bluuebunny/crossref_metadata_2025 huggingface dataset:
Dexamethasone augments CXCR4-mediated signaling in resting human T cells via the activation of the Src kinase Lck
Authors: Ghosh Manik C. , Baatar Dolgor , Collins Gary , Carter Arnell , Indig Fred , Biragyn Arya , Taub Dennis D.
Published: October 2008

Dexamethasone (DM) is a synthetic member of the glucocorticoid (GC) class of hormones that possesses anti-inflammatory and immunosuppressant activity and is commonly used to treat chronic inflammatory disorders, severe allergies, and other disease states. Although GCs are known to mediate well-defined transcriptional effects via GC receptors (GCR), there is increasing evidence that GCs also initiate rapid nongenomic signaling events in a variety of cell types. Here, we report that DM induces the phosphorylation of Lck and the activation of other downstream mediators, including p59Fyn, Zap70, Rac1, and Vav in resting but not activated human T cells. DM treatment also augments CXCL12-mediated signaling in resting T cells through its cell surface receptor, CXCR4 resulting in the enhanced actin polymerization, Rac activation, and cell migration on ligand exposure. Lck was found to be a critical intermediate in these DM-induced signaling activities. Moreover, DM-mediated Lck phosphorylation in T cells was dependent on the presence of both the GCR and the CD45 molecule. Overall, these results elucidate additional nongenomic effects of DM and the GCR on resting human T cells, inducing Lck and downstream kinase activation and augmenting chemokine signaling and function.
The Axl/Gas6 pathway is required for optimal cytokine signaling during human natural killer cell development
Authors: Park Il-Kyoo , Giovenzana Chiara , Hughes Tiffany L. , Yu Jianhua , Trotta Rossana , Caligiuri Michael A.
Published: October 2008

Interleukin-15 (IL-15) is essential for natural killer (NK) cell differentiation. In this study, we assessed whether the receptor tyrosine kinase Axl and its ligand, Gas6, are involved in IL-15–mediated human NK differentiation from CD34+ hematopoietic progenitor cells (HPCs). Blocking the Axl-Gas6 interaction with a soluble Axl fusion protein (Axl-Fc) or the vitamin K inhibitor warfarin significantly diminished the absolute number and percentage of CD3−CD56+ NK cells derived from human CD34+ HPCs cultured in the presence of IL-15, probably resulting in part from reduced phosphorylation of STAT5. In addition, CD3−CD56+ NK cells derived from culture of CD34+ HPCs with IL-15 and Axl-Fc had a significantly diminished capacity to express interferon-γ or its master regulator, T-BET. Culture of CD34+ HPCs in the presence of c-Kit ligand and Axl-Fc resulted in a significant decrease in the frequency of NK precursor cells responding to IL-15, probably the result of reduced c-Kit phosphorylation. Collectively, our data suggest that the Axl/Gas6 pathway contributes to normal human NK-cell development, at least in part via its regulatory effects on both the IL-15 and c-Kit signaling pathways in CD34+ HPCs, and to functional NK-cell maturation via an effect on the master regulatory transcription factor T-BET.
PhySIC_IST: cleaning source trees to infer more informative supertrees
Authors: Scornavacca Celine , Berry Vincent , Lefort Vincent , Douzery Emmanuel JP , Ranwez Vincent
Published: October 2008

Background

Supertree methods combine phylogenies with overlapping sets of taxa into a larger one. Topological conflicts frequently arise among source trees for methodological or biological reasons, such as long branch attraction, lateral gene transfers, gene duplication/loss or deep gene coalescence. When topological conflicts occur among source trees, liberal methods infer supertrees containing the most frequent alternative, while veto methods infer supertrees not contradicting any source tree, i.e. discard all conflicting resolutions. When the source trees host a significant number of topological conflicts or have a small taxon overlap, supertree methods of both kinds can propose poorly resolved, hence uninformative, supertrees.

Results

To overcome this problem, we propose to infer non-plenary supertrees, i.e. supertrees that do not necessarily contain all the taxa present in the source trees, discarding those whose position greatly differs among source trees or for which insufficient information is provided. We detail a variant of the PhySIC veto method called PhySIC_IST that can infer non-plenary supertrees. PhySIC_IST aims at inferring supertrees that satisfy the same appealing theoretical properties as with PhySIC, while being as informative as possible under this constraint. The informativeness of a supertree is estimated using a variation of the CIC (Cladistic Information Content) criterion, that takes into account both the presence of multifurcations and the absence of some taxa. Additionally, we propose a statistical preprocessing step called STC (Source Trees Correction) to correct the source trees prior to the supertree inference. STC is a liberal step that removes the parts of each source tree that significantly conflict with other source trees. Combining STC with a veto method allows an explicit trade-off between veto and liberal approaches, tuned by a single parameter.

Performing large-scale simulations, we observe that STC+PhySIC_IST infers much more informative supertrees than PhySIC, while preserving low type I error compared to the well-known MRP method. Two biological case studies on animals confirm that the STC preprocess successfully detects anomalies in the source trees while STC+PhySIC_IST provides well-resolved supertrees agreeing with current knowledge in systematics.

Conclusion

The paper introduces and tests two new methodologies, PhySIC_IST and STC, that demonstrate the interest in inferring non-plenary supertrees as well as preprocessing the source trees. An implementation of the methods is available at: http://www.atgc-montpellier.fr/physic_ist/.
Pol II promoter prediction using characteristic 4-mer motifs: a machine learning approach
Authors: Anwar Firoz , Baker Syed Murtuza , Jabid Taskeed , Mehedi Hasan Md , Shoyaib Mohammad , Khan Haseena , Walshe Ray
Published: October 2008

Background

Eukaryotic promoter prediction using computational analysis techniques is one of the most difficult jobs in computational genomics that is essential for constructing and understanding genetic regulatory networks. The increased availability of sequence data for various eukaryotic organisms in recent years has necessitated for better tools and techniques for the prediction and analysis of promoters in eukaryotic sequences. Many promoter prediction methods and tools have been developed to date but they have yet to provide acceptable predictive performance. One obvious criteria to improve on current methods is to devise a better system for selecting appropriate features of promoters that distinguish them from non-promoters. Secondly improved performance can be achieved by enhancing the predictive ability of the machine learning algorithms used.

Results

In this paper, a novel approach is presented in which 128 4-mer motifs in conjunction with a non-linear machine-learning algorithm utilising a Support Vector Machine (SVM) are used to distinguish between promoter and non-promoter DNA sequences. By applying this approach to plant, Drosophila, human, mouse and rat sequences, the classification model has showed 7-fold cross-validation percentage accuracies of 83.81%, 94.82%, 91.25%, 90.77% and 82.35% respectively. The high sensitivity and specificity value of 0.86 and 0.90 for plant; 0.96 and 0.92 for Drosophila; 0.88 and 0.92 for human; 0.78 and 0.84 for mouse and 0.82 and 0.80 for rat demonstrate that this technique is less prone to false positive results and exhibits better performance than many other tools. Moreover, this model successfully identifies location of promoter using TATA weight matrix.

Conclusion

The high sensitivity and specificity indicate that 4-mer frequencies in conjunction with supervised machine-learning methods can be beneficial in the identification of RNA pol II promoters comparative to other methods. This approach can be extended to identify promoters in sequences for other eukaryotic genomes.
Prediction of evolutionarily conserved interologs in Mus musculus
Authors: Yellaboina Sailu , Dudekula Dawood B , Ko Minoru SH
Published: October 2008

Background

Identification of protein-protein interactions is an important first step to understand living systems. High-throughput experimental approaches have accumulated large amount of information on protein-protein interactions in human and other model organisms. Such interaction information has been successfully transferred to other species, in which the experimental data are limited. However, the annotation transfer method could yield false positive interologs due to the lack of conservation of interactions when applied to phylogenetically distant organisms.

Results

To address this issue, we used phylogenetic profile method to filter false positives in interologs based on the notion that evolutionary conserved interactions show similar patterns of occurrence along the genomes. The approach was applied to Mus musculus, in which the experimentally identified interactions are limited. We first inferred the protein-protein interactions in Mus musculus by using two approaches: i) identifying mouse orthologs of interacting proteins (interologs) based on the experimental protein-protein interaction data from other organisms; and ii) analyzing frequency of mouse ortholog co-occurrence in predicted operons of bacteria. We then filtered possible false-positives in the predicted interactions using the phylogenetic profiles. We found that this filtering method significantly increased the frequency of interacting protein-pairs coexpressed in the same cells/tissues in gene expression omnibus (GEO) database as well as the frequency of interacting protein-pairs shared the similar Gene Ontology (GO) terms for biological processes and cellular localizations. The data supports the notion that phylogenetic profile helps to reduce the number of false positives in interologs.

Conclusion

We have developed protein-protein interaction database in mouse, which contains 41109 interologs. We have also developed a web interface to facilitate the use of database http://lgsun.grc.nia.nih.gov/mppi/.
RNAi-directed downregulation of OsBADH2 results in aroma (2-acetyl-1-pyrroline) production in rice (Oryza sativa L.)
Authors: Niu Xiangli , Tang Wei , Huang Weizao , Ren Guangjun , Wang Qilin , Luo Di , Xiao Yingyong , Yang Shimei , Wang Feng , Lu Bao-Rong , Gao Fangyuan , Lu Tiegang , Liu Yongsheng
Published: October 2008

Background

Aromatic rice is popular worldwide because of its characteristic fragrance. Genetic studies and physical fine mapping reveal that a candidate gene (fgr/OsBADH2) homologous to betaine aldehyde dehydrogenase is responsible for aroma metabolism in fragrant rice varieties, but the direct evidence demonstrating the functions of OsBADH2 is lacking. To elucidate the physiological roles of OsBADH2, sequencing approach and RNA interference (RNAi) technique were employed to analyze allelic variation and functions of OsBADH2 gene in aroma production. Semi-quantitative, real-time reverse transcription-polymerase chain reaction (RT-PCR), as well as gas chromatography-mass spectrometry (GC-MS) were conducted to determine the expression levels of OsBADH2 and the fragrant compound in wild type and transgenic OsBADH2-RNAi repression lines, respectively.

Results

The results showed that multiple mutations identical to fgr allele occur in the 13 fragrant rice accessions across China; OsBADH2 is expressed constitutively, with less expression abundance in mature roots; the disrupted OsBADH2 by RNA interference leads to significantly increased 2-acetyl-1-pyrroline production.

Conclusion

We have found that the altered expression levels of OsBADH2 gene influence aroma accumulation, and the prevalent aromatic allele probably has a single evolutionary origin.
Upregulated HSP27 in human breast cancer cells reduces Herceptin susceptibility by increasing Her2 protein stability
Authors: Kang Se Hun , Kang Keon Wook , Kim Kyung-Hee , Kwon Bumi , Kim Seok-Ki , Lee Ho-Young , Kong Sun-Young , Lee Eun Sook , Jang Sang-Geun , Yoo Byong Chul
Published: October 2008

Background

Elucidating the molecular mechanisms by which tumors become resistant to Herceptin is critical for the treatment of Her2-overexpressed metastatic breast cancer.

Methods

To further understand Herceptin resistance mechanisms at the molecular level, we used comparative proteome approaches to analyze two human breast cancer cell lines; Her2-positive SK-BR-3 cells and its Herceptin-resistant SK-BR-3 (SK-BR-3 HR) cells.

Results

Heat-shock protein 27 (HSP27) expression was shown to be upregulated in SK-BR-3 HR cells. Suppression of HSP27 by specific siRNA transfection increased the susceptibility of SK-BR-3 HR cells to Herceptin. In the presence of Herceptin, Her2 was downregulated in both cell lines. However, Her2 expression was reduced by a greater amount in SK-BR-3 parent cells than in SK-BR-3 HR cells. Interestingly, co-immunoprecipitation analysis showed that HSP27 can bind to Her2. In the absence of Herceptin, HSP27 expression is suppressed and Her2 expression is reduced, indicating that downregulation of Her2 by Herceptin can be obstructed by the formation of a Her2-HSP27 complex.

Conclusion

Our present study demonstrates that upregulated HSP27 in human breast cancer cells can reduce Herceptin susceptibility by increasing Her2 protein stability.
A construct with fluorescent indicators for conditional expression of miRNA
Authors: Qiu Linghua , Wang Hongyan , Xia Xugang , Zhou Hongxia , Xu Zuoshang
Published: October 2008

Background

Transgenic RNAi holds promise as a simple, low-cost, and fast method for reverse genetics in mammals. It may be particularly useful for producing animal models for hypomorphic gene function. Inducible RNAi that permits spatially and temporally controllable gene silencing in vivo will enhance the power of transgenic RNAi approach. Furthermore, because microRNA (miRNA) targeting specific genes can be expressed simultaneously with protein coding genes, incorporation of fluorescent marker proteins can simplify the screening and analysis of transgenic RNAi animals.

Results

We sought to optimally express a miRNA simultaneously with a fluorescent marker. We compared two construct designs. One expressed a red fluorescent protein (RFP) and a miRNA placed in its 3' untranslated region (UTR). The other expressed the same RFP and miRNA, but the precursor miRNA (pre-miRNA) coding sequence was placed in an intron that was inserted into the 3'-UTR. We found that the two constructs expressed comparable levels of miRNA. However, the intron-containing construct expressed a significantly higher level of RFP than the intron-less construct. Further experiments indicate that the 3'-UTR intron enhances RFP expression by its intrinsic gene-expression-enhancing activity and by eliminating the inhibitory effect of the pre-miRNA on the expression of RFP. Based on these findings, we incorporated the intron-embedded pre-miRNA design into a conditional expression construct that employed the Cre-loxP system. This construct initially expressed EGFP gene, which was flanked by loxP sites. After exposure to Cre recombinase, the transgene stopped EGFP expression and began expression of RFP and a miRNA, which silenced the expression of specific cellular genes.

Conclusion

We have designed and tested a conditional miRNA-expression construct and showed that this construct expresses both the marker genes strongly and can silence the target gene efficiently upon Cre-mediated induction of the miRNA expression. This construct can be used to increase the efficiency of making cell lines or transgenic animals that stably express miRNA targeting specific genes.
Down-regulation of DNMT3b in PC3 cells effects locus-specific DNA methylation, and represses cellular growth and migration
Authors: Yaqinuddin Ahmed , Qureshi Sohail A , Qazi Romena , Abbas Farhat
Published: October 2008

Background

Aberrations in DNA methylation patterns promote changes in gene expression patterns and are invariably associated with neoplasia. DNA methylation is carried out and maintained by several DNA methyltransferases (DNMTs) among which DNMT1 functions as a maintenance methylase while DNMT3a and 3b serve as de novo enzymes. Although DNMT3b has been shown to preferentially target the methylation of DNA sequences residing in pericentric heterochromatin whether it is involved in gene specific methylation remains an open question. To address this issue, we have silenced the expression of DNMT3b in the prostate-derived PC3 cells through RNA interference and subsequently studied the accompanied cellular changes as well as the expression profiles of selected genes.

Results

Our results demonstrate that DNMT3b depletion results in increased apoptosis and reduced migration of PC3 cells compared to the untransfected control cells. Reduced DNMT3b expression resulted in hypomethylation of retinoblastoma (Rb), retinoic-acid receptor β (RAR-β), and adenomatous polyposis coli (APC) gene promoters, and also culminated in increased expression of CDKN3 and cytochrome b5. Although DNMT3b silenced cells were found to have reduced growth and migratory potential, there was no apparent changes in their invasive ability compared to the parental PC3 cell line.

Conclusion

Our findings reveal that DNMT3b preferentially targets certain gene promoters in PC3 cells and that its depletion significantly reduces growth and migration of PC3 cells.
Lentivirus-mediated RNAi silencing targeting ABCC2 increasing the sensitivity of a human nasopharyngeal carcinoma cell line against cisplatin
Authors: Xie Si Ming , Fang Wei Yi , Liu Zhen , Wang Shuang Xi , Li Xin , Liu Teng Fei , Xie Wei Bing , Yao Kai Tai
Published: October 2008

Background

High resistance to drug is taken as a characteristic of human tumors, which is usually mediated by multidrug resistance-associated genes. ABCC2, an ATP-binding cassette multidrug resistance transporter, is found to be expressed in a variety of human cancers. In this study the effect of a RNAi construct targeting ABCC2 on the chemosensitivity of NPC cell line CNE2 against cisplatin was investigated.

Methods

Lentiviral vectors were constructed to allow an efficient expression of anti-ABCC2 siRNA. The effective target sequence comprised nucleotides 1707–1727 of the human ABCC2 mRNA. The cell clones expressing the construct were picked and expanded, followed by identification using qRT-PCR and western blot method. As control, lentiviral vector containing invalid RNAi sequence was transfected to CNE2 cells.In vitro, cellular accumulation of cisplatin was detected by HPLC. The capacity of cellular growth and sensitivity of cells against cisplatin were detected by MTT assay.In vivo, the sensitivity of the tumor tissues against cisplatin were evaluated by transplanted CNE2 nude mice model.

Results

Two CNE2 cell clones with reduced expression of targeted ABCC2 mRNA and protein for more than 70% by qRT-PCR and western blot were established, and no differences were shown in proliferation rates compared to control CNE2 cells by growth curves analysis.In vitrothe accumulation of intracellular cisplatin in these CNE2 cell clones with reduced expression of ABCC2 increased markedly, accompanied by increased sensitivity against cisplatin.In vivo, the growth of CNE2 solid tumors with a stably transfected anti-ABCC2 siRNA construct was significantly inhibited by cisplatin in transplanted nude mice model.

Conclusion

Our investigation demonstrated that lentivirus-mediated RNAi silencing targeting ABCC2 might reverse the ABCC2-related drug resistance of NPC cell line CNE2 against cisplatin.
A new family of polymerases related to superfamily A DNA polymerases and T7-like DNA-dependent RNA polymerases
Authors: Iyer Lakshminarayan M , Abhiman Saraswathi , Aravind L
Published: October 2008

Using sequence profile methods and structural comparisons we characterize a previously unknown family of nucleic acid polymerases in a group of mobile elements from genomes of diverse bacteria, an algal plastid and certain DNA viruses, including the recently reported Sputnik virus. Using contextual information from domain architectures and gene-neighborhoods we present evidence that they are likely to possess both primase and DNA polymerase activity, comparable to the previously reported prim-pol proteins. These newly identified polymerases help in defining the minimal functional core of superfamily A DNA polymerases and related RNA polymerases. Thus, they provide a framework to understand the emergence of both DNA and RNA polymerization activity in this class of enzymes. They also provide evidence that enigmatic DNA viruses, such as Sputnik, might have emerged from mobile elements coding these polymerases.

Reviewers

This article was reviewed by Eugene Koonin and Mark Ragan.
Diverse histologic appearances in pulmonary mucinous cystic neoplasia: A case report
Authors: Wynveen Christine , Behmaram Behnaz , Haasler George , Rao Nagarjun
Published: October 2008

Introduction

Primary pulmonary mucinous cystic neoplasia comprises a group of tumors, from benign cystadenoma to mucinous cystadenocarcinoma.

Case presentation

We report a case of primary pulmonary mucinous cystadenocarcinoma in a 75-year-old woman who was found to have a right hilar mass on a routine chest X-ray. A lobectomy was performed and the resection specimen revealed a multicystic mucinous tumor. Microscopically, the tumor was composed of confluent mucin-filled cystic spaces lined by columnar mucin-secreting cells which ranged from cytologically bland to moderately atypical with 'bronchioloalveolar pattern' invasion into the adjacent parenchyma. Immunohistochemically, tumor cells were positive diffusely for Cytokeratin 7, and focally for Cytokeratin 20 and Thyroid Transcription Factor-1.

Conclusion

This case highlights the continuous spectrum of pulmonary mucinous cystic neoplasia from benign mucinous cystadenoma to malignant mucinous cystadenocarcinoma, and the probable existence of a 'borderline' mucinous cystic tumor. Although molecular data are lacking to substantiate progression from benign to malignant in these neoplasms, the importance of recognizing the morphologic continuum lies in alerting pathologists to thoroughly examine specimens to rule out invasive foci in tumors with 'borderline' morphology.
Erratum to: Lutzomyia longipalpis s.l. in Brazil and the impact of the Sao Francisco River in the speciation of this sand fly vector
Authors: Coutinho-Abreu Iliano V , Sonoda Ivan V , Fonseca Jose A , Melo Marcia A , Balbino Valdir Q , Ramalho-Ortigão Marcelo
Published: October 2008

In our recently published article "Lutzomyia longipalpis s.l. in Brazil and the impact of the Sao Francisco River in the speciation of this sand fly vector" by Iliano V. Coutinho-Abreu et al. a sentence located in paragraph 8 in the Discussion section had its meaning altered due to the improper insertion of three words.
Takotsubo cardiomyopathy associated with anesthesia: three case reports
Authors: Littlejohn F Craig , Syed Omar , Ornstein Eugene , Connolly E Sander , Heyer Eric J
Published: October 2008

Takotsubo cardiomyopathy is a form of transient, reversible left ventricular dysfunction that can mimic an acute coronary event. However, cardiac catheterization often reveals normal coronary arteries. Patients are often postmenopausal women who experience acute physical or emotional distress. The prognosis for this entity is quite favorable. In this report, we present three cases of Takotsubo cardiomyopathy in patients having procedures involving anesthesia. Each case illustrates a different etiology for the syndrome: Patient, procedure, and anesthetic management.
Necrotizing fasciitis with toxic shock syndrome in a child: a case report and review of literature
Authors: Abass Kotb , Saad Hekma , Abd-Elsayed Alaa A
Published: October 2008

Introduction

Necrotizing fasciitis was described as early as the fifth century BC. It showed an increased incidence worldwide in the past several years.

Case presentation

An 8-year-old Arabian boy was referred for admission as a case of cellulitis of the left thigh. Ten days prior to admission he had a cat scratch to his left thigh and the parents did not seek medical advice at that time. The child was again examined by orthopedic surgeon and a diagnosis of cellulites was made at that time.

Physical examination on admission revealed a very toxic appearing weak child with cold extremities and poor peripheral perfusion.

Examination of the left thigh revealed extensive swelling, induration and edema with dusky skin, blistering and bleb formation, in addition to an area of gangrenous skin. Laboratory investigation revealed white blood cell count of 22,400 × 109 with toxic granulation on peripheral blood smear.

The child was admitted to the pediatric intensive care unit and dopamine and dobutamine infusions were started after volume expansion. Penicillin and clindamycin also were started in addition to multiple transfusions of fresh frozen plasma. Surgical debridement of all necrotic tissues and drainage of involved fascia planes via extensive fasciotomy were done for our patient after stabilization of his vital signs and improvement of his general condition.

Blood cultures grew group A streptococcus, as did wound swab culture.

The child showed great improvements in his clinical condition after the 3rd day of antibiotics and supportive treatment and the wound healed normally and antibiotics were administered for 21 days.

Conclusion

Necrotizing fasciitis in children is a frequently misdiagnosed condition; early identification of the necrotizing process can improve the outcome of this life-threatening disease. Surgical debridement and antibiotics were the most important therapeutic measures.
Variations in the transcriptome of Alzheimer's disease reveal molecular networks involved in cardiovascular diseases
Authors: Ray Monika , Ruan Jianhua , Zhang Weixiong
Published: October 2008

Background

Because of its polygenic nature, Alzheimer's disease is believed to be caused not by defects in single genes, but rather by variations in a large number of genes and their complex interactions. A systems biology approach, such as the generation of a network of co-expressed genes and the identification of functional modules and cis-regulatory elements, to extract insights and knowledge from microarray data will lead to a better understanding of complex diseases such as Alzheimer's disease. In this study, we perform a series of analyses using co-expression networks, cis-regulatory elements, and functions of co-expressed gene modules to analyze single-cell gene expression data from normal and Alzheimer's disease-affected subjects.

Results

We identified six co-expressed gene modules, each of which represented a biological process perturbed in Alzheimer's disease. Alzheimer's disease-related genes, such as APOE, A2M, PON2 and MAP4, and cardiovascular disease-associated genes, including COMT, CBS and WNK1, all congregated in a single module. Some of the disease-related genes were hub genes while many of them were directly connected to one or more hub genes. Further investigation of this disease-associated module revealed cis-regulatory elements that match to the binding sites of transcription factors involved in Alzheimer's disease and cardiovascular disease.

Conclusion

Our results show the extensive links between Alzheimer's disease and cardiovascular disease at the co-expression and co-regulation levels, providing further evidence for the hypothesis that cardiovascular disease and Alzheimer's disease are linked. Our results support the notion that diseases in which the same set of biochemical pathways are affected may tend to co-occur with each other.
Prostaglandin H2 induces the migration of human eosinophils through the chemoattractant receptor homologous molecule of Th2 cells, CRTH2
Authors: Schuligoi Rufina , Sedej Miriam , Waldhoer Maria , Vukoja Anela , Sturm Eva M , Lippe Irmgard T , Peskar Bernhard A , Heinemann Akos
Published: October 2008

The major mast cell product PGD2 is released during the allergic response and stimulates the chemotaxis of eosinophils, basophils, and Th2-type T lymphocytes. The chemoattractant receptor homologous molecule of Th2 cells (CRTH2) has been shown to mediate the chemotactic effect of PGD2. PGH2 is the common precursor of all PGs and is produced by several cells that express cyclooxygenases. In this study, we show that PGH2 selectively stimulates human peripheral blood eosinophils and basophils but not neutrophils, and this effect is prevented by the CRTH2 receptor antagonist (+)-3-[[(4-fluorophenyl)sulfonyl] methyl amino]-1,2,3,4-tetrahydro-9H-carbazole-9-acetic acid (Cay10471) but not by the hematopoietic PGD synthase inhibitor 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL79). In chemotaxis assays, eosinophils showed a pronounced migratory response toward PGH2, but eosinophil degranulation was inhibited by PGH2. Moreover, collagen-induced platelet aggregation was inhibited by PGH2 in platelet-rich plasma, which was abrogated in the presence of the D-type prostanoid (DP) receptor antagonist 3-[(2-cyclohexyl-2-hydroxyethyl)amino]-2,5-dioxo-1-(phenylmethyl)-4-imidazolidine-heptanoic acid (BWA868c). Each of these effects of PGH2 was enhanced in the presence of plasma and/or albumin. In eosinophils, PGH2-induced calcium ion (Ca2+) flux was subject to homologous desensitization with PGD2. Human embryo kidney (HEK)293 cells transfected with human CRTH2 or DP likewise responded with Ca2+ flux, and untransfected HEK293 cells showed no response. These data indicate that PGH2 causes activation of the PGD2 receptors CRTH2 and DP via a dual mechanism: by interacting directly with the receptors and/or by giving rise to PGD2 after catalytic conversion by plasma proteins.
Vitamin D and Human Health: Lessons from Vitamin D Receptor Null Mice
Authors: Bouillon Roger , Carmeliet Geert , Verlinden Lieve , van Etten Evelyne , Verstuyf Annemieke , Luderer Hilary F. , Lieben Liesbet , Mathieu Chantal , Demay Marie
Published: October 2008

The vitamin D endocrine system is essential for calcium and bone homeostasis. The precise mode of action and the full spectrum of activities of the vitamin D hormone, 1,25-dihydroxyvitamin D [1,25-(OH)2D], can now be better evaluated by critical analysis of mice with engineered deletion of the vitamin D receptor (VDR). Absence of a functional VDR or the key activating enzyme, 25-OHD-1α-hydroxylase (CYP27B1), in mice creates a bone and growth plate phenotype that mimics humans with the same congenital disease or severe vitamin D deficiency. The intestine is the key target for the VDR because high calcium intake, or selective VDR rescue in the intestine, restores a normal bone and growth plate phenotype.

The VDR is nearly ubiquitously expressed, and almost all cells respond to 1,25-(OH)2D exposure; about 3% of the mouse or human genome is regulated, directly and/or indirectly, by the vitamin D endocrine system, suggesting a more widespread function. VDR-deficient mice, but not vitamin D- or 1α-hydroxylase-deficient mice, and man develop total alopecia, indicating that the function of the VDR and its ligand is not fully overlapping. The immune system of VDR- or vitamin D-deficient mice is grossly normal but shows increased sensitivity to autoimmune diseases such as inflammatory bowel disease or type 1 diabetes after exposure to predisposing factors. VDR-deficient mice do not have a spontaneous increase in cancer but are more prone to oncogene- or chemocarcinogen-induced tumors. They also develop high renin hypertension, cardiac hypertrophy, and increased thrombogenicity. Vitamin D deficiency in humans is associated with increased prevalence of diseases, as predicted by the VDR null phenotype. Prospective vitamin D supplementation studies with multiple noncalcemic endpoints are needed to define the benefits of an optimal vitamin D status.
Once-Monthly Oral Ibandronate Improves Biomechanical Determinants of Bone Strength in Women with Postmenopausal Osteoporosis
Authors: Lewiecki E. Michael , Keaveny Tony M. , Kopperdahl David L. , Genant Harry K. , Engelke Klaus , Fuerst Thomas , Kivitz Alan , Davies Richard Y. , Fitzpatrick Lorraine A.
Published: October 2008

Context: Bone strength and fracture resistance are determined by bone mineral density (BMD) and structural, mechanical, and geometric properties of bone.

Design, Setting, and Objectives: This randomized, double-blind, placebo-controlled outpatient study evaluated effects of once-monthly oral ibandronate on hip and lumbar spine BMD and calculated strength using quantitative computed tomography (QCT) with finite element analysis (FEA) and dual-energy x-ray absorptiometry (DXA) with hip structural analysis (HSA).

Participants: Participants were women aged 55–80 yr with BMD T-scores −2.0 or less to −5.0 or greater (n = 93).

Intervention: Oral ibandronate 150 mg/month (n = 47) or placebo (n = 46) was administered for 12 months.

Outcome Measures: The primary end point was total hip QCT BMD change from baseline; secondary end points included other QCT BMD sites, FEA, DXA, areal BMD, and HSA. All analyses were exploratory, with post hoc P values.

Results: Ibandronate increased integral total hip QCT BMD and DXA areal BMD more than placebo at 12 months (treatment differences: 2.2%, P = 0.005; 2.0%, P = 0.003). FEA-derived hip strength to density ratio and femoral, peripheral, and trabecular strength increased with ibandronate vs. placebo (treatment differences: 4.1%, P < 0.001; 5.9%, P < 0.001; 2.5%, P = 0.011; 3.5%, P = 0.003, respectively). Ibandronate improved vertebral, peripheral, and trabecular strength and anteroposterior bending stiffness vs. placebo [7.1% (P < 0.001), 7.8% (P < 0.001), 5.6% (P = 0.023), and 6.3% (P < 0.001), respectively]. HSA-estimated femoral narrow neck cross-sectional area and moment of inertia and outer diameter increased with ibandronate vs. placebo (respectively 3.6%, P = 0.003; 4.0%, P = 0.052; 2.2%, P = 0.049).

Conclusions: Once-monthly oral Ibandronate for 12 months improved hip and spine BMD measured by QCT and DXA and strength estimated by FEA of QCT scans.
Being Like a State: A Historical Anthropology of Translocal Representation (in Both Senses of the Term)
Authors: Watanabe John M.
Published: October 2008

This commentary addresses issues of representation in its delegative and political as well as sign-making senses intrinsic to bottom-up histories of state power and the meanings such power precipitates. Brokers as representatives in a political sense ideally reveal the dynamics, but also limits, of state power because, as Eric Wolf noted long ago, brokers by definition never work simply to resolve the contending interests they mediate but must also perpetuate them if they want to retain their own strategic positions. At the same time, in ethnically stratified societies such as Mexico and Guatemala, brokers also often come to represent in a semiotic sense the very oppositions they seek to negotiate through their literal embodiment of the affinities and antipathies that their relations with those above and those below help to institutionalize. Teasing out these political dynamics and ethnic images requires careful attention to institutional structures and the construction of national, ethnic, and ultimately inter-individual identities, as well as to events in real (that is, document-based) historical time. Methodologically, the writing of such cultural histories of power thus entails not necessarily privileging ethnographic “structure” or historical “event,” but rather developing (often ethnographically derived) conceptual models to guide inquiry into historical documents.
The regulation of salt transport and blood pressure by the WNK-SPAK/OSR1 signalling pathway
Authors: Richardson Ciaran , Alessi Dario R.
Published: October 2008

It has recently been shown that the WNK [with-no-K(Lys)] kinases (WNK1, WNK2, WNK3 and WNK4) have vital roles in the control of salt homeostasis and blood pressure. This Commentary focuses on recent findings that have uncovered the backbone of a novel signal-transduction network that is controlled by WNK kinases. Under hyperosmotic or hypotonic low-Cl– conditions, WNK isoforms are activated, and subsequently phosphorylate and activate the related protein kinases SPAK and OSR1. SPAK and OSR1 phosphorylate and activate ion co-transporters that include NCC, NKCC1 and NKCC2, which are targets for the commonly used blood-pressure-lowering thiazide-diuretic and loop-diuretic drugs. The finding that mutations in WNK1, WNK4, NCC and NKCC2 cause inherited blood-pressure syndromes in humans highlights the importance of these enzymes. We argue that these new findings indicate that SPAK and OSR1 are promising drug targets for the treatment of hypertension, because inhibiting these enzymes would reduce NCC and NKCC2 activity and thereby suppress renal salt re-absorption. We also discuss unresolved and controversial questions in this field of research.
The protein tyrosine phosphatase TCPTP controls VEGFR2 signalling
Authors: Mattila Elina , Auvinen Kaisa , Salmi Marko , Ivaska Johanna
Published: October 2008

Vascular endothelial growth factor (VEGF) is a major angiogenic factor that triggers formation of new vessels under physiological and pathological conditions. However, the mechanisms that limit the VEGF responses in target cells and hence prevent excessive and harmful angiogenesis are not well understood. Here, our objective was to study whether T-cell protein tyrosine phosphatase (TCPTP, also known as PTN2), which we found to be expressed in human endothelial cells, could alter VEGF signalling by controlling phosphorylation of VEGFR2. We show that a TCPTP substrate-trapping mutant interacts with VEGFR2. Moreover, TCPTP dephosphorylates VEGFR2 in a phosphosite-specific manner, inhibits its kinase activity and prevents its internalization from the cell surface. We found that TCPTP activity is induced upon integrin-mediated binding of endothelial cells to collagen matrix. TCPTP activation was also induced by using cell-permeable peptides from the cytoplasmic tail of the collagen-binding integrin α1. Controlled activation of TCPTP results in inhibition of VEGF-triggered endothelial cell proliferation, angiogenic sprouting, chemokinesis and chemotaxis. We conclude that matrix-controlled TCPTP phosphatase activity can inhibit VEGFR2 signalling, and the growth, migration and differentiation of human endothelial cells.
Real-Time Evaluation of E-mail Campaign Performance
Authors: Bonfrer André , Drèze Xavier
Published: October 2008

We develop a testing methodology that can be used to predict the performance of e-mail marketing campaigns in real time. We propose a split-hazard model that makes use of a time transformation (a concept we call virtual time) to allow for the estimation of straightforward parametric hazard functions and generate early predictions of an individual campaign's performance (as measured by open and click propensities). We apply this pretesting methodology to 25 e-mail campaigns and find that the method is able to produce in an hour and fifteen minutes estimates that are more accurate and more reliable than those that the traditional method (doubling time) produces after 14 hours. Other benefits of our method are that we make testing independent of the time of day and we produce meaningful confidence intervals. Thus, our methodology can be used not only for testing purposes, but also for live monitoring. The testing procedure is coupled with a formal decision theoretic framework to generate a sequential testing procedure useful for the real time evaluation of campaigns.
The Value of Component Commonality in a Dynamic Inventory System with Lead Times
Authors: Song Jing-Sheng , Zhao Yao
Published: October 2008

Component commonality has been widely recognized as a key factor in achieving product variety at low cost. Yet the theory on the value of component commonality is rather limited in the inventory literature. The existing results were built primarily on single-period models or periodic-review models with zero lead times. In this paper, we consider a continuous-review system with positive lead times. We find that although component commonality is in general beneficial, its value depends strongly on component costs, lead times, and dynamic allocation rules. Under certain conditions, several previous findings based on static models do not hold. In particular, component commonality does not always generate inventory benefits under certain commonly used allocation rules. We provide insight on when component commonality generates inventory benefits and when it may not. We further establish some asymptotic properties that connect component lead times and costs to the impact of component commonality. Through numerical studies, we demonstrate the value of commonality and its sensitivity to various system parameters in between the asymptotic limits. In addition, we show how to evaluate the system under a new allocation rule, a modified version of the standard first-in-first-out rule.
Physiological responses of the alga Cyclotella caspia to bisphenol A exposure
Authors: Li Rui , Liu Yu , Chen Guizhu , Tam Nora F.Y. , Shin Paul K.S. , Cheung Sin Gin , Luan Tiangang
Published: October 2008

The endocrine-disrupting chemical bisphenol A (BPA) has attracted attention because of its estrogenic activity and its extensive environmental distribution. The objective of this study was to investigate the physiological response of the alga Cyclotella caspia, a dominant species isolated from Futian Nature Mangrove Reserve, Shenzhen, China, to BPA at different concentrations (4, 6, 8, 10 and 12 mg l-1). We studied the effects of BPA on biomass, growth rate, chlorophyll (chl) a content, cellular morphology, and superoxide dismutase (SOD) activity of C. caspia. The effective concentration of BPA that inhibited algal growth by 50% at 96 h was 7.96±0.23 mg l-1. Algal biomass, growth rate and chl a content decreased with increasing BPA concentration. BPA concentrations greater than 6 mg l-1 strongly inhibited cell division, significantly increased cell volume, and caused cellular inclusions to appear. SOD activity increased with the BPA concentration, but decreased with prolonged exposure time, showing a dynamic process from induction to inhibition. Our results provide baseline information for the development of marine ecotoxicology and physiology theories concerning BPA.
Novel Selective Allosteric Activator of the M1Muscarinic Acetylcholine Receptor Regulates Amyloid Processing and Produces Antipsychotic-Like Activity in Rats
Authors: Jones Carrie K. , Brady Ashley E. , Davis Albert A. , Xiang Zixiu , Bubser Michael , Tantawy Mohammed Noor , Kane Alexander S. , Bridges Thomas M. , Kennedy J. Phillip , Bradley Stefania R. , Peterson Todd E. , Ansari M. Sib , Baldwin Ronald M. , Kessler Robert M. , Deutch Ariel Y. , Lah James J. , Levey Allan I. , Lindsley Craig W. , Conn P. Jeffrey
Published: October 2008

Recent studies suggest that subtype-selective activators of M1/M4muscarinic acetylcholine receptors (mAChRs) may offer a novel approach for the treatment of psychotic symptoms associated with schizophrenia and Alzheimer's disease. Previously developed muscarinic agonists have provided clinical data in support of this hypothesis, but failed in clinical development because of a lack of true subtype specificity and adverse effects associated with activation of other mAChR subtypes. We now report characterization of a novel highly selective agonist for the M1receptor with no agonist activity at any of the other mAChR subtypes, termed TBPB [1-(1′-2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one]. Mutagenesis and molecular pharmacology studies revealed that TBPB activates M1through an allosteric site rather than the orthosteric acetylcholine binding site, which is likely critical for its unprecedented selectivity. Whole-cell patch-clamp recordings demonstrated that activation of M1by TBPB potentiates NMDA receptor currents in hippocampal pyramidal cells but does not alter excitatory or inhibitory synaptic transmission, responses thought to be mediated by M2and M4. TBPB was efficacious in models predictive of antipsychotic-like activity in rats at doses that did not produce catalepsy or peripheral adverse effects of other mAChR agonists. Finally, TBPB had effects on the processing of the amyloid precursor protein toward the non-amyloidogenic pathway and decreased Aβ productionin vitro. Together, these data suggest that selective activation of M1may provide a novel approach for the treatment of symptoms associated with schizophrenia and Alzheimer's disease.
Opposite Neural Signatures of Motion-Induced Blindness in Human Dorsal and Ventral Visual Cortex
Authors: Donner Tobias H. , Sagi Dov , Bonneh Yoram S. , Heeger David J.
Published: October 2008

Motion-induced blindness (MIB) is a visual phenomenon in which a salient static target spontaneously fluctuates in and out of visual awareness when surrounded by a moving mask pattern. It has been hypothesized that MIB reflects an antagonistic interplay between cortical representations of the static target and moving mask. Here, we report evidence for such antagonism between human ventral and dorsal visual cortex during MIB. Functional magnetic resonance imaging (fMRI) responses in ventral visual area V4 decreased with the subjective disappearance of the target. These response decreases were specific for the cortical subregion corresponding retinotopically to the target, occurred early in time with respect to the perceptual report, and could not be explained by shifts of attention in reaction to target disappearance. At the same time, responses increased in mask-specific subregions in dorsal visual areas in and around the intraparietal sulcus. These opposite responses in ventral and dorsal visual areas occurred only during subjective target disappearance, not when the target was physically removed. Perceptual reports of target disappearance were furthermore associated with a “global” modulation of activity, which was delayed in time, and evident throughout early visual cortex, for both subjective target disappearance and physical target removal. We conclude that awareness of the target is tightly linked to the strength of its representation in ventral visual cortex, and that the mask representation in dorsal visual cortex plays a crucial role in the spontaneous suppression of the target representation during MIB.
GABAergic Afferents Activate Both GABAAand GABABReceptors in Mouse Substantia Nigra Dopaminergic NeuronsIn Vivo
Authors: Brazhnik Elena , Shah Fulva , Tepper James M.
Published: October 2008

Mostin vivoelectrophysiological studies of substantia nigra have used rats. With the recent proliferation of the use of mice forin vitroneurophysiological studies because of the availability of various genetically modified strains to identify the roles of various channels and proteins in neuronal function, it is crucial to obtain data onin vivoresponses in mice to verify that thein vitroresults reflect functioning of systems comparable with those that have been well studied in rat.

Inhibitory responses of rat nigral dopaminergic neurons by stimulation of afferents from striatum, globus pallidus, or pars reticulata have been shown to be mediated predominantly or exclusively by GABAAreceptors. This is puzzling given the substantial expression of GABABreceptors and the ubiquitous appearance of GABABsynaptic responses in rat dopaminergic neuronsin vitro. In the present study, we studied electrically evoked GABAergic inhibition in nigral dopaminergic neurons in C57BL/6J mice. Stimulation of the three major GABAergic inputs elicited stronger and longer-lasting inhibitory responses than those seen in rats. The early inhibition was GABAAmediated, whereas the later component, absent in rats, was GABABmediated and selectively enhanced by GABA uptake inhibition. Striatal-evoked inhibition exhibited a slower onset and a weaker initial component compared with inhibition from globus pallidus or substantia nigra pars reticulata. These results are discussed with respect to differences in the size and neuronal density of the rat and mouse brain and the different sites of synaptic contact of the synapses from the three GABAergic afferents.