoral" analysis of such events can suggest ecologically critical pathways of emergence for further research. Such analyses emphasize the urgency of implementing safety measures when pathogens enter globally traded products.
The global diet: trade and novel infections
Authors: Hodges Jill R , Kimball Ann Marie
Published: April 2005

Practices designed to meet the demands of global trade can amplify food safety problems. Ever-increasing pressure to churn out more product and better sides of beef has generated processes that compromise existing safety measures. Among the concerns are intensified food production, use of antimicrobials and hormones as growth promoters, and poor sanitary infrastructure in some food producing countries. Accompanying the innovations designed to serve the diversifying global palate are emerging and re-emerging infectious diseases, or "trade-related infections." The joint efforts of international public health and industry are required to effectively address these growing health challenges.
The evolution of the Global Burden of Disease framework for disease, injury and risk factor quantification: developing the evidence base for national, regional and global public health action
Authors: Lopez Alan D
Published: April 2005

Reliable, comparable information about the main causes of disease and injury in populations, and how these are changing, is a critical input for debates about priorities in the health sector. Traditional sources of information about the descriptive epidemiology of diseases, injuries and risk factors are generally incomplete, fragmented and of uncertain reliability and comparability. Lack of a standardized measurement framework to permit comparisons across diseases and injuries, as well as risk factors, and failure to systematically evaluate data quality have impeded comparative analyses of the true public health importance of various conditions and risk factors. As a consequence the impact of major conditions and hazards on population health has been poorly appreciated, often leading to a lack of public health investment. Global disease and risk factor quantification improved dramatically in the early 1990s with the completion of the first Global Burden of Disease Study. For the first time, the comparative importance of over 100 diseases and injuries, and ten major risk factors, for global and regional health status could be assessed using a common metric (Disability-Adjusted Life Years) which simultaneously accounted for both premature mortality and the prevalence, duration and severity of the non-fatal consequences of disease and injury. As a consequence, mental health conditions and injuries, for which non-fatal outcomes are of particular significance, were identified as being among the leading causes of disease/injury burden worldwide, with clear implications for policy, particularly prevention. A major achievement of the Study was the complete global descriptive epidemiology, including incidence, prevalence and mortality, by age, sex and Region, of over 100 diseases and injuries. National applications, further methodological research and an increase in data availability have led to improved national, regional and global estimates for 2000, but substantial uncertainty around the disease burden caused by major conditions, including, HIV, remains. The rapid implementation of cost-effective data collection systems in developing countries is a key priority if global public policy to promote health is to be more effectively informed.
International nurse recruitment and NHS vacancies: a cross-sectional analysis
Authors: Batata Amber S
Published: April 2005

Background

Foreign-trained nurse recruits exceeded the number of new British-trained recruits on the UK nurse register for the first time in 2001. As the nursing shortage continues, health care service providers rely increasingly on overseas nurses to fill the void. Which areas benefit the most? And where would the NHS be without them?

Methods

Using cross-sectional data from the 2004 Nursing and Midwifery Council register, nurse resident postcodes are mapped to Strategic Health Authorities to see where foreign recruits locate and how they affect nurse shortages throughout the UK.

Results

Areas with the highest vacancy rates also have the highest representation of foreign recruits, with 24% of foreign-trained nurses in the UK residing in the London area and another 16% in the SouthEast (comparable numbers for British-trained nurses are 11% and 13%, respectively). Without foreign recruitment, vacancy rates could be up to five times higher (three times higher if only Filipino recruits remained).

Conclusion

The UK heavily relies on foreign recruitment to fill vacancies, without which the staffing crisis would be far worse, particularly in high vacancy areas.
Behavioral and Brain Functions. A new journal
Authors: Sagvolden Terje
Published: April 2005

Behavioral and Brain Functions (BBF) is an Open Access, peer-reviewed, online journal considering original research, review, and modeling articles in all aspects of neurobiology or behavior, favoring research that relates to both domains. Behavioral and Brain Functions is published by BioMed Central. The greatest challenge for empirical science is to understand human behavior; how human behavior arises from the myriad functions such as attention, language, memory and emotion; how these functions are reflected in brain structures and functions; and how the brain and behavior are altered in disease. Behavioral and Brain Functions covers the entire area of behavioral and cognitive neuroscience – an area where animal studies traditionally play a prominent role. Behavioral and Brain Functions is published online, allowing unlimited space for figures, extensive datasets to allow readers to study the data for themselves, and moving pictures, which are important qualities assisting communication in modern science.
Methylphenidate improves prefrontal cortical cognitive function through α2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in Attention Deficit Hyperactivity Disorder
Authors: Arnsten Amy FT , Dudley Anne G
Published: April 2005

Background

Methylphenidate (MPH) is the classic treatment for Attention Deficit Hyperactivity Disorder (ADHD), yet the mechanisms underlying its therapeutic actions remain unclear. Recent studies have identified an oral, MPH dose regimen which when given to rats produces drug plasma levels similar to those measured in humans. The current study examined the effects of these low, orally-administered doses of MPH in rats performing a delayed alternation task dependent on prefrontal cortex (PFC), a brain region that is dysfunctional in ADHD, and is highly sensitive to levels of catecholamines. The receptor mechanisms underlying the enhancing effects of MPH were explored by challenging the MPH response with the noradrenergic α2 adrenoceptor antagonist, idazoxan, and the dopamine D1 antagonist, SCH23390.

Results

MPH produced an inverted U dose response whereby moderate doses (1.0–2.0 mg/kg, p.o.) significantly improved delayed alternation performance, while higher doses (2.0–3.0 mg/kg, p.o.) produced perseverative errors in many animals. The enhancing effects of MPH were blocked by co-administration of either the α2 adrenoceptor antagonist, idazoxan, or the dopamine D1 antagonist, SCH23390, in doses that had no effect on their own.

Conclusion

The administration of low, oral doses of MPH to rats has effects on PFC cognitive function similar to those seen in humans and patients with ADHD. The rat can thus be used as a model for examination of neural mechanisms underlying the therapeutic effects of MPH on executive functions in humans. The efficacy of idazoxan and SCH23390 in reversing the beneficial effects of MPH indicate that both noradrenergic α2 adrenoceptor and dopamine D1 receptor stimulation contribute to cognitive-enhancing effects of MPH.
Learning spatial orientation tasks in the radial-maze and structural variation in the hippocampus in inbred mice
Authors: Crusio Wim E , Schwegler Herbert
Published: April 2005

In the present paper we review a series of experiments showing that heritable variations in the size of the hippocampal intra- and infrapyramidal mossy fiber (IIPMF) terminal fields correlate with performance in spatial, but not non-spatial radial-maze tasks. Experimental manipulation of the size of this projection by means of early postnatal hyperthyroidism produces the effects predicted from the correlations obtained with inbred mouse strains. Although the physiological mechanisms behind these correlations are unknown as yet, several lines of evidence indicate that these correlations are causal.
Dishabituation of the BOLD response to speech sounds
Authors: Zevin Jason D , McCandliss Bruce D
Published: April 2005

Background

Neural systems show habituation responses at multiple levels, including relatively abstract language categories. Dishabituation – responses to non-habituated stimuli – can provide a window into the structure of these categories, without requiring an overt task.

Methods

We used an event-related fMRI design with short interval habituation trials, in which trains of stimuli were presented passively during 1.5 second intervals of relative silence between clustered scans. Trains of four identical stimuli (standard trials) and trains of three identical stimuli followed by a stimulus from a different phonetic category (deviant trials) were presented. This paradigm allowed us to measure and compare the time course of overall responses to speech, and responses to phonetic change.

Results

Comparisons between responses to speech and silence revealed strong responses throughout the extent of superior temporal gyrus (STG) bilaterally. Comparisons between deviant and standard trials revealed dishabituation responses in a restricted region of left posterior STG, near the border with supramarginal gyrus (SMG). Novelty responses to deviant trials were also observed in right frontal regions and hippocampus.

Conclusion

A passive, dishabituation paradigm provides results similar to studies requiring overt responses. This paradigm can readily be extended for the study of pre-attentive processing of speech in populations such as children and second-language learners whose overt behavior is often difficult to interpret because of ancillary task demands.
Mycobacterium bovisBacillus Calmette-Guérin infects DC-SIGN– dendritic cell and causes the inhibition of IL-12 and the enhancement of IL-10 production
Authors: Gagliardi Maria Cristina , Teloni Raffaela , Giannoni Federico , Pardini Manuela , Sargentini Valeria , Brunori Lara , Fattorini Lanfranco , Nisini Roberto
Published: April 2005

The only available vaccine against tuberculosis is Mycobacterium bovis Bacillus Calmette Guérin (BCG), although its efficacy in preventing pulmonary tuberculosis is controversial. Early interactions between dendritic cells (DC) and BCG or Mycobacterium tuberculosis (Mtb) are thought to be critical for mounting a protective antimycobacterial immune response. Recent studies have shown that BCG and Mtb target the DC-specific C-type lectin intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) to infect DC and inhibit their immunostimulatory function. This would occur through the interaction of the mycobacterial mannosylated lipoarabinomannan to DC-SIGN, which would prevent DC maturation and induce the immunosuppressive cytokine interleukin (IL)-10 synthesis. Here, we confirm that DC-SIGN is expressed in DC derived from monocytes cultured in granulocyte macrophage-colony stimulating factor (GM-CSF) and IL-4 and show that it is not expressed in DC derived from monocytes cultured in GM-CSF and interferon-α (IFN-α). We also demonstrate that DC-SIGN– DC cultured in GM-CSF and IFN-α are able to phagocytose BCG and to undergo a maturation program as well as DC-SIGN+ DC cultured in IL-4 and GM-CSF. We also show that BCG causes the impairment of IL-12 and the induction of IL-10 secretion by DC, irrespective of DC-SIGN expression. Finally, we demonstrate that the capacity to stimulate a mixed leukocyte reaction of naïve T lymphocytes is not altered by the treatment of both DC populations with BCG. These data suggest that DC-SIGN cannot be considered as the unique DC receptor for BCG internalization, and it is more interesting that the mycobacteria-induced immunosuppression cannot be attributed to the engagement of a single receptor.
Reduced endocannabinoid immune modulation by a common cannabinoid 2 (CB2) receptor gene polymorphism: possible risk for autoimmune disorders
Authors: Sipe Jack C , Arbour Nathalie , Gerber Alexandra , Beutler Ernest
Published: April 2005

Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the “immunocannabinoid” system. This system can be an important signaling pathway for immune modulation. To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation. The CB2 cDNA 188–189 GG/GG polymorphism predicts the substitution of glutamine at amino acid position 63 by arginine. T lymphocytes from CB2 188–189 GG/GG homozygotes had approximately twofold reduction of endocannabinoid-induced inhibition of proliferation compared with cells from CB2 188–189 AA/AA homozygotes. In GG/GG subjects, the reduced endocannabinoid inhibitory response was highly significant for N-arachidonylglycine and nearly significant for 2-arachidonylglycerol, and a specific CB2 receptor antagonist partially blocked these effects. Also, patients with autoimmune diseases had an increased prevalence of the homozygous GG/GG genotype. Collectively, these results demonstrate reduced endogenous fatty acid amide immunomodulatory responses in individuals with the CB2 188–189 GG/GG genotype and suggest that this CB2 gene variation may be a risk factor for autoimmunity. The results also support the proposition that the CB2 receptor may represent a novel pharmacological target for selective agonists designed to suppress autoreactive immune responses while avoiding CB1 receptor-mediated cannabinoid adverse effects.
Leptin Modulates both Resorption and Formation while Preventing Disuse-Induced Bone Loss in Tail-Suspended Female Rats
Authors: Martin Aline , de Vittoris Raphaël , David Valentin , Moraes Ricardo , Bégeot Martine , Lafage-Proust Marie-Hélène , Alexandre Christian , Vico Laurence , Thomas Thierry
Published: April 2005

In vitro studies have demonstrated leptin-positive effects on the osteoblast lineage and negative effects on osteoclastogenesis. Therefore, we tested the hypothesis that leptin may prevent tail-suspension-induced bone loss characterized by an uncoupling pattern of bone remodeling, through both mechanisms. Female rats were randomly tail-suspended or not and treated either with ip administration of leptin or vehicle for 3, 7, and 14 d. As measured by dual energy x-ray absorptiometry, tail-suspension induced a progressive decrease in tibia-metaphysis bone mineral density, which was prevented by leptin. Histomorphometry showed that this was related to the prevention of the transient increase in osteoclast number observed with suspension at d 7. These effects could be mediated by the receptor activator of nuclear factor κB-ligand (RANKL)/osteoprotegerin (OPG) pathway since we observed using direct RT-PCR, a suspension-induced increase in RANKL gene expression in proximal tibia at d 3, which was counterbalanced by leptin administration with a similar 3-fold increase in OPG expression and a RANKL to OPG ratio close to nonsuspended conditions. In addition, leptin prevented the decrease in bone formation rate induced by tail-suspension at d 14. The latter could be related to the role of leptin in mediating the reciprocal differentiation between adipocytes and osteoblasts, because leptin concurrently blunted the disuse-induced increase in bone marrow adipogenesis. In summary, these data suggest that peripheral administration of leptin could prevent disuse-induced bone loss through, first, a major inhibitory effect on bone resorption and, second, a delayed effect preventing the decrease in bone formation.
The Inhibition of RANKL Causes Greater Suppression of Bone Resorption and Hypercalcemia Compared with Bisphosphonates in Two Models of Humoral Hypercalcemia of Malignancy
Authors: Morony Sean , Warmington Kelly , Adamu Stephen , Asuncion Frank , Geng Zhaopo , Grisanti Mario , Tan Hong Lin , Capparelli Casey , Starnes Charlie , Weimann Bernadette , Dunstan Colin R. , Kostenuik Paul J.
Published: April 2005

Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone by inducing the expression of receptor activator for nuclear factor-κB ligand (RANKL), a protein that is essential for osteoclast formation, activation, and survival. RANKL does not influence renal calcium reabsorption, so RANKL inhibition is a rational approach to selectively block, and thereby reveal, the relative contribution of bone calcium to HHM. We used the RANKL inhibitor osteoprotegerin (OPG) to evaluate the role of osteoclast-mediated hypercalcemia in two murine models of HHM. Hypercalcemia was induced either by sc inoculation of syngeneic colon (C-26) adenocarcinoma cells or by sc injection of high-dose recombinant PTHrP (0.5 mg/kg, sc, twice per day). In both models, OPG (0.2–5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg). OPG also caused greater reductions in osteoclast surface and biochemical markers of bone resorption compared with either bisphosphonate. In both models, hypercalcemia gradually returned despite clear evidence of ongoing suppression of bone resorption by OPG. These data demonstrate that osteoclasts and RANKL are important mediators of HHM, particularly in the early stages of the condition. Aggressive antiresorptive therapy with a RANKL inhibitor therefore might be a rational approach to controlling HHM.
Proliferation of Endothelial and Tumor Epithelial Cells by Progestin-Induced Vascular Endothelial Growth Factor from Human Breast Cancer Cells: Paracrine and Autocrine Effects
Authors: Liang Yayun , Hyder Salman M.
Published: April 2005

Angiogenesis, the formation of new blood vessels, is essential for tumor expansion, and vascular endothelial growth factor (VEGF) is one of the most potent angiogenic growth factors known. We have previously shown that natural and synthetic progestins, including those used in hormone replacement therapy and oral contraception, induce the synthesis and secretion of VEGF in a subset of human breast cancer cells in a progesterone receptor-dependent manner. We now report that conditioned medium from progestin-treated breast tumor cells can induce the proliferation of endothelial cells in a paracrine manner and induce the proliferation of tumor epithelial cells in a paracrine and an autocrine manner. The use of an anti-VEGF antibody and SU-1498, an inhibitor of VEGF receptor-2 (VEGFR-2 or flk/kdr) tyrosine kinase activity, demonstrated that these effects involve interactions between VEGF and VEGFR-2. Also, blockage of progestin-induced VEGF by the antiprogestin RU-486 (mifepristone) eliminated VEGF-induced proliferative effects. The ability of VEGF to increase the proliferation of endothelial cells and tumor cells, including those that do not release VEGF in response to progestins, suggests that these effects are mediated by amplification of the progestin signal, which culminates in angiogenesis and tumor growth. These novel findings suggest that targeting the release of VEGF from tumor epithelial cells as well as blocking interactions between VEGF and VEGFR-2 on both endothelial and tumor epithelial cells may facilitate the development of new antiangiogenic therapies for progestin-dependent breast tumors. Furthermore, these data indicate that it would be useful to develop selective progesterone receptor modulators that prevent the release of angiogenic growth factors from breast cancer cells.
Insulin-Like Growth Factor (IGF)-I Stimulates Cell Proliferation and Induces IGF Binding Protein (IGFBP)-3 and IGFBP-5 Gene Expression in Cultured Growth Plate Chondrocytes via Distinct Signaling Pathways
Authors: Kiepe Daniela , Ciarmatori Sonia , Hoeflich Andreas , Wolf Eckhard , Tönshoff Burkhard
Published: April 2005

The bioactivity of IGF-I in the cellular microenvironment is modulated by both inhibitory and stimulatory IGF binding proteins (IGFBPs), whose production is partially under control of IGF-I. However, little is known on the IGF-mediated regulation of these IGFBPs in the growth plate. We therefore studied the effect of IGF-I on IGFBP synthesis and the involved intracellular signaling pathways in two cell culture models of rat growth plate chondrocytes. In growth plate chondrocytes in primary culture, incubation with IGF-I increased the concentrations of IGFBP-3 and IGFBP-5 in conditioned cell culture medium in a dose- and time-dependent manner. Coincubation of IGF-I with specific inhibitors of the p42/44 MAPK pathway (PD098059 or U0126) completely abolished the stimulatory effect of IGF-I on IGFBP-3 mRNA expression but did not affect increased IGFBP-5 mRNA levels. In contrast, inhibition of the phosphatidylinositol-3 kinase signaling pathway by LY294002 abrogated both IGF-I-stimulated IGFBP-3 and -5 mRNA expression. Comparable results regarding IGFBP-5 were obtained in the mesenchymal chondrogenic cell line RCJ3.1C5.18, which does not express IGFBP-3. The IGF-I-induced IGFBP-5 gene expression required de novo mRNA transcription and de novo protein synthesis. These data suggest that IGF-I modulates its activity in cultured rat growth plate chondrocytes by the synthesis of both inhibitory (IGFBP-3) and stimulatory (IGFBP-5) binding proteins. The finding that IGF-I uses different and only partially overlapping intracellular signaling pathways for the regulation of two IGFBPs with opposing biological functions might be important for the modulation of IGF bioactivity in the cellular microenvironment.
Progesterone Inhibits the Estrogen-Induced Phosphoinositide 3-Kinase→AKT→GSK-3β→Cyclin D1→pRB Pathway to Block Uterine Epithelial Cell Proliferation
Authors: Chen Bo , Pan Haiyan , Zhu Liyin , Deng Yan , Pollard Jeffrey W.
Published: April 2005

The mammalian cell cycle is regulated by the cyclin/cyclin-dependent kinase (CDK) phosphorylation of the retinoblastoma (pRB) family of proteins. Cyclin D1 with its CDK4/6 partners initiates the cell cycle and acts as the link between extracellular signals and the cell cycle machinery. Estradiol-17β (E2) stimulates uterine epithelial cell proliferation, a process that is completely inhibited by pretreatment with progesterone (P4). Previously, we identified cyclin D1 localization as a key point of regulation in these cells with E2 causing its nuclear accumulation and P4 retaining it in the cytoplasm with the resultant inhibition of pRB phosphorylation. Here we show that E2 stimulates phosphoinositide 3-kinase to activate phosphokinase B/AKT to effect an inhibitory phosphorylation of glycogen synthase kinase (GSK-3β). This pathway is suppressed by P4. Inhibition of the GSK-3β activity in P4-treated uteri by the specific inhibitor, LiCl, reversed the nuclear accumulation of cyclin D1 and in doing so, caused pRB phosphorylation and the induction of downstream genes, proliferating cell nuclear antigen and Ki67. Conversely, inhibition of phosphoinositide 3 kinase by LY294002 or Wortmanin reversed the E2-induced GSK-3β Ser9 inhibitory phosphorylation and blocked nuclear accumulation of cyclin D1. These data show the reciprocal actions of E2 and P4 on the phosphoinositide 3-kinase through to the GSK-3β pathway that in turn regulates cyclin D1 localization and cell cycle progression. These data reveal a novel signaling pathway that links E2 and P4 action to growth factor-mediated signaling in the uterus.
Virtual-mechanism-based analysis of cooperative manipulation
Authors: Liu H , Dai J S , Xu H Y , Li H
Published: April 2005

This paper proposes a new approach for analysing cooperative manipulation in which cooperative manipulators form a mechanism closure that allows a virtual-mechanism-based analysis to take place. The method is based on the geometry of manipulators during manipulation and converts the cooperative manipulation problem into the analysis of a hypothetical mechanism so that the mechanism theory can be used for the manipulation. This mechanism is hence generated by the fact that the end points (or geometric centres of respective grippers) of cooperative manipulators coincide with a virtual joint during cooperative manipulation. The analysis not only generates positions and orientations of the end effectors of cooperative manipulators but also produces corresponding link configurations that can be used for manipulation planning. The approach is further used for the orientation-based trajectory planning with two different cases. Simulations and discussions are made with respect to cooperative manipulations using two 2R manipulators and one 2R manipulators and one 3R manipulator.
A method for the prediction of ductile fracture by central bursts in axisymmetric extrusion
Authors: McAllen P , Phelan P
Published: April 2005

A new approach for the prediction of central burst defects in extrusion and wire drawing is proposed. Central burst defects are troublesome in industry as it is impossible to detect these defects by simple visual examination alone. It is therefore important to identify the combination of process parameters that will reduce the probability of these defects occurring. The proposed approach is capable of accurately predicting when and where a central burst is likely to occur. The influence of die geometry on damage development and subsequent central burst formation is examined using the modelling capabilities of Abaqus finite element software. The ductile fracture criteria of Cockcroft and Latham, Oyane and Chaouadi were employed using a Fortran subroutine, and their ability to predict the onset and evolution of the central burst defect was examined. For relatively lower area reductions and die angles the considered criteria are capable of accurately predicting the morphology of the defect. Under these conditions, the proposed approach shows good agreement with experimental results, confirming its effectiveness and suitability for industrial application. The failure criteria are inadequate in predicting central burst defect formation during conditions of large reduction in area and large semi-die angles. Further development of ductile failure criteria is necessary to accurately simulate defect evolution for all die angles and area reductions.
The failure of threaded fasteners due to vibration
Authors: Chen J-H , Hsieh S-C , Lee A-C
Published: April 2005

The main objective of this paper is to study the loosening tendency of a threaded fastener. To achieve the objective, the threaded fastener looseness model is constructed through the following procedures. Firstly, static and dynamic threaded fastener models are derived to find the static and dynamic interior forces respectively. Secondly, for investigating the bolt loosening behaviour, the effects of thread lead angle, initial preload, vibration frequency, and the nature of material on the bolt looseness, the threaded fastener looseness model is constructed by combining the above models with a Karnopp frictional model. The proposed approach not only analyses both the static and the dynamic behaviours of the bolt as well as the bolt loosening but also detects whether the bolt is within the elastic range or not. The approach can serve as a guide for designing a thread fastening procedure to avoid the failure of threaded fasteners due to vibration.
Simulation of free-surface flow in a tank using the Navier-Stokes model and unstructured finite volume method
Authors: Zhang X , Sudharsan N M , Ajaykumar R , Kumar K
Published: April 2005

Modelling free-surface flow has very important applications in many engineering areas such as oil transportation and offshore structures. Current research focuses on the modelling of free surface flow in a tank by solving the Navier-Stokes equation. An unstructured finite volume method is used to discretize the governing equations. The free surface is tracked by dynamically adapting the mesh and making it always surface conforming. A mesh-smoothing scheme based on the spring analogy is also implemented to ensure mesh quality throughout the computaiton. Studies are performed on the sloshing response of a liquid in an elastic container subjected to various excitation frequencies. Further investigations are also carried out on the critical frequency that leads to large deformation of the tank walls. Another numerical simulation involves the free-surface flow past as submerged obstacle placed in the tank to show the flow separation and vortices. All these cases demonstrate the capability of this numerical method in modelling complicated practical problems.
An Efficient Improve for the Kröhnke Reaction: One-pot Synthesis of 2,4,6-Triarylpyridines Using Raw Materials under Microwave Irradiation
Authors: Tu Shujiang , Li Tuanjie , Shi Feng , Fang Fang , Zhu Songlei , Wei Xianyong , Zong Zhimin
Published: April 2005

A series of 2,4,6-triarylpyridines have been prepared by the one-pot reaction of aldehydes with aromatic ketones in the presence of ammonium acetate under microwave irradiation without catalyst. This method has the advantage of easier workup, shorter reaction time, higher yield, and environment-friendly.
Lights in Space
Authors: Brewer Daniel
Published: April 2005

Recent disciplinary reconfigurations have shifted focus from a temporal-historical explanation of social life to one designed to investigate the latter's spatial dimension. This article examines the development of various spaces in the eighteenth century—physical, social, colonized, epistemological, and esthetic—and proposes a mode of cultural analysis and of historical understanding relating to the eighteenth century that takes account of these disicplinary shifts.
The Dutch Wives' Good Husbandry: Defoe's Roxana and Financial Literacy
Authors: Gabbard D. Christopher
Published: April 2005

This article argues the supposed economic mastery displayed by Defoe's heroine Roxana is the product of financial self-fashioning. Bookkeeping and Dutchness, deployed as metaphors for economic competence, belie Roxana's pretensions. In the English imagination of the period, Dutch wives were reputed to possess commercial wisdom. Roxana's financial illiteracy and inability to heed her Dutch husband's request to do "as the Wives do in Holland" undermine the assumption that she manipulates the forces of emerging capitalism. Her inability to keep books correlates with her poor literary accounting; these interrelated failings suggest that Defoe's novel should be read as an inversion of the spiritual autobiography.
Consumption and the World of Ideas: Consumer Revolution and the Moral Economy of the Marquis de Mirabeau
Authors: Kwass Michael
Published: April 2005

This article explores the intellectual transformations that accompanied the rise of consumption in eighteenth-century France by examining a best-seller, L'Ami des hommes (1756), by the marquis de Mirabeau. The most popular work of political economy of its time, L'Ami des hommes made a particularly important intervention in the luxury debate. Straddling two seemingly contradictory strains of eighteenth-century political and social thought—a classical republicanism that looked backward to ancient civic virtue and an economic liberalism that looked forward to material progress—the book offered readers the best of both worlds: a moral economy of prosperity. This article analyzes Mirabeau's pathology of consumption and places his moral economy of prosperity in the broader context of Enlightenment thought.