bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro -Osteoclastic Activity Studies on Surfaces of 3D Printed Calcium Phosphate Scaffolds
Authors: Detsch Rainer , Schaefer Susannne , Deisinger Ulrike , Ziegler Guenter , Seitz Hermann , Leukers Barbara
Published: July 2010

Various biomaterials have been developed for the use as bone substitutes for bone defects. To optimize their integration and functionality, they should be adapted to the individual defect. Rapid prototyping is a manufacturing method to tailor materials to the 3D geometry of the defect. Especially 3D printing allows the manufacture of implants, the shape of which can be designed to fit the bone defect using anatomical information obtained from the patient. 3D printing of calcium phosphates, which are well established as bone substitutes, involves a sintering step after gluing the granules together by a binder liquid. In this study, we analyzed if and how these 3D printed calcium phosphate surfaces can be resorbed by osteoclast-like cells. On 3D printed scaffold surfaces consisting of pure HA and β-TCP as well as a biphasic mixture of HA and TCP the osteoclastic cell differentiation was studied. In this regard, cell proliferation, differentiation, and activation were analyzed with the monocytic cell line RAW 264.7. The results show that osteoclast-like cells were able to resorb calcium phosphate surfaces consisting of granules. Furthermore, biphasic calcium phosphate ceramics exhibit, because of their osteoclastic activation ability, the most promising surface properties to serve as 3D printed bone substitute scaffolds.
Characterization of the metabolic phenotype of chronically activated lymphocytes
Authors: Wahl DR , Petersen B. , Warner R. , Richardson BC , Glick GD , Opipari AW
Published: July 2010

Activated lymphocytes proliferate, secrete cytokines, and can make antibodies. Normally activated B and T cells meet the bioenergetic demand for these processes by up-regulating aerobic glycolysis. In contrast, several lines of evidence suggest that pathogenic lymphocytes in autoimmune diseases like lupus meet ATP demands through oxidative phosphorylation. Using 13C-glucose as a stable tracer, we found that splenocytes from mice with lupus derive the same fraction of lactate from glucose as control animals, suggesting comparable levels of glycolysis and non-oxidative ATP production. However, lupus splenocytes increase glucose oxidation by 40% over healthy control animals. The ratio between pentose phosphate cycle (PPC) activity and glycolysis is the same for each group, indicating that increased glucose oxidation is due to increased activity of the TCA cycle in lupus splenocytes. Repetitive stimulation of cultured human T cells was used to model chronic lymphocyte activation, a phenotype associated with lupus. Chronically activated T cells rely primarily on oxidative metabolism for ATP synthesis suggesting that chronic antigen stimulation may be the basis for the metabolic findings observed in lupus mice. Identification of disease-related bioenergetic phenotypes should contribute to new diagnostic and therapeutic strategies for immune diseases.
Livedoid vasculopathy and recurrent thrombosis in a patient with lupus: seronegative antiphospholipid syndrome?
Authors: Sopeña B. , Pérez-Rodríguez MT , Rivera A. , Ortiz-Rey JA , Lamas J. , Freire-Dapena MC
Published: July 2010

Livedoid vasculopathy is a rare condition which predominantly affects young women. It is characterized by intense painful purpuric maculae in the legs, ankles and feet, due to thrombosis of the small and medium-sized dermal vessels, in the absence of vasculitis. Livedoid vasculopathy has been frequently associated with hypercoagulable states and antiphospholipid syndrome. We describe a 34-year-old White woman suffering from systemic lupus erythematosus, livedo reticularis, haemolytic anaemia, severe thrombocytopenia and recurrent venous thrombosis who was admitted to the hospital for extremely painful purpuric lesions in her lower limbs. The clinical and histological findings were diagnostic of livedoid vasculopathy. Once the initial sub-therapeutic international normalized ratio levels were corrected, livedoid vasculopathy did not recur. Tests for antiphospholipid antibodies were repeatedly negative. This case, the first reported of livedoid vasculopathy in a patient with seronegative antiphospholipid syndrome and systemic lupus erythematosus, draws attention to livedoid vasculopathy, a thrombotic dermopathy that may be under-diagnosed in patients with antiphospholipid syndrome. Lupus (2010) 19, 1340—1343.
Evaluating Development Interventions in Peace-Precarious Situations
Authors: Elkins Catherine
Published: July 2010

International development assistance tackles sociopolitical and socioeconomic problems, typically with formal host government and population buy-in (or acquiescence), in settings with complex interrelated challenges. A new subset of contemporary interventions, however, faces all of the usual development challenges plus security threats affecting foreign and local staff, host country leadership, and local counterparts necessary for generating sustainable improvements. Threats can arise as a function of individuals’ roles in promoting development. Evaluations of the results of development interventions in peace-precarious situations not only confront the same extra challenges implementation does in these settings, but must also account for the consequences of a panoply of interactive intangibles, shifting dynamically over time. Salient contextual features shaping feasible and useful approaches to evaluation in peace-precarious situations include adherence to management and monitoring and evaluation (M&E) systems; elasticity in design and resources; and dynamics of stakeholder politics and broader political relationships.
Criteria and Theory in the Evaluation of Organizations
Authors: Befani Barbara
Published: July 2010

This article argues that evaluation-specific logic, which involves the identification of relevant criteria and performance standards for the evaluand (considered as a whole or in its single dimensions), can benefit from research on the causal chains leading from programme inputs to the final outcomes; and on the contexts and mechanisms responsible, which are normally investigated when adopting a theory-based or realistic evaluation approach. The arguments presented are both theoretical — how explanations can be used to redefine the evaluand in order to improve criteria selection — and applied. The latter are taken from the evaluation of two organizations: Italian universities and the Food and Agricultural Organization of the United Nations (FAO).
A Developing Evaluation Culture in Romania: Myths, Gaps and Triggers
Authors: Mihalache Roxana
Published: July 2010

Most of the efforts undertaken to build national evaluation capacity in Romania are directed towards institutionalizing evaluation. These efforts might lead to the establishment of a national evaluation system. But a national evaluation culture — not easily created by regulations, formal tools and institutional hierarchies alone — is nevertheless emerging and is already having an impact on the formal institutionalization of evaluation. In these circumstances the supply and demand sides of evaluation are expected to remain interdependent. For that reason, analysing the national evaluation culture from the perspective of the values shared by practitioners who contribute to the establishment of the evaluation capacity might be relevant. It is important to know if the practitioners who are engaged in the evaluation process share a language when they undertake various activities: speak about evaluation; prepare terms of reference for an evaluation assignment; select the best approach to that evaluation; carry it out; assess its quality; and use its outputs. The hypothesis of this study was that in an emerging evaluation culture — as there is in Romania — there is a difference between the values shared by evaluation managers (demand) and by evaluators (supply) and furthermore, that within each of these groups there are values not shared by the majority. In the Romanian context what are these differences? What explains them? And what are their implications?
First and second language knowledge in the language classroom
Authors: Horst Marlise , White Joanna , Bell Philippa
Published: July 2010

This feasibility study investigated how language instruction can be designed to help learners build on first language (L1) knowledge in acquiring a new language. It seems likely that learners will benefit from activities that draw their attention to features of their L1, but attempts to bridge the first and second language (L2) curricula often break down because the teachers typically work in isolation and are uncertain how to proceed. We attempted to address these problems by designing a series of cross-linguistic awareness (CLA) activities to be implemented on a trial basis with 48 young francophone learners of English (age 9—10 years) at a school in Montreal, Quebec. We observed language instruction in their French (L1) classes and identified features and themes that lent themselves to reinvestment in their English (L2) classes. Then 11 CLA teaching packages were developed and piloted with in an intensive year-long English as a second language (ESL) program. Classroom observations, interviews with both L1 and L2 teachers, and learner journal responses indicated that the activities were well received and that CLA instruction can usefully address a wide variety of linguistic features. Problems highlighted by the study are discussed; we also outline new research that will explore whether this promising experimental pedagogy leads to distinct language learning benefits.
The relationship between reading skills in early English as a foreign language and Hungarian as a first language
Authors: Nikolov Marianne , Csapó Benő
Published: July 2010

In recent years, similarly to other educational contexts in the European Union and other parts of the world, early foreign language programs have become widely spread in Hungary. This article looks into the relationship between Hungarian learners’ reading skills in English as a foreign language (L2) and in their first language (L1) Hungarian. We analyze data from two quantitative cross-sectional studies to explore how they interact. In the first one, participants were representative samples of Hungarian students ( n > 4700 in Grade 6 and n > 3900 in Grade 8; age 12 and 14, respectively). Besides their proficiency in reading comprehension in L2, their reading skills were also tested in the mother tongue. The other study involved a representative sample of eighth graders ( n = 247) in one particular county of Hungary (Baranya). This enquiry tapped into learners’ proficiency in reading comprehension in English and in Hungarian, but besides reading, their listening comprehension and writing skills were also assessed in the two languages. Both studies found evidence for the interdependence hypothesis: a close relationship was found between L1 and L2 performances. However, relationships between L2 skills proved to be stronger than those between L1 and L2 as well as between L1 skills.
Re-contextualizing pre-sentence reports
Authors: Hannah-Moffat Kelly , Maurutto Paula
Published: July 2010

In the past two decades, Canadian policies governing the structure and content of presentence reports (PSRs) have shifted to focus more directly on the systematic identification of offender’s criminogenic risk and needs. In this article, we (1) examine how risk-based approaches to offender management have altered the structure and format of the PSR in Canada, and (2) contrast the structure of risk-based PSRs to Gladue reports for Aboriginal offenders in Canada. Gladue reports are designed to identify the unique systemic race/cultural and historical factors specific to Aboriginal offenders and to recommend alternatives to incarceration. We argue that although risk-based PSRs incorporate recognition of race-related issues, their structure and emphasis on actuarially based risk assessments frames race and risk differently from Gladue reports. In Gladue reports, holistic approaches and cultural impact factors are documented and used to understand risk and need. Finally, we argue that the conceptualization and relevance of race is limited by actuarial risk logic.
Pre-sentence reports, magisterial discourse and agency in the Youth Courts in England and Wales
Authors: Phoenix Jo
Published: July 2010

This article draws on interviews with Youth Court magistrates to examine if and how discourses, strategies and technologies of risk governance have affected Youth Court magistrates in England and Wales. The aim of the article is to detail the complex relationship between magisterial agency in decision making and youth justice policies which focus on risk control and management. The article demonstrates that, contrary to what might be assumed from the youth and risk governance theoretical literature, Youth Offending Team risk assessments form only one part of the information used by magistrates to explain young people’s presence in courts. This article concludes that magisterial decision making is framed not by formal, expert assessments of risk, but by magistrates’ claims that they are ‘knowing outsiders’, who through judicious use of information presented to them and their own life experiences are able to make objective judgements about both the risk assessments authored by Youth Offending Teams and the young lawbreakers before them.
Behavioral and Neurophysiological Effects of Repetitive Transcranial Magnetic Stimulation on the Minimally Conscious State
Authors: Piccione Francesco , Cavinato Marianna , Manganotti Paolo , Formaggio Emanuela , Storti Silvia Francesca , Battistin Leontino , Cagnin Annachiara , Tonin Paolo , Dam Mauro
Published: July 2010

Background. In 2007, Schiff et al reported a patient in a minimally conscious state (MCS) who responded to deep brain stimulation (DBS), but clinicians cannot predict which patients might respond prior to the implantation of electrodes. Methods. A patient in a MCS for 5 years participated in an ABA design alternating between repetitive transcranial magnetic stimulation (rTMS) and peripheral nerve stimulation. rTMS (condition A) involved the delivery of 10 trains of 100 stimuli at 20 Hz using a stimulator with a 70-mm figure-of-eight coil to elicit a contraction of the abductor pollicis brevis. Condition B used median nerve electrical stimulation. Results. After peripheral stimulation, the patient did not exhibit clinical, behavioral, or electroencephalographic (EEG) changes. The frequency of specific and meaningful behaviors increased after rTMS, along with the absolute and relative power of the EEG δ, β, and α bands. Conclusion. These results suggest that rTMS may improve awareness and arousal in MCS. If these results are reproducible, rTMS may identify subgroups of MCS patients who might benefit from DBS.
Use of probiotics in gastrointestinal disorders: what to recommend?
Authors: Verna Elizabeth C. , Lucak Susan
Published: July 2010

Perturbation of bacterial microflora of the gastrointestinal (GI) tract may play an important role in the pathophysiology of some GI disorders. Probiotics have been used as a treatment modality for over a century. They may restore normal bacterial microflora and effect the functioning of the GI tract by a variety of mechanisms. Probiotics are not currently regulated and only few randomized controlled trials exist investigating their efficacy in different GI disorders. They are available in a variety of formulations and delivery systems making interpretation and comparison of studies even more difficult. The efficacy of probiotics, either as a single strain or a combination of probiotics, has been tested in antibiotic-associated diarrhea, Clostridium difficile colitis, infectious diarrhea, ulcerative colitis, Crohn’s disease, pouchitis, and irritable bowel syndrome, among other disorders. Results of the studies are reviewed in this article and recommendations for probiotic use in these disorders are made. Although probiotics appear to be generally safe in an outpatient setting, the situation may be different in immunocompromised, hospitalized patients who may be at a greater risk of developing probiotic sepsis. No studies exist addressing the issue of safety specifically. Many questions regarding use of probiotics in GI disorders remain to be answered in future studies, such as most optimal doses, duration of treatment, physiological and immunological effects, efficacy of specific probiotics in specific disease states, and safety in debilitated patients.
Guest Service Management and Processes in Restaurants: What We Have Learned in Fifty Years
Authors: Susskind Alex M.
Published: July 2010

Although restaurant-related research has long focused on boosting sales, the focus on revenue as a quantitative discipline has arisen only in the past fifteen years, with restaurant revenue management. This series of studies is emblematic of the increased focus on scientific studies to help restaurateurs improve their operations. Another thread of research, on service process management, included a series of articles explaining the many elements beyond the food itself that go into a successful restaurant operation. A particular element in guest satisfaction is the extent to which employees believe that their restaurant maintains service standards. Finally, when service goes awry, service recovery requires handling guest complaints in a prompt and appropriate fashion. Service failures subject restaurants to negative word of mouth, but it is not simply a matter of a dissatisfied guest complaining to a certain number of friends. Instead, the nature and number of subsequent negative comments depends on the type of failure—with food quality being most critical.
Comparison between Platelet-Rich Plasma and Autologous Iliac Grafts for Tibial Osteotomy
Authors: D’Elia Caio Oliveira , de Rezende Márcia Uchôa , Bitar Alexandre Carneiro , Tatsui Nelson , Pécora José Ricardo , Hernandez Arnaldo José , Camanho Gilberto Luis
Published: July 2010

Objective:

Platelet-rich plasma (PRP) has the capacity to improve the bone-healing process. The aim of this pilot study was to investigate the occurrence of bone healing and the time taken to achieve this in patients submitted to medial opening wedge high tibial osteotomy (MOWHTO), comparing platelet-rich plasma with bone marrow aspirate to autologous iliac graft.

Design:

Twenty-five patients who underwent tibial osteotomy were randomly divided into 2 groups: a control group, which received autologous iliac grafts (14 patients), and a study group, which received a compound of PRP and bone marrow aspirate (11 patients).

Results:

The bone-healing rates achieved were 100% in the control group and 91% in the study group. There was no difference in the time taken to achieve bone healing between the groups.

Conclusions:

The use of a combination of PRP and bone marrow aspirate, as a bone substitute, did not demonstrate any advantage over the use of an autologous iliac graft in MOWHTO.
Effect of local volume fraction of microporosity on tensile properties in Al–Si–Mg cast alloy
Authors: Kobayashi M. , Dorce Y. , Toda H. , Horikawa H.
Published: July 2010

Porosity in Al–Si–Mg cast alloys utilised in automotive parts affects directly products quality, i.e. mechanical properties. In this study, the effect of micropores on mechanical properties has been investigated by X-ray tomography from the viewpoint of clustering micropores. The local volume fraction (LVF) of porosity was introduced to analyse the effect of clustering micropores. The statistical Weibull method was also used in order to explain strength of the alloy tested. The fracture strain decreased drastically from 17 to 3% on an inverse parabolic relationship with increasing porosity. In the case of the specimens that contain the largest pore higher than 100 m m, the ultimate tensile strength decreases monotonically. It is found that the fracture surface passes through high LVF regions. The fracture strain obviously depends on the ratio of LVF higher than 10%. It is confirmed that the LVF, which represents unevenly distribution of micropores cluster, is one of important dominant factor for managing the mechanical properties in the Al–Si–Mg cast alloy.
Study on formation of surface and microstructure of stainless steel part produced by selective laser melting
Authors: Jinhui L. , Ruidi L. , Wenxian Z. , Liding F. , Huashan Y.
Published: July 2010

In order to further develop selective laser melting (SLM) technology, the formation of surface and microstructure of 316 stainless steel SLM parts was studied using optical microscopy and SEM, differential thermal analysis and thermal gravity analysis methods. Some effects such as heat transmission, energy distribution and rapid cooling and solidification during SLM process on the formation of surface and microstructure were mainly discussed. The results indicated that the surface morphology was affected by viscosity and fluidity of steel melts, which were governed by laser energy, heat transmission history and material properties, while porosity was influenced by surface morphology of each intermediate layer and the cooling rates of steel melts, which were determined by laser energy, heat transmission conditions and laser scanning history. The microstructures of 316 stainless steel SLM part were irregular non-equilibrium ones that converted to normal austenite after being heated at 627°C h–1.
Atomic-scale models of dislocation cores in minerals: progress and prospects
Authors: Walker A. M. , Carrez P. , Cordier P.
Published: July 2010

Recent advances in computer simulation at the atomic scale have made it possible to probe the structure and behaviour of the cores of dislocations in minerals. Such simulation offers the possibility to understand and predict the dislocation-mediated properties of minerals such as mechanisms of plastic deformation, pipe diffusion and crystal growth. In this review the three major methods available for the simulation of dislocation cores are described and compared. The methods are: (1) cluster-based models which combine continuum elastic theory of the extended crystal with an atomistic model of the core; (2) dipole models which seek to cancel the long-range elastic displacement caused by the dislocation by arranging for the simulation to contain several dislocations with zero net Burgers vector, thus allowing a fully periodic super-cell calculation; and (3) the Peierls-Nabarro approach which attempts to recast the problem so that it can be solved using only continuum-based methods, but parameterizes the model using results from atomic-scale calculations. The strengths of these methods are compared and illustrated by some of the recent studies of dislocations in mantle silicate minerals. Some of the unresolved problems in the field are discussed.
Evolution of nepheline from mafic to highly differentiated members of the alkaline series: the Messum complex, Namibia
Authors: Blancher S. B. , D'Arco P. , Fonteilles M. , Pascal M.-L.
Published: July 2010

The change in chemical composition trend of magmatic nepheline through magma evolution has been characterized from the alkaline series of the Messum complex in which nepheline occurs in a succession of different mineral parageneses from mafic-rich (theralites) to strongly evolved felsic-rich rock types (nepheline syenites). The nepheline compositions are dependent on those of coexisting feldspar(s). They record an evolution parallel to that of the melt schematized according to experimental phase diagrams, from initially Ca-rich compositions in equilibrium with calcic plagioclase towards increasingly Ca-poor, Na-rich and Si-rich compositions. The K contents show a maximum that corresponds to the appearance of alkali feldspar in the parageneses. This evolution is qualitatively preserved in spite of the low-T Na/K re-equilibration typical of plutonic nephelines. Although a slight increase in the silica content of nepheline is consistent with the experimentally defined magmatic trend, several high-silica nephelines from the Messum rocks as well as from other reported occurrences, cannot be reconciled with the experimental data. The nepheline solid-solution model available suggests that such ‘abnormal’ compositions might be related to different crystallization mechanisms between natural nephelines and some synthetic analogues.
Feldspars defined and described: a pair of posters published by the Mineralogical Society. Sources and supporting information
Authors: Parsons I.
Published: July 2010

The Mineralogical Society of Great Britain & Ireland has published two full-colour posters describing the feldspar minerals, designed primarily for student use. They may be downloaded free of charge by all fromhttp://www.minersoc.org/pages/education/edu.htmland are designed to be printed at A3 size, although they are legible at A4 and in greyscale. Sheet 1 deals with nomenclature, crystal structure and phase relationships, while Sheet 2 covers phase behaviour. For brevity no sources are given on the posters, and these are provided in the present article, together with supporting notes and suggested reading on the more complex topics.
The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status
Authors: Green Claire L. , Evans Catherine M. , Hills Robert K. , Burnett Alan K. , Linch David C. , Gale Rosemary E.
Published: July 2010

Mutations in the isocitrate dehydrogenase gene (IDH1) were recently described in patients with acute myeloid leukemia (AML). To investigate their prognostic significance we determined IDH1 status in 1333 young adult patients, excluding acute promyelocytic leukemia, treated in the United Kingdom MRC AML10 and 12 trials. A mutation was detected in 107 patients (8%). Most IDH1+ patients (91%) had intermediate-risk cytogenetics. Mutations correlated significantly with an NPM1 mutation (P < .0001) but not a FLT3/ITD (P = .9). No difference in outcome between IDH1+ and IDH1− patients was found in univariate or multivariate analysis, or if the results were stratified by NPM1 mutation status. However, when stratified by FLT3/ITD status, an IDH1 mutation was an independent adverse factor for relapse in FLT3/ITD− patients (P = .008) and a favorable factor in FLT3/ITD+ patients (P = .02). These results suggest that metabolic changes induced by an IDH1 mutation may influence chemoresistance in a manner that is context-dependent.
Granulysin activates antigen-presenting cells through TLR4 and acts as an immune alarmin
Authors: Tewary Poonam , Yang De , de la Rosa Gonzalo , Li Yana , Finn Michael W. , Krensky Alan M. , Clayberger Carol , Oppenheim Joost J.
Published: July 2010

Granulysin (GNLY), an antimicrobial protein present in the granules of human cytotoxic T lymphocytes and natural killer (NK) cells, is produced as an intact 15-kDa form that is cleaved to yield a 9-kDa form. Alarmins are endogenous mediators that can induce recruitment and activation of antigen-presenting cells (APCs) and consequently promote the generation of immune response. We hypothesized that GNLY might function as an alarmin. Here, we report that both 9- and 15-kDa forms of recombinant GNLY-induced in vitro chemotaxis and activation of both human and mouse dendritic cells (DCs), recruited inflammatory leucocytes, including APCs in mice, and promoted antigen-specific immune responses upon coadministration with an antigen. GNLY-induced APC recruitment and activation required the presence of Toll-like receptor 4. The observed activity of recombinant GNLY was not due to endotoxin contamination. The capability of the supernatant of GNLY-expressing HuT78 cells to activate DC was blocked by anti-GNLY antibodies. Finally we present evidence that supernatants of degranulated human NK92 or primary NK cells also activated DCs in a GNLY- and Toll-like receptor 4–dependent manner, indicating the physiologic relevance of our findings. Thus, GNLY is the first identified lymphocyte-derived alarmin capable of promoting APC recruitment, activation, and antigen-specific immune response.
Pannexin-1 hemichannel–mediated ATP release together with P2X1 and P2X4 receptors regulate T-cell activation at the immune synapse
Authors: Woehrle Tobias , Yip Linda , Elkhal Abdallah , Sumi Yuka , Chen Yu , Yao Yongli , Insel Paul A. , Junger Wolfgang G.
Published: July 2010

Engagement of T cells with antigen-presenting cells requires T-cell receptor (TCR) stimulation at the immune synapse. We previously reported that TCR stimulation induces the release of cellular adenosine-5′-triphosphate (ATP) that regulates T-cell activation. Here we tested the roles of pannexin-1 hemichannels, which have been implicated in ATP release, and of various P2X receptors, which serve as ATP-gated Ca2+ channels, in events that control T-cell activation. TCR stimulation results in the translocation of P2X1 and P2X4 receptors and pannexin-1 hemichannels to the immune synapse, while P2X7 receptors remain uniformly distributed on the cell surface. Removal of extracellular ATP or inhibition, mutation, or silencing of P2X1 and P2X4 receptors inhibits Ca2+ entry, nuclear factors of activated T cells (NFAT) activation, and induction of interleukin-2 synthesis. Inhibition of pannexin-1 hemichannels suppresses TCR-induced ATP release, Ca2+ entry, and T-cell activation. We conclude that pannexin-1 hemichannels and P2X1 and P2X4 receptors facilitate ATP release and autocrine feedback mechanisms that control Ca2+ entry and T-cell activa-tion at the immune synapse.
The oligodeoxynucleotide sequences corresponding to never-expressed peptide motifs are mainly located in the non-coding strand
Authors: Capone Giovanni , Novello Giuseppe , Fasano Candida , Trost Brett , Bickis Mik , Kusalik Anthony , Kanduc Darja
Published: July 2010

Background

We study the usage of specific peptide platforms in protein composition. Using the pentapeptide as a unit of length, we find that in the universal proteome many pentapeptides are heavily repeated (even thousands of times), whereas some are quite rare, and a small number do not appear at all. To understand the physico-chemical-biological basis underlying peptide usage at the proteomic level, in this study we analyse the energetic costs for the synthesis of rare and never-expressed versus frequent pentapeptides. In addition, we explore residue bulkiness, hydrophobicity, and codon number as factors able to modulate specific peptide frequencies. Then, the possible influence of amino acid composition is investigated in zero- and high-frequency pentapeptide sets by analysing the frequencies of the corresponding inverse-sequence pentapeptides. As a final step, we analyse the pentadecamer oligodeoxynucleotide sequences corresponding to the never-expressed pentapeptides.

Results

We find that only DNA context-dependent constraints (such as oligodeoxynucleotide sequence location in the minus strand, introns, pseudogenes, frameshifts, etc.) provide a coherent mechanistic platform to explain the occurrence of never-expressed versus frequent pentapeptides in the protein world.

Conclusions

This study is of importance in cell biology. Indeed, the rarity (or lack of expression) of specific 5-mer peptide modules implies the rarity (or lack of expression) of the corresponding n-mer peptide sequences (with n > 5), so possibly modulating protein compositional trends. Moreover the data might further our understanding of the role exerted by rare pentapeptide modules as critical biological effectors in protein-protein interactions.
Compartmentalization of the Edinburgh Human Metabolic Network
Authors: Hao Tong , Ma Hong-Wu , Zhao Xue-Ming , Goryanin Igor
Published: July 2010

Background

Direct in vivo investigation of human metabolism is complicated by the distinct metabolic functions of various sub-cellular organelles. Diverse micro-environments in different organelles may lead to distinct functions of the same protein and the use of different enzymes for the same metabolic reaction. To better understand the complexity in the human metabolism, a compartmentalized human metabolic network with integrated sub-cellular location information is required.

Results

We extended the previously reconstructed Edinburgh Human Metabolic Network (EHMN) [Ma, et al. Molecular Systems Biology, 3:135, 2007] by integrating the sub-cellular location information for the reactions, adding transport reactions and refining the protein-reaction relationships based on the location information. Firstly, protein location information was obtained from Gene Ontology and complemented by a Swiss-Prot location keywords search. Then all the reactions in EHMN were assigned to a location based on the protein-reaction relationships to get a preliminary compartmentalized network. We investigated the localized sub-networks in each pathway to identify gaps and isolated reactions by connectivity analysis and refined the location information based on information from literature. As a result, location information for hundreds of reactions was revised and hundreds of incorrect protein-reaction relationships were corrected. Over 1400 transport reactions were added to link the location specific metabolic network. To validate the network, we have done pathway analysis to examine the capability of the network to synthesize or degrade certain key metabolites. Compared with a previously published human metabolic network (Human Recon 1), our network contains over 1000 more reactions assigned to clear cellular compartments.

Conclusions

By combining protein location information, network connectivity analysis and manual literature search, we have reconstructed a more complete compartmentalized human metabolic network. The whole network is available at http://www.ehmn.bioinformatics.ed.ac.uk and free for academic use.
Mobile genetic element proliferation and gene inactivation impact over the genome structure and metabolic capabilities of Sodalis glossinidius, the secondary endosymbiont of tsetse flies
Authors: Belda Eugeni , Moya Andrés , Bentley Stephen , Silva Francisco J
Published: July 2010

Background

Genome reduction is a common evolutionary process in symbiotic and pathogenic bacteria. This process has been extensively characterized in bacterial endosymbionts of insects, where primary mutualistic bacteria represent the most extreme cases of genome reduction consequence of a massive process of gene inactivation and loss during their evolution from free-living ancestors. Sodalis glossinidius, the secondary endosymbiont of tsetse flies, contains one of the few complete genomes of bacteria at the very beginning of the symbiotic association, allowing to evaluate the relative impact of mobile genetic element proliferation and gene inactivation over the structure and functional capabilities of this bacterial endosymbiont during the transition to a host dependent lifestyle.

Results

A detailed characterization of mobile genetic elements and pseudogenes reveals a massive presence of different types of prophage elements together with five different families of IS elements that have proliferated across the genome of Sodalis glossinidius at different levels. In addition, a detailed survey of intergenic regions allowed the characterization of 1501 pseudogenes, a much higher number than the 972 pseudogenes described in the original annotation. Pseudogene structure reveals a minor impact of mobile genetic element proliferation in the process of gene inactivation, with most of pseudogenes originated by multiple frameshift mutations and premature stop codons. The comparison of metabolic profiles of Sodalis glossinidius and tsetse fly primary endosymbiont Wiglesworthia glossinidia based on their whole gene and pseudogene repertoires revealed a novel case of pathway inactivation, the arginine biosynthesis, in Sodalis glossinidius together with a possible case of metabolic complementation with Wigglesworthia glossinidia for thiamine biosynthesis.

Conclusions

The complete re-analysis of the genome sequence of Sodalis glossinidius reveals novel insights in the evolutionary transition from a free-living ancestor to a host-dependent lifestyle, with a massive proliferation of mobile genetic elements mainly of phage origin although with minor impact in the process of gene inactivation that is taking place in this bacterial genome. The metabolic analysis of the whole endosymbiotic consortia of tsetse flies have revealed a possible phenomenon of metabolic complementation between primary and secondary endosymbionts that can contribute to explain the co-existence of both bacterial endosymbionts in the context of the tsetse host.
Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation
Authors: Gotfryd Kamil , Skladchikova Galina , Lepekhin Eugene A , Berezin Vladimir , Bock Elisabeth , Walmod Peter S
Published: July 2010

Background

The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.

Methods

The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).

Results

VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed.

Conclusions

These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.
An exploration of the association between very early rehabilitation and outcome for the patients with acute ischaemic stroke in Japan: a nationwide retrospective cohort survey
Authors: Matsui Hiroki , Hashimoto Hideki , Horiguchi Hiromasa , Yasunaga Hideo , Matsuda Shinya
Published: July 2010

Background

Very early rehabilitation is expected to improve functional outcomes after stroke, although its effectiveness has not been fully evaluated. The purpose of this study was to investigate the association between very early intervention (VEI), and patient outcomes at discharge by using nationwide large data and statistical treatment for selection bias.

Methods

In this study, we defined VEI as rehabilitation commencing within 3 days of stroke admission. The data were derived from a nationwide survey of acute-care hospitals conducted in 2007 for designing a reimbursement scheme and from a concurrent survey on rehabilitation services among a convenient subgroup of hospitals participating in the above survey. We included patients with a diagnosis code of ischaemic cerebrovascular disease with acute onset who underwent any rehabilitation services during hospitalisation. Surgery cases, those with no functional deficit, and those with a severe consciousness deficit upon admission were excluded. A total of 5,482 patients were enrolled from 294 hospitals. To correct for any potential selection bias, we used Friday admission as an instrumental variable (IV) and conducted a bivariate probit model analysis.

Results

We found that VEI for acute stroke patients was significantly associated with a lesser degree of disability at discharge. Even after considering endogenous problems due to treatment selection, VEI improved the chance of reducing disability by 15.3% (p < 0.001). There was no significant association between VEI and in-hospital mortality, suggesting that VEI was not likely to lead to an adverse outcome.

Conclusions

These data suggest that VEI may lead to a better outcome with no increase in adverse events compared to delayed rehabilitation.
Placental transfer of the polybrominated diphenyl ethers BDE-47, BDE-99 and BDE-209 in a human placenta perfusion system: an experimental study
Authors: Frederiksen Marie , Vorkamp Katrin , Mathiesen Line , Mose Tina , Knudsen Lisbeth E
Published: July 2010

Background

Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants in consumer products. PBDEs may affect thyroid hormone homeostasis, which can result in irreversible damage of cognitive performance, motor skills and altered behaviour. Thus, in utero exposure is of very high concern due to critical windows in fetal development.

Methods

A human ex vivo placenta perfusion system was used to study the kinetics and extent of the placental transfer of BDE-47, BDE-99 and BDE-209 during four-hour perfusions. The PBDEs were added to the maternal circulation and monitored in the maternal and fetal compartments. In addition, the perfused cotyledon, the surrounding placental tissue as well as pre-perfusion placental tissue and umbilical cord plasma were also analysed. The PBDE analysis included Soxhlet extraction, clean-up by adsorption chromatography and GC-MS analysis.

Results and Discussion

Placental transfer of BDE-47 was faster and more extensive than for BDE-99. The fetal-maternal ratios (FM-ratio) after four hours of perfusion were 0.47 and 0.25 for BDE-47 and BDE-99, respectively, while the indicative permeability coefficient (IPC) measured after 60 minutes of perfusion was 0.26 h-1 and 0.10 h-1, respectively. The transport of BDE-209 seemed to be limited. These differences between the congeners may be related to the degree of bromination. Significant accumulation was observed for all congeners in the perfused cotyledon as well as in the surrounding placental tissue.

Conclusion

The transport of BDE-47 and BDE-99 indicates in utero exposure to these congeners. Although the transport of BDE-209 was limited, however, possible metabolic debromination may lead to products which are both more toxic and transportable. Our study demonstrates fetal exposure to PBDEs, which should be included in risk assessment of PBDE exposure of women of child-bearing age.
NF-κB activation enhances cell death by antimitotic drugs in human prostate cancer cells
Authors: Parrondo Ricardo , Pozas Alicia de las , Reiner Teresita , Rai Priyamvada , Perez-Stable Carlos
Published: July 2010

Background

NF-κB is a transcription factor that promotes inhibition of apoptosis and resistance to chemotherapy. It is commonly believed that inhibition of NF-κB activity can increase sensitivity of cancer cells to chemotherapy. However, there is evidence that NF-κB activation can sensitize cells to apoptosis and that inhibition of NF-κB results in resistance to chemotherapy. In prostate cancer, it is not clear in the different cell types (androgen-dependent and castration-resistant) if activation or inhibition of NF-κB is required for stimulation of apoptosis by chemotherapy.

Results

Our data indicate that the response of prostate cancer (PC) cells to the antimitotic drugs docetaxel (Doc) and 2-methoxyestradiol (2ME2) is dependent on the levels of NF-κB activity. In androgen-dependent LNCaP cells, Doc and 2ME2 treatment increased the low basal NF-κB activity, as determined by Western blot analysis of phospho-IκBα/p65, NF-κB promoter reporter assays, and p65 localization. Treatment of LNCaP cells with parthenolide, a pharmacologic inhibitor of NF-κB, or introduction of dominant-negative IκBα, or an shRNA specific for p65, a component of the NF-κB heterodimer, blocked apoptosis induced by Doc and 2ME2. In castration-resistant DU145 and PC3 cells, Doc and 2ME2 had little effect on the high basal NF-κB activity and addition of parthenolide did not enhance cell death. However, the combination of Doc or 2ME2 with betulinic acid (BA), a triterpenoid that activates NF-κB, stimulated apoptosis in LNCaP and non-apoptotic cell death in DU145 and PC3 cells. Increased sensitivity to cell death mediated by the Doc or 2ME2 + BA combination is likely due to increased NF-κB activity.

Conclusions

Our data suggest that the combination of antimitotic drugs with NF-κB inhibitors will have antagonistic effects in a common type of PC cell typical of LNCaP. However, combination strategies utilizing antimitotic drugs with BA, an activator of NF-κB, will universally enhance cell death in PC cells, notably in the aggressive, castration-resistant variety that does not respond to conventional therapies.
Emphysema is associated with increased inflammation in lungs of atherosclerosis-prone mice by cigarette smoke: implications in comorbidities of COPD
Authors: Arunachalam Gnanapragasam , Sundar Isaac K , Hwang Jae-woong , Yao Hongwei , Rahman Irfan
Published: July 2010

Background

Chronic obstructive pulmonary disease is associated with numerous vascular effects including endothelial dysfunction, arterial stiffness and atherogenesis. It is also known that a decline in lung function is associated with increased cardiovascular comorbidity in smokers. The mechanism of this cardiopulmonary dual risk by cigarette smoke (CS) is not known. We studied the molecular mechanisms involved in development of emphysema in atherosclerosis-prone apolipoprotein E-deficient (ApoE-/-) mice in response to CS exposure.

Methods

Adult male and female wild-type (WT) mice of genetic background C57BL/6J and ApoE-/-mice were exposed to CS, and lung inflammatory responses, oxidative stress (lipid peroxidation products), mechanical properties as well as airspace enlargement were assessed.

Results and Discussion

The lungs of ApoE-/-mice showed augmented inflammatory response and increased oxidative stress with development of distal airspace enlargement which was accompanied with decline in lung function. Interestingly, the levels and activities of matrix metalloproteinases (MMP-9 and MMP-12) were increased, whereas the level of eNOS was decreased in lungs of CS-exposed ApoE-/-mice as compared to air-exposed ApoE-/-mice or CS-exposed WT mice.

Conclusion

These findings suggest that CS causes premature emphysema and a decline of lung function in mice susceptible to cardiovascular abnormalities via abnormal lung inflammation, increased oxidative stress and alterations in levels of MMPs and eNOS.
Assessing the spatial distribution of methadone clinic clients and their access to treatment
Authors: Wong Ngai Sze , Lee Shui Shan , Lin Hui
Published: July 2010

Using Geographic Information System (GIS), the spatial distribution of methadone clinic clients and their utilization of a treatment service in Hong Kong was analysed. A majority (93.7%) of the 63 methadone users recruited were residing in the same district, of which 84.1% spent not more than 15 minutes for traveling. Walking (55.6%) was the commonest transport mode followed by cycling (30.2%). There was no distance decay effect on traveling time, but an association between distance and transport selection could be demonstrated. The residence locations displayed a compact distribution, merging with the general population without any evidence of clustering. Though the distribution of methadone users could have been shaped by the location of clinic, it can also be concluded that methadone clinics at convenient locations are needed if maintenance is a key determinant of service effectiveness.