bluuebunny/crossref_metadata_2025 huggingface dataset:
AC220 is a uniquely potent and selective inhibitor of FLT3 for the treatment of acute myeloid leukemia (AML)
Authors: Zarrinkar Patrick P. , Gunawardane Ruwanthi N. , Cramer Merryl D. , Gardner Michael F. , Brigham Daniel , Belli Barbara , Karaman Mazen W. , Pratz Keith W. , Pallares Gabriel , Chao Qi , Sprankle Kelly G. , Patel Hitesh K. , Levis Mark , Armstrong Robert C. , James Joyce , Bhagwat Shripad S.
Published: August 2009

Activating mutations in the receptor tyrosine kinase FLT3 are present in up to approximately 30% of acute myeloid leukemia (AML) patients, implicating FLT3 as a driver of the disease and therefore as a target for therapy. We report the characterization of AC220, a second-generation FLT3 inhibitor, and a comparison of AC220 with the first-generation FLT3 inhibitors CEP-701, MLN-518, PKC-412, sorafenib, and sunitinib. AC220 exhibits low nanomolar potency in biochemical and cellular assays and exceptional kinase selectivity, and in animal models is efficacious at doses as low as 1 mg/kg given orally once daily. The data reveal that the combination of excellent potency, selectivity, and pharmacokinetic properties is unique to AC220, which therefore is the first drug candidate with a profile that matches the characteristics desirable for a clinical FLT3 inhibitor.
Donor-recipient mismatches in MHC class I chain-related gene A in unrelated donor transplantation lead to increased incidence of acute graft-versus-host disease
Authors: Parmar Simrit , del Lima Marcos , Zou Yizhou , Patah Poliana A. , Liu Ping , Cano Pedro , Rondon Gabriela , Pesoa Susana , de Padua Silva Leandro , Qazilbash Muzaffar H. , Hosing Chitra , Popat Uday , Kebriaei Partow , Shpall Elizabeth J. , Giralt Sergio , Champlin Richard E. , Stastny Peter , Fernandez-Vina Marcelo
Published: August 2009

The polymorphic products of major histocompatibility complex class I–related chain A (MICA) genes are important in solid organ transplantation rejection. MICA expression is limited to gut epithelium and may play a role in triggering acute graft-versus-host disease (aGVHD). A total of 236 recipients of unrelated donor transplantation were studied. Donor-recipient human leukocyte antigen (HLA) match was 10/10 human leukocyte antigen (HLA-A, -B, -C, -DRB1, -DQB1) in 73% and MICA mismatch in 8.4%. Because of physical vicinity of the loci, MICA mismatch was significantly associated with mismatch at HLA-B and HLA-C. A higher rate of grade II-IV aGVHD was seen in MICA-mismatched patients (80% vs 40%, P = .003) irrespective of degree of HLA matching (HLA 10/10 match: 75% vs 39%, P = .02) and HLA any mismatch (83% vs 46%, P = .003). The rate of grade II-IV gastrointestinal aGVHD was also higher in MICA-mismatched patients (35% vs 17%, P = .05). We conclude that MICA may represent novel a transplantation antigen recognized by human allogeneic T cells. This study was registered at ClinicalTrials.gov (Identifier NCT00506922).
Resolving deconvolution ambiguity in gene alternative splicing
Authors: She Yiyuan , Hubbell Earl , Wang Hui
Published: August 2009

Background

For many gene structures it is impossible to resolve intensity data uniquely to establish abundances of splice variants. This was empirically noted by Wang et al. in which it was called a "degeneracy problem". The ambiguity results from an ill-posed problem where additional information is needed in order to obtain an unique answer in splice variant deconvolution.

Results

In this paper, we analyze the situations under which the problem occurs and perform a rigorous mathematical study which gives necessary and sufficient conditions on how many and what type of constraints are needed to resolve all ambiguity. This analysis is generally applicable to matrix models of splice variants. We explore the proposal that probe sequence information may provide sufficient additional constraints to resolve real-world instances. However, probe behavior cannot be predicted with sufficient accuracy by any existing probe sequence model, and so we present a Bayesian framework for estimating variant abundances by incorporating the prediction uncertainty from the micro-model of probe responsiveness into the macro-model of probe intensities.

Conclusion

The matrix analysis of constraints provides a tool for detecting real-world instances in which additional constraints may be necessary to resolve splice variants. While purely mathematical constraints can be stated without error, real-world constraints may themselves be poorly resolved. Our Bayesian framework provides a generic solution to the problem of uniquely estimating transcript abundances given additional constraints that themselves may be uncertain, such as regression fit to probe sequence models. We demonstrate the efficacy of it by extensive simulations as well as various biological data.
Multi-level learning: improving the prediction of protein, domain and residue interactions by allowing information flow between levels
Authors: Yip Kevin Y , Kim Philip M , McDermott Drew , Gerstein Mark
Published: August 2009

Background

Proteins interact through specific binding interfaces that contain many residues in domains. Protein interactions thus occur on three different levels of a concept hierarchy: whole-proteins, domains, and residues. Each level offers a distinct and complementary set of features for computationally predicting interactions, including functional genomic features of whole proteins, evolutionary features of domain families and physical-chemical features of individual residues. The predictions at each level could benefit from using the features at all three levels. However, it is not trivial as the features are provided at different granularity.

Results

To link up the predictions at the three levels, we propose a multi-level machine-learning framework that allows for explicit information flow between the levels. We demonstrate, using representative yeast interaction networks, that our algorithm is able to utilize complementary feature sets to make more accurate predictions at the three levels than when the three problems are approached independently. To facilitate application of our multi-level learning framework, we discuss three key aspects of multi-level learning and the corresponding design choices that we have made in the implementation of a concrete learning algorithm. 1) Architecture of information flow: we show the greater flexibility of bidirectional flow over independent levels and unidirectional flow; 2) Coupling mechanism of the different levels: We show how this can be accomplished via augmenting the training sets at each level, and discuss the prevention of error propagation between different levels by means of soft coupling; 3) Sparseness of data: We show that the multi-level framework compounds data sparsity issues, and discuss how this can be dealt with by building local models in information-rich parts of the data. Our proof-of-concept learning algorithm demonstrates the advantage of combining levels, and opens up opportunities for further research.

Availability

The software and a readme file can be downloaded at http://networks.gersteinlab.org/mll. The programs are written in Java, and can be run on any platform with Java 1.4 or higher and Apache Ant 1.7.0 or higher installed. The software can be used without a license.
Comparative genomic analysis uncovers 3 novel loci encoding type six secretion systems differentially distributed in Salmonella serotypes
Authors: Blondel Carlos J , Jiménez Juan C , Contreras Inés , Santiviago Carlos A
Published: August 2009

Background

The recently described Type VI Secretion System (T6SS) represents a new paradigm of protein secretion in bacteria. A number of bioinformatic studies have been conducted to identify T6SS gene clusters in the available bacterial genome sequences. According to these studies, Salmonella harbors a unique T6SS encoded in the Salmonella Pathogenicity Island 6 (SPI-6). Since these studies only considered few Salmonella genomes, the present work aimed to identify novel T6SS loci by in silico analysis of every genome sequence of Salmonella available.

Results

The analysis of sequencing data from 44 completed or in progress Salmonella genome projects allowed the identification of 3 novel T6SS loci. These clusters are located in differentially-distributed genomic islands we designated SPI-19, SPI-20 and SPI-21, respectively. SPI-19 was identified in a subset of S. enterica serotypes including Dublin, Weltevreden, Agona, Gallinarum and Enteritidis. In the later, an internal deletion eliminated most of the island. On the other hand, SPI-20 and SPI-21 were restricted to S. enterica subspecies arizonae (IIIa) serotype 62:z4,z23:-. Remarkably, SPI-21 encodes a VgrG protein containing a C-terminal extension similar to S-type pyocins of Pseudomonas aeruginosa. This is not only the first evolved VgrG described in Salmonella, but also the first evolved VgrG including a pyocin domain described so far in the literature. In addition, the data indicate that SPI-6 T6SS is widely distributed in S. enterica and absent in serotypes Enteritidis, Gallinarum, Agona, Javiana, Paratyphi B, Virchow, IIIa 62:z4,z23:- and IIIb 61:1,v:1,5,(7). Interestingly, while some serotypes harbor multiple T6SS (Dublin, Weltvreden and IIIa 62:z4,z23:-) others do not encode for any (Enteritidis, Paratyphi B, Javiana, Virchow and IIIb 61:1,v:1,5,(7)). Comparative and phylogenetic analyses indicate that the 4 T6SS loci in Salmonella have a distinct evolutionary history. Finally, we identified an orphan Hcp-like protein containing the Hcp/COG3157 domain linked to a C-terminal extension. We propose to designate this and related proteins as "evolved Hcps".

Conclusion

Altogether, our data suggest that (i) the Salmonella T6SS loci were acquired by independent lateral transfer events and (ii) evolved to contribute in the adaptation of the serotypes to different lifestyles and environments, including animal hosts. Notably, the presence of an evolved VgrG protein related to pyocins suggests a novel role for T6SS in bacterial killing. Future studies on the roles of the identified T6SS loci will expand our knowledge on Salmonella pathogenesis and host specificity.
Genome-wide computational identification of functional RNA elements in Trypanosoma brucei
Authors: Mao Yuan , Najafabadi Hamed Shateri , Salavati Reza
Published: August 2009

Background

Post-transcriptional regulation of gene expression is the dominant regulatory mechanism in trypanosomatids as their mRNAs are transcribed from polycistronic units. A few cis-acting RNA elements in 3'-untranslated regions of mRNAs have been identified in trypanosomatids, which affect the mRNA stability or translation rate in different life stages of these parasites. Other functional RNAs (fRNAs) also play essential roles in these organisms. However, there has been no genome-wide analysis for identification of fRNAs in trypanosomatids.

Results

Functional RNAs, including non-coding RNAs (ncRNAs) and cis-acting RNA elements involved in post-transcriptional gene regulation, were predicted based on two independent computational analyses of the genome of Trypanosoma brucei. In the first analysis, the predicted candidate ncRNAs were identified based on conservation with the related trypanosomatid Leishmania braziliensis. This prediction had a substantially low estimated false discovery rate, and a considerable number of the predicted ncRNAs represented novel classes with unknown functions. In the second analysis, we identified a number of function-specific regulatory motifs, based on which we devised a classifier that can be used for homology-independent function prediction in T. brucei.

Conclusion

This first genome-wide analysis of fRNAs in trypanosomatids restricts the search space of experimental approaches and, thus, can significantly expedite the process of characterization of these elements. Our classifier for function prediction based on cis-acting regulatory elements can also, in combination with other methods, provide the means for homology-independent annotation of trypanosomatid genomes.
Moderate strength (0.23–0.28 T) static magnetic fields (SMF) modulate signaling and differentiation in human embryonic cells
Authors: Wang Zhiyun , Sarje Anshu , Che Pao-Lin , Yarema Kevin J
Published: August 2009

Background

Compelling evidence exists that magnetic fields modulate living systems. To date, however, rigorous studies have focused on identifying the molecular-level biosensor (e.g., radical ion pairs or membranes) or on the behavior of whole animals leaving a gap in understanding how molecular effects are translated into tissue-wide and organism-level responses. This study begins to bridge this gulf by investigating static magnetic fields (SMF) through global mRNA profiling in human embryonic cells coupled with software analysis to identify the affected signaling pathways.

Results

Software analysis of gene expression in cells exposed to 0.23–0.28 T SMF showed that nine signaling networks responded to SMF; of these, detailed biochemical validation was performed for the network linked to the inflammatory cytokine IL-6. We found the short-term (<24 h) activation of IL-6 involved the coordinate up-regulation of toll-like receptor-4 (TLR4) with complementary changes to NEU3 and ST3GAL5 that reduced ganglioside GM3 in a manner that augmented the activation of TLR4 and IL-6. Loss of GM3 also provided a plausible mechanism for the attenuation of cellular responses to SMF that occurred over longer exposure periods. Finally, SMF-mediated responses were manifest at the cellular level as morphological changes and biochemical markers indicative of pre-oligodendrocyte differentiation.

Conclusion

This study provides a framework describing how magnetic exposure is transduced from a plausible molecular biosensor (lipid membranes) to cell-level responses that include differentiation toward neural lineages. In addition, SMF provided a stimulus that uncovered new relationships – that exist even in the absence of magnetic fields – between gangliosides, the time-dependent regulation of IL-6 signaling by these glycosphingolipids, and the fate of embryonic cells.
Comparative genomics in chicken and Pekin duck using FISH mapping and microarray analysis
Authors: Skinner Benjamin M , Robertson Lindsay BW , Tempest Helen G , Langley Elizabeth J , Ioannou Dimitris , Fowler Katie E , Crooijmans Richard PMA , Hall Anthony D , Griffin Darren K , Völker Martin
Published: August 2009

Background

The availability of the complete chicken (Gallus gallus) genome sequence as well as a large number of chicken probes for fluorescent in-situ hybridization (FISH) and microarray resources facilitate comparative genomic studies between chicken and other bird species. In a previous study, we provided a comprehensive cytogenetic map for the turkey (Meleagris gallopavo) and the first analysis of copy number variants (CNVs) in birds. Here, we extend this approach to the Pekin duck (Anas platyrhynchos), an obvious target for comparative genomic studies due to its agricultural importance and resistance to avian flu.

Results

We provide a detailed molecular cytogenetic map of the duck genome through FISH assignment of 155 chicken clones. We identified one inter- and six intrachromosomal rearrangements between chicken and duck macrochromosomes and demonstrated conserved synteny among all microchromosomes analysed. Array comparative genomic hybridisation revealed 32 CNVs, of which 5 overlap previously designated "hotspot" regions between chicken and turkey.

Conclusion

Our results suggest extensive conservation of avian genomes across 90 million years of evolution in both macro- and microchromosomes. The data on CNVs between chicken and duck extends previous analyses in chicken and turkey and supports the hypotheses that avian genomes contain fewer CNVs than mammalian genomes and that genomes of evolutionarily distant species share regions of copy number variation ("CNV hotspots"). Our results will expedite duck genomics, assist marker development and highlight areas of interest for future evolutionary and functional studies.
A proposed syntax for Minimotif Semantics, version 1
Authors: Vyas Jay , Nowling Ronald J , Maciejewski Mark W , Rajasekaran Sanguthevar , Gryk Michael R , Schiller Martin R
Published: August 2009

Background

One of the most important developments in bioinformatics over the past few decades has been the observation that short linear peptide sequences (minimotifs) mediate many classes of cellular functions such as protein-protein interactions, molecular trafficking and post-translational modifications. As both the creators and curators of a database which catalogues minimotifs, Minimotif Miner, the authors have a unique perspective on the commonalities of the many functional roles of minimotifs. There is an obvious usefulness in standardizing functional annotations both in allowing for the facile exchange of data between various bioinformatics resources, as well as the internal clustering of sets of related data elements. With these two purposes in mind, the authors provide a proposed syntax for minimotif semantics primarily useful for functional annotation.

Results

Herein, we present a structured syntax of minimotifs and their functional annotation. A syntax-based model of minimotif function with established minimotif sequence definitions was implemented using a relational database management system (RDBMS). To assess the usefulness of our standardized semantics, a series of database queries and stored procedures were used to classify SH3 domain binding minimotifs into 10 groups spanning 700 unique binding sequences.

Conclusion

Our derived minimotif syntax is currently being used to normalize minimotif covalent chemistry and functional definitions within the MnM database. Analysis of SH3 binding minimotif data spanning many different studies within our database reveals unique attributes and frequencies which can be used to classify different types of binding minimotifs. Implementation of the syntax in the relational database enables the application of many different analysis protocols of minimotif data and is an important tool that will help to better understand specificity of minimotif-driven molecular interactions with proteins.
General and specific responsiveness of the amygdala during explicit emotion recognition in females and males
Authors: Derntl Birgit , Habel Ute , Windischberger Christian , Robinson Simon , Kryspin-Exner Ilse , Gur Ruben C , Moser Ewald
Published: August 2009

Background

The ability to recognize emotions in facial expressions relies on an extensive neural network with the amygdala as the key node as has typically been demonstrated for the processing of fearful stimuli. A sufficient characterization of the factors influencing and modulating amygdala function, however, has not been reached now. Due to lacking or diverging results on its involvement in recognizing all or only certain negative emotions, the influence of gender or ethnicity is still under debate.

This high-resolution fMRI study addresses some of the relevant parameters, such as emotional valence, gender and poser ethnicity on amygdala activation during facial emotion recognition in 50 Caucasian subjects. Stimuli were color photographs of emotional Caucasian and African American faces.

Results

Bilateral amygdala activation was obtained to all emotional expressions (anger, disgust, fear, happy, and sad) and neutral faces across all subjects. However, only in males a significant correlation of amygdala activation and behavioral response to fearful stimuli was observed, indicating higher amygdala responses with better fear recognition, thus pointing to subtle gender differences. No significant influence of poser ethnicity on amygdala activation occurred, but analysis of recognition accuracy revealed a significant impact of poser ethnicity that was emotion-dependent.

Conclusion

Applying high-resolution fMRI while subjects were performing an explicit emotion recognition task revealed bilateral amygdala activation to all emotions presented and neutral expressions. This mechanism seems to operate similarly in healthy females and males and for both in-group and out-group ethnicities. Our results support the assumption that an intact amygdala response is fundamental in the processing of these salient stimuli due to its relevance detecting function.
A meta-analysis of the effect of antibody therapy for the prevention of severe respiratory syncytial virus infection
Authors: Morris Shaun K , Dzolganovski Biljana , Beyene Joseph , Sung Lillian
Published: August 2009

Background

The primary objective of this meta-analytic study was to determine the impact of RSV-IGIV and palivizumab on risk of respiratory syncytial virus (RSV)-related hospitalization. Secondary objectives were to determine if antibody therapy decreases the risk of RSV infection, intensive care admission, mechanical ventilation, and mortality in high risk infant populations.

Methods

We performed searches of electronic data bases from 1966 to April 2009. Inclusion and exclusion criteria were defined a priori. Inclusion criteria were as follows: 1) There was randomization between polyclonal or monoclonal antibodies and placebo or no therapy, and 2) Polyclonal or monoclonal antibodies were given as prophylaxis.

Results

Of the six included studies, three utilized RSV-IGIV (total of 533 randomized to treatment groups) and three utilized palivizumab (total of 1,663 randomized to treatment groups). The absolute risk of hospitalization in the control arms was 12% and overall RR for all 2,196 children who received one of the antibody products was 0.53 (95% CI 0.43, 0.66), P < 0.00001. When looking only at the children who received palivizumab, the RR for hospitalization was 0.50 (95% CI 0.38, 0.66), P < 0.00001. For the children receiving RSV-IGIV, the RR for hospitalization was 0.59 (95% CI 0.42, 0.83, P < 0.002). The use of palivizumab resulted in a significant decrease in admission to the ICU (RR 0.29 (95% CI 0.14, 0.59; P = 0.0007). There was no significant reduction in the risk of mechanical ventilation or mortality with the use of antibody prophylaxis. Infants born at less than 35 weeks gestational age, and those with chronic lung and congenital heart disease all had a significant reduction in the risk of RSV hospitalization with children born under 35 weeks gestational age showing a trend towards the greatest benefit.

Conclusion

Both palivizumab and RSV-IGIV decrease the incidence of RSV hospitalization and ICU admission and their effect appears to be qualitatively similarly. There was neither a statistically significant reduction in the incidence of mechanical ventilation nor in all cause mortality. This meta-analysis separately quantifies the impact of RSV-IGIV and palivizumab on various measures of severe RSV disease and builds upon a previous study that was only able to examine the pooled effect of all antibody products together.
Minimal change nephrotic syndrome in an 82 year old patient following a tetanus-diphteria-poliomyelitis-vaccination
Authors: Clajus Christian , Spiegel Janine , Bröcker Verena , Chatzikyrkou Christos , Kielstein Jan T
Published: August 2009

Background

The most common cause of idiopathic nephrotic syndrome in children and younger adults is the minimal change nephrotic syndrome (MCNS). In the elderly MCNS is relatively uncommon. Over the last decade some reports suggest a rare but possible association with the administration of various vaccines.

Case presentation

A 82-year old Caucasian female presented with pronounced nephrotic syndrome (proteinuria of 7.1 g/d, hypoproteinemia of 47 g/l). About six weeks prior to admission, she had received a combination vaccination for tetanus, diphtheria and poliomyelitis as a booster-vaccination from her general practitioner. The renal biopsy revealed typical minimal change lesions. She responded well to the initiated steroid treatment. As through physical examination as well as extensive laboratory and imaging studies did neither find any evidence for malignancies nor infections we suggest that the minimal change nephrotic syndrome in this patient might be related to the activation of the immune system triggered by the vaccination.

Conclusion

Our case as well as previous anecdotal reports suggests that vaccination and the resulting stimulations of the immune system might cause MCNS and other severe immune-reactions. Increased awareness in that regard might help to expand the database of those cases.
A proteomic strategy to identify novel serum biomarkers for liver cirrhosis and hepatocellular cancer in individuals with fatty liver disease
Authors: Gray Joe , Chattopadhyay Dipankar , Beale Gary S , Patman Gillian L , Miele Luca , King Barry P , Stewart Stephen , Hudson Mark , Day Christopher P , Manas Derek M , Reeves Helen L
Published: August 2009

Background

Non-alcoholic fatty liver disease (NAFLD) has a prevalence of over 20% in Western societies. Affected individuals are at risk of developing both cirrhosis and hepatocellular cancer (HCC). Presently there is no cost effective population based means of identifying cirrhotic individuals and even if there were, our ability to perform HCC surveillance in the at risk group is inadequate. We have performed a pilot proteomic study to assess this as a strategy for serum biomarker detection.

Methods

2D Gel electrophoresis was performed on immune depleted sera from 3 groups of patients, namely those with (1) pre-cirrhotic NAFLD (2) cirrhotic NAFLD and (3) cirrhotic NAFLD with co-existing HCC. Five spots differentiating at least one of these three groups were characterised by mass spectroscopy. An ELISA assay was optimised and a cross sectional study assessing one of these serum spots was performed on serum from 45 patients with steatohepatitis related cirrhosis and HCC and compared to 77 patients with histologically staged steatohepatitis.

Results

Four of the spots identified were apolipoprotein isoforms, the pattern of which was able to differentiate the three groups. The 5th spot, seen in the serum of cirrhotic individuals and more markedly in those with HCC, was identified as CD5 antigen like (CD5L). By ELISA assay, although CD5L was markedly elevated in a number of cirrhotic individuals with HCC, its overall ability to distinguish non-cancer from cancer individuals as determined by AUC ROC analysis was poor. However, serum CD5L was dramatically increased, independently of age, sex, and the presence of necroinflammation, in the serum of individuals with NAFLD cirrhosis relative to those with pre-cirrhotic disease.

Conclusion

This novel proteomic strategy has identified a number of candidate biomarkers which may have benefit in the surveillance and diagnosis of individuals with chronic liver disease and/or HCC.
Coral bleaching under thermal stress: putative involvement of host/symbiont recognition mechanisms
Authors: Vidal-Dupiol Jeremie , Adjeroud Mehdi , Roger Emmanuel , Foure Laurent , Duval David , Mone Yves , Ferrier-Pages Christine , Tambutte Eric , Tambutte Sylvie , Zoccola Didier , Allemand Denis , Mitta Guillaume
Published: August 2009

Background

Coral bleaching can be defined as the loss of symbiotic zooxanthellae and/or their photosynthetic pigments from their cnidarian host. This major disturbance of reef ecosystems is principally induced by increases in water temperature. Since the beginning of the 1980s and the onset of global climate change, this phenomenon has been occurring at increasing rates and scales, and with increasing severity. Several studies have been undertaken in the last few years to better understand the cellular and molecular mechanisms of coral bleaching but the jigsaw puzzle is far from being complete, especially concerning the early events leading to symbiosis breakdown. The aim of the present study was to find molecular actors involved early in the mechanism leading to symbiosis collapse.

Results

In our experimental procedure, one set ofPocillopora damicornisnubbins was subjected to a gradual increase of water temperature from 28°C to 32°C over 15 days. A second control set kept at constant temperature (28°C). The differentially expressed mRNA between the stressed states (sampled just before the onset of bleaching) and the non stressed states (control) were isolated by Suppression Subtractive Hybridization. Transcription rates of the most interesting genes (considering their putative function) were quantified by Q-RT-PCR, which revealed a significant decrease in transcription of two candidates six days before bleaching. RACE-PCR experiments showed that one of them (PdC-Lectin) contained a C-Type-Lectin domain specific for mannose. Immunolocalisation demonstrated that this host gene mediates molecular interactions between the host and the symbionts suggesting a putative role in zooxanthellae acquisition and/or sequestration. The second gene corresponds to a gene putatively involved in calcification processes (Pdcyst-rich). Its down-regulation could reflect a trade-off mechanism leading to the arrest of the mineralization process under stress.

Conclusion

Under thermal stress zooxanthellae photosynthesis leads to intense oxidative stress in the two partners. This endogenous stress can lead to the perception of the symbiont as a toxic partner for the host. Consequently, we propose that the bleaching process is due in part to a decrease in zooxanthellae acquisition and/or sequestration. In addition to a new hypothesis in coral bleaching mechanisms, this study provides promising biomarkers for monitoring coral health.
Adenovector GAD65 Gene Delivery into the Rat Trigeminal Ganglion Produces Orofacial Analgesia
Authors: Vit Jean-Philippe , Ohara Peter T , Sundberg Christopher , Rubi Blanca , Maechler Pierre , Liu Chunyan , Puntel Mariana , Lowenstein Pedro , Castro Maria , Jasmin Luc
Published: August 2009

Background

Our goal is to use gene therapy to alleviate pain by targeting glial cells. In an animal model of facial pain we tested the effect of transfecting the glutamic acid decarboxylase (GAD) gene into satellite glial cells (SGCs) of the trigeminal ganglion by using a serotype 5 adenovector with high tropisms for glial cells. We postulated that GABA produced from the expression of GAD would reduce pain behavior by acting on GABA receptors on neurons within the ganglion.

Results

Injection of adenoviral vectors (AdGAD65) directly into the trigeminal ganglion leads to sustained expression of the GAD65 isoform over the 4 weeks observation period. Immunohistochemical analysis showed that adenovirus-mediated GAD65 expression and GABA synthesis were mainly in SGCs. GABAA and GABAB receptors were both seen in sensory neurons, yet only GABAA receptors decorated the neuronal surface. GABA receptors were not found on SGCs. Six days after injection of AdGAD65 into the trigeminal ganglion, there was a statistically significant decrease of pain behavior in the orofacial formalin test, a model of inflammatory pain. Rats injected with control virus (AdGFP or AdLacZ) had no reduction in their pain behavior. AdGAD65-dependent analgesia was blocked by bicuculline, a selective GABAA receptor antagonist, but not by CGP46381, a selective GABAB receptor antagonist.

Conclusion

Transfection of glial cells in the trigeminal ganglion with the GAD gene blocks pain behavior by acting on GABAA receptors on neuronal perikarya.
Characterization of the human Nα-terminal acetyltransferase B enzymatic complex
Authors: Ametzazurra Amagoia , Gázquez Cristina , Lasa Marta , Larrea Esther , Prieto Jesús , Aldabe Rafael
Published: August 2009

Background

Human Nα-acetyltransferase complex B (hNatB) is integrated by hNaa20p (hNAT5/hNAT3) and hNaa25p (hMDM20) proteins. Previous data have shown that this enzymatic complex is implicated in cell cycle progression and carcinogenesis. In yeast this enzyme acetylates peptides composed by methionine and aspartic acid or glutamic acid in their first two positions respectively and it has been shown the same specificity in human cells.

Methods

We have silenced hNAA20 expression in hepatic cell lines using recombinant adenoviruses that express specific siRNAs against this gene and analyzed cell cycle progression and apoptosis induction after this treatment. Immunopurified hNatB enzymatic complexes from human cell lines were used for analyzing hNatB in vitro enzymatic activity using as substrate peptides predicted to be acetylated by NatB.

Results

hNAA20 silencing in hepatic cell lines reduces cell proliferation in a p53 dependent and independent manner. At the same time this treatment sensitizes the cells to a proapototic stimulus. We have observed that the hNatB complex isolated from human cell lines can acetylate in vitro peptides that present an aspartic or glutamic acid in their second position as has been described in yeast.

Conclusion

hNatB enzymatic complex is implicated in cell cycle progression but it exerts its effects through different mechanisms depending on the cellular characteristics. This is achievable because it can acetylate a great number of peptides composed by an aspartic or glutamic acid at their second residue and therefore it can regulate the activity of a great number of proteins.
cGMP-dependent protein kinase Iα associates with the antidepressant-sensitive serotonin transporter and dictates rapid modulation of serotonin uptake
Authors: Steiner Jennifer A , Carneiro Ana MarinD , Wright Jane , Matthies Heinrich JG , Prasad Harish C , Nicki Christian K , Dostmann Wolfgang R , Buchanan Carrie C , Corbin Jackie D , Francis Sharron H , Blakely Randy D
Published: August 2009

Background

The Na+/Cl--dependent serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is a critical element in neuronal 5-HT signaling, being responsible for the efficient elimination of 5-HT after release. SERTs are not only targets for exogenous addictive and therapeutic agents but also can be modulated by endogenous, receptor-linked signaling pathways. We have shown that neuronal A3 adenosine receptor activation leads to enhanced presynaptic 5-HT transport in vitro and an increased rate of SERT-mediated 5-HT clearance in vivo. SERT stimulation by A3 adenosine receptors derives from an elevation of cGMP and subsequent activation of both cGMP-dependent protein kinase (PKG) and p38 mitogen-activated protein kinase. PKG activators such as 8-Br-cGMP are known to lead to transporter phosphorylation, though how this modification supports SERT regulation is unclear.

Results

In this report, we explore the kinase isoform specificity underlying the rapid stimulation of SERT activity by PKG activators. Using immortalized, rat serotonergic raphe neurons (RN46A) previously shown to support 8-Br-cGMP stimulation of SERT surface trafficking, we document expression of PKGI, and to a lower extent, PKGII. Quantitative analysis of staining profiles using permeabilized or nonpermeabilized conditions reveals that SERT colocalizes with PKGI in both intracellular and cell surface domains of RN46A cell bodies, and exhibits a more restricted, intracellular pattern of colocalization in neuritic processes. In the same cells, SERT demonstrates a lack of colocalization with PKGII in either intracellular or surface membranes. In keeping with the ability of the membrane permeant kinase inhibitor DT-2 to block 8-Br-cGMP stimulation of SERT, we found that DT-2 treatment eliminated cGMP-dependent kinase activity in PKGI-immunoreactive extracts resolved by liquid chromatography. Similarly, treatment of SERT-transfected HeLa cells with small interfering RNAs targeting endogenous PKGI eliminated 8-Br-cGMP-induced regulation of SERT activity. Co-immunoprecipitation studies show that, in transporter/kinase co-transfected cells, PKGIα specifically associates with hSERT.

Conclusion

Our findings provide evidence of a physical and compartmentalized association between SERT and PKGIα that supports rapid, 8-Br-cGMP-induced regulation of SERT. We discuss a model wherein SERT-associated PKGIα supports sequentially the mobilization of intracellular transporter-containing vesicles, leading to enhanced surface expression, and the production of catalytic-modulatory SERT phosphorylation, leading to a maximal enhancement of 5-HT clearance capacity.
Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin
Authors: Coffey Greg P. , Rajapaksa Ranjani , Liu Raymond , Sharpe Orr , Kuo Chiung-Chi , Krauss Sharon Wald , Sagi Yael , Davis R. Eric , Staudt Louis M. , Sharman Jeff P. , Robinson William H. , Levy Shoshana
Published: August 2009

CD81 is a tetraspanin family member involved in diverse cellular interactions in the immune and nervous systems and in cell fusion events. However, the mechanism of action of CD81 and of other tetraspanins has not been defined. We reasoned that identifying signaling molecules downstream of CD81 would provide mechanistic clues. We engaged CD81 on the surface of B-lymphocytes and identified the induced tyrosine-phosphorylated proteins by mass spectrometry. This analysis showed that the most prominent tyrosine phosphorylated protein was ezrin, an actin-binding protein and a member of the ezrin-radixin-moesin family. We also found that CD81 engagement induces spleen tyrosine kinase (Syk) and that Syk was involved in tyrosine phosphorylation of ezrin. After engagement of CD81, it colocalized with ezrin and F-actin, and this association was disrupted when Syk activation was blocked. Taken together, these studies suggest a model in which CD81 interfaces between the plasma membrane and the cytoskeleton by activating Syk, mobilizing ezrin, and recruiting F-actin to facilitate cytoskeletal reorganization and cell signaling. This mechanism might explain the pleiotropic effects induced in response to stimulation of cells by anti-CD81 antibodies or by the hepatitis C virus, which uses this molecule as its key receptor.
Y RNA functions at the initiation step of mammalian chromosomal DNA replication
Authors: Krude Torsten , Christov Christo P. , Hyrien Olivier , Marheineke Kathrin
Published: August 2009

Non-coding Y RNAs have recently been identified as essential novel factors for chromosomal DNA replication in mammalian cell nuclei, but mechanistic details of their function have not been defined. Here, we identify the execution point for Y RNA function during chromosomal DNA replication in a mammalian cell-free system. We determined the effect of degradation of Y3 RNA on replication origin activation and on fork progression rates at single-molecule resolution by DNA combing and nascent-strand analysis. Degradation of Y3 RNA inhibits the establishment of new DNA replication forks at the G1- to S-phase transition and during S phase. This inhibition is negated by addition of exogenous Y1 RNA. By contrast, progression rates of DNA replication forks are not affected by degradation of Y3 RNA or supplementation with exogenous Y1 RNA. These data indicate that Y RNAs are required for the establishment, but not for the elongation, of chromosomal DNA replication forks in mammalian cell nuclei. We conclude that the execution point for non-coding Y RNA function is the activation of chromosomal DNA replication origins.
The primary cilium coordinates early cardiogenesis and hedgehog signaling in cardiomyocyte differentiation
Authors: Clement Christian A. , Kristensen Stine G. , Møllgård Kjeld , Pazour Gregory J. , Yoder Bradley K. , Larsen Lars A. , Christensen Søren T.
Published: August 2009

Defects in the assembly or function of primary cilia, which are sensory organelles, are tightly coupled to developmental defects and diseases in mammals. Here, we investigated the function of the primary cilium in regulating hedgehog signaling and early cardiogenesis. We report that the pluripotent P19.CL6 mouse stem cell line, which can differentiate into beating cardiomyocytes, forms primary cilia that contain essential components of the hedgehog pathway, including Smoothened, Patched-1 and Gli2. Knockdown of the primary cilium by Ift88 and Ift20 siRNA or treatment with cyclopamine, an inhibitor of Smoothened, blocks hedgehog signaling in P19.CL6 cells, as well as differentiation of the cells into beating cardiomyocytes. E11.5 embryos of the Ift88tm1Rpw (Ift88-null) mice, which form no cilia, have ventricular dilation, decreased myocardial trabeculation and abnormal outflow tract development. These data support the conclusion that cardiac primary cilia are crucial in early heart development, where they partly coordinate hedgehog signaling.
The nuclear receptor NHR-25 cooperates with the Wnt/β-catenin asymmetry pathway to control differentiation of the T seam cell inC. elegans
Authors: Hajduskova Martina , Jindra Marek , Herman Michael A. , Asahina Masako
Published: August 2009

Asymmetric cell divisions produce new cell types during animal development. Studies in Caenorhabditis elegans have identified major signal-transduction pathways that determine the polarity of cell divisions. How these relatively few conserved pathways interact and what modulates them to ensure the diversity of multiple tissue types is an open question. The Wnt/β-catenin asymmetry pathway governs polarity of the epidermal T seam cell in the C. elegans tail. Here, we show that the asymmetry of T-seam-cell division and morphogenesis of the male sensory rays require NHR-25, an evolutionarily conserved nuclear receptor. NHR-25 ensures the neural fate of the T-seam-cell descendants in cooperation with the Wnt/β-catenin asymmetry pathway. Loss of NHR-25 enhances the impact of mutated nuclear effectors of this pathway, POP-1 (TCF) and SYS-1 (β-catenin), on T-seam-cell polarity, whereas it suppresses the effect of the same mutations on asymmetric division of the somatic gonad precursor cells. Therefore, NHR-25 can either synergize with or antagonize the Wnt/β-catenin asymmetry pathway depending on the tissue context. Our findings define NHR-25 as a versatile modulator of Wnt/β-catenin-dependent cell-fate decisions.
Structural investigation of InAs nanowires with coherent X-rays
Authors: Chamard V , Diaz A , Stangl J , Labat S
Published: August 2009

Detailed knowledge of the internal structure of nanocrystals is of major importance in order to understand and monitor new physical properties. However, the experimental characterization remains challenging. The development of coherent X-ray sources at third-generation synchrotrons opens new possibilities based on the high sensitivity of the coherent beam with the internal nanocrystal displacement field. This paper aims at illustrating the use of coherent X-ray Bragg diffraction for crystalline defect investigation and lens-less imaging of morphology and strain. The two approaches are used to characterize an InAs nanowire sample. Limits of the method and near-future perspectives are discussed in the framework of strain analysis in nanocrystals.
Dynamic analysis of a heavy duty marine gearbox with gear mesh coupling
Authors: Zhu C-C , Lu B , Song C-S , Qin D-T
Published: August 2009

A three-dimensional finite-element model of a coupled gear—rotor—bearing—housing system is developed by combining the gearbox transmission model with the housing structure model of a heavy duty marine gearbox. The numerical simulation of the dynamic characteristics is performed to analyse the effects of both internal gear meshing and external shaft-related dynamic excitations on the gearbox transmission response. The natural modes, vibration response, and generated noise levels are computed in the simulation process. These results are employed to gain insights into the primary controlling parameters, to forecast the severity of the dynamic response, and to assess the acceptability of the gearbox design. In fact, the proposed modelling approach not only provides a more comprehensive understanding of the heavy duty marine gearbox system, but can also serve as the basis for gear dynamic optimization. To demonstrate the salient features of the proposed simulation model, a specific marine gearbox example is studied in detail. Finally, a vibration experimental study was performed on the marine gearbox system. The vibrations at some locations concerned were monitored and analysed. The experimental vibration and structure noise results compared well with the analytical prediction.
Analytical solution for the buckling of rectangular plates under uni-axial compression with variable thickness and elasticity modulus in the y-direction
Authors: Saeidifar M , Sadeghi S N , Saviz M R
Published: August 2009

The present study introduces a highly accurate numerical calculation of buckling loads for an elastic rectangular plate with variable thickness, elasticity modulus, and density in one direction. The plate has two opposite edges ( x = 0 and a) simply supported and other edges ( y = 0 and b) with various boundary conditions including simply supported, clamped, free, and beam (elastically supported). In-plane normal stresses on two opposite simply supported edges ( x = 0 and a) are not limited to any predefined mathematical equation. By assuming the transverse displacement to vary as sin( mπ x/ a), the governing partial differential equation of plate motion will reduce to an ordinary differential equation in terms of y with variable coefficients, for which an analytical solution is obtained in the form of power series (Frobenius method). Applying the boundary conditions on ( y = 0 and b) yields the problem of finding eigenvalues of a fourth-order characteristic determinant. By retaining sufficient terms in power series, accurate buckling loads for different boundary conditions will be calculated. Finally, the numerical examples have been presented and, in some cases, compared to the relevant numerical results.
An availability analysis of dual-fuel engines at part loads: The effects of pilot fuel quantity on availability terms
Authors: Hosseinzadeh A , Khoshbakhi Saray R
Published: August 2009

It is well known that dual-fuel engines at part load inevitably suffer from lower thermal efficiency and higher emission of carbon monoxide and unburned fuel. A quasi-two-zone combustion model has been developed for studying the second-law analysis of a dual-fuel (diesel-gas) engine operating under part load conditions. This quasi-two-zone combustion model is able to establish the development of combustion process with time and associated important operating parameters, such as pressure, temperature, heat release rate, and species concentration. The present study is an attempt to investigate the combustion phenomenon from the second law point of view at part load and increasing pilot fuel quantity is considered to improve the above-mentioned problems. By employing different quantities of pilot fuel, it is found that increasing the pilot fuel quantity increases the work availability and reduces chemical availability of unburned fuels. Also, the results indicate that, compared to the baseline dual-fuel engine, increasing the pilot fuel quantity in about 12 per cent results in an increase of 23 per cent in availability destruction and 29 per cent in the second law efficiency. This enhancement is due to a better combustion progress and increased indicated work when a high amount of pilot fuel quantity is employed.
Relationship Among Challenging, Repetitive, and Communicative Behaviors in Children With Severe Intellectual Disabilities
Authors: Petty Jane , Allen Debbie , Oliver Chris
Published: August 2009

We used experimental and descriptive functional analyses and lag sequential analyses to examine the functional and temporal relationship among the self-injurious (SIB), potentially injurious, repetitive, challenging, and pragmatic communicative behaviors of 6 children with intellectual disabilities. Functional analyses revealed social function for SIB, potentially injurious, and repetitive behaviors across 5, 4, and 5 participants, respectively. Sixteen functionally equivalent response classes were identified across participants using both experimental and naturalistic observation data. Repetitive, potentially injurious, and SIB behaviors were significantly temporally associated, and pragmatic communicative behaviors were strongly temporally associated with challenging behaviors. The importance of the temporal and functional relationship between imperative communicative acts and challenging behavior is discussed.