bluuebunny/crossref_metadata_2025 huggingface dataset:
The Chinese Reform Experience: A Critical Assessment
Authors: Hart-Landsberg Martin
Published: September 2010

The consensus among economists is that China’s post-1978 market reform policies have produced one of the world’s greatest economic success stories. Some progressives believe that China is now capable of serving as an anchor for a new (non-U.S. dominated) global economy. A few claim that the reform experience demonstrates the workability (and desirability) of market socialism. This article is critical of these views. Its four main conclusions are as follows: first, the reforms have led to the restoration of capitalism, not a new form of market socialism. Second, the gains attributed to the reforms have been seriously overstated. Early successes were largely due to the economic foundation established during the pre-reform Mao era. Moreover, the reform process has begun to undermine this foundation, increasing the country’s dependence on foreign investment, technology, and markets. Third, the reforms have produced an increasingly exploitative growth process, one that generates considerable wealth for a minority at unacceptably high cost for the majority. Finally, the reforms also produced a growth process whose logic led it to become enmeshed in, and dependent upon, a broader process of transnational restructuring, one controlled by transnational capital. As a result, China is not only incapable of serving as an anchor for an alternative global economy, its accumulation dynamics actually contribute to the strengthening of existing structures of power and the global imbalances and tensions they generate.

JEL classification:O53, P30, F23
One Hundred Million Jobs for the Chinese Workers! Why China’s Current Model of Development Is Unsustainable and How a Progressive Economic Program Can Help the Chinese Workers, the Chinese Economy, and China’s Environment
Authors: Piovani Chiara , Li Minqi
Published: September 2010

This paper argues that China’s current model of development led by exports and investment is not sustainable for economic, social, and environmental reasons. The accumulation of economic, social, and environmental imbalances could potentially lead to a major crisis for China and the global economy. The paper proposes a progressive economic program that could help China move towards a more equitable and ecologically sustainable model of development.

JEL classification: E60, O53, P30
In Vitro Characterization of Calcium Phosphate Biomaterial Loaded with Linezolid for Osseous Bone Defect Implantation
Authors: Gautier Hélène , Plumecocq Adrien , Amador Gilles , Weiss Pierre , Merle Christian , Bouler Jean-Michel
Published: September 2010

Osteomyelitis is a severe bone infection frequently caused by Staphylococcus aureus, which shows significant resistance to methicillin. One therapeutic treatment would be to insert a bone substitute loaded to an antibiotic, which would enable the bone to be filled while the illness is being treated. Linezolid is an oxazolidinone antibiotic with a large spectrum of action. It is effective against most Gram-positive bacteria and displays a specific mode of action. The aim of this work was to study the association of linezolid with a calcium phosphate-deficient apatite matrix. Granules containing 10% and 50% linezolid were prepared by wet granulation and characterized. Porosity analyses performed by mercury porosimetry and scanning electron microscopy revealed that grain porosity with 50% linezolid was higher than that of the grains containing 10% linezolid. NMR analyses showed no change in structure of linezolid when linked to calcium-deficient apatite. These results were confirmed by studying the antibacterial activity of linezolid, which remained proportional to the quantity of loaded linezolid, proving that the antibiotic released was active. The in vitro release time varied from 9 days for granules containing 10% linezolid to 26 days for granules containing 50% linezolid.
Protecting Children From Online Predators: The Use of Covert Investigation Techniques by Law Enforcement
Authors: Urbas Gregor
Published: September 2010

As the range of cybercrimes expands, law enforcement agencies develop new strategies for their investigation. One method being adopted by police in some countries is to exploit the same anonymity that criminals use to operate online and engage with actual or potential suspects using assumed identities. For example, police investigating online child grooming may assume the identity of a child or young person and engage in chats or email or SMS communication with a suspect. In some situations they may take over the identity of a real child who has been contacted by a suspected child groomer, for example, if contacted by a concerned parent, but in others they may invent an entirely fictitious identity. Where this investigative technique results in arrest and prosecution, arguments about entrapment, or illegal/improper obtaining of evidence may arise. It is therefore important to clarify the legal basis on which such covert investigations may be conducted and to ensure that the substantive and procedural law that apply enable proper and effective law enforcement while at the same time guarding against improper manipulation of persons using electronic communications technologies. This article explores situations in which cybercrimes such as online child grooming can be covertly investigated and seeks to identify best practice for effective online law enforcement.
Changes in Emotions Related to Medication Used to Treat ADHD. Part I: Literature Review
Authors: Manos Michael J. , Brams Matthew , Childress Ann C. , Findling Robert L. , López Frank A. , Jensen Peter S.
Published: September 2010

Objective: To summarize the literature investigating changes in emotional expression (EE) as a function of pharmacotherapy in the treatment of ADHD and to differentiate emotional effects related to ADHD pharmacotherapy from emotional effects related to ADHD as a disorder. Method: English language articles published from January 1, 1988, through August 31, 2008 were identified through a PubMed literature search using the search terms attention, ADHD, hyperactive, hyperkinesis, and ADD cross-referenced with medication terms amphetamine, lisdexamfetamine, methylphenidate , guanfacine, atomoxetine, and clonidine. The search was limited to randomized, controlled trials. Abstracts from all identified articles were selected for further review if they met criteria including (a) presence of a placebo arm, (b) children ≤18 years of age, (c) ≥20 participants, and (b) study design elements that would allow reviewers to determine whether EE phenomena were specifically attributable to medication effects versus alternative explanations (e.g., time, maturation, baseline comorbidity, selection artifacts, or treatments other than the medication-placebo contrast). Qualifying full-text articles were reviewed for prespecified EE terms. Results: Of 148 articles that met selection criteria, 47 reported varying types of EE. Eight of these included two active treatment arms. Hence, 55 data sets were identified. Patterns of change in EE in studies meeting search criteria are discussed. Data sets that reported accounts of EE by the percentage of patients were compiled and further analyzed for specific medication classes. The changes in EE are further discussed as (a) salutary or detrimental, (b) associated with time of day or circumscribed, and (c) presumed to be caused by pharmacological effects. Conclusions: Definitive methodologies for assessing the presence of changes in EE in clinical trials and guidelines for the evaluation of EE in clinical practice are yet to be established and are needed. Such guidelines could be used by clinicians to monitor positive and negative changes in emotion when patients are taking medications for their ADHD. (J. of Att. Dis. 2011; 15(2) 101-112)
Parent Ratings of ADHD Symptoms
Authors: Gomez Rapson
Published: September 2010

Objective: Generalized partial credit model, which is based on item response theory (IRT), was used to test differential item functioning (DIF) for the Diagnostic and Statistical Manual of Mental Disorders (4th ed.), inattention (IA), and hyperactivity/impulsivity (HI) symptoms across boys and girls. Method: To accomplish this, parents completed an ADHD rating scale for 403 boys and 380 girls, between 6 and 11 years of age. Results: The findings indicated no DIF for all the slope parameters for both the IA and HI symptoms. For location parameters, there was no DIF for all the IA symptoms and for seven of the nine HI symptoms. However, the effect sizes for the DIF symptoms were small. Thus, there was good support for gender equivalency for the ADHD symptoms. Conclusion: These findings extend existing data on gender equivalency of ADHD symptoms, obtained using other methodologies for testing measurement equivalency.
Is it language relearning or language reacquisition? Hints from a young boy’s code-switching during his journey back to his native language
Authors: Dahl Tove I. , Rice Curt , Steffensen Marie , Amundsen Ludmila
Published: September 2010

Do we reacquire or relearn latent native languages? How can we tell? The language used by a 4-year-old ‘language reactivator’ in his preschool setting was audio recorded for several weeks upon return to the language community of his latent native language. Through a sociocultural lens focusing particularly on the use of code-switching and mixing during the language reactivation process, we analyzed how this young boy spoke, how that gradually changed over time and how he used the social and linguistic resources around him to facilitate that. The type and content of the boy’s code-switching and mixing showed time- and proficiency-related patterns that were both similar to and different from what one would expect of bilingual and of non-native language learners. Furthermore, the boy showed resourcefulness in how he used the linguistic resources around him — interacting primarily with interlocutors who had some competence in both his active and latent native languages early on until he developed sufficient proficiency to interact in the reactivated target language with his monolingual peers thereafter. This suggests a degree of learner mindfulness that distinguishes the language reactivation process from what one might expect were the process purely a matter of reacquiring bilingual proficiency.
The Orthogonality of Praise and Condemnation in Moral Judgment
Authors: Wiltermuth Scott S. , Monin Benoît , Chow Rosalind M.
Published: September 2010

The present studies examined whether the tendency to praise others for positive (i.e., moral) behaviors correlates with the tendency to condemn others for negative (i.e., immoral) behaviors. Across three studies, factor analyses revealed that these tendencies are orthogonal. The results refute the hypothesis that simply caring deeply about morality leads individuals to praise moral behaviors and condemn immoral ones. The research instead suggests that individuals who are most praising of positive behavior are not necessarily those who are most condemning of negative behavior, because orthogonal conceptions of morality influence each type of judgment. Although the tendency to condemn depends on how much one personally cares about morality (internalization), the tendency to praise seems to depend on one’s public moral persona (symbolization).
Embryonic stem cell–derived hemangioblasts remain epigenetically plastic and require PRC1 to prevent neural gene expression
Authors: Mazzarella Luca , Jørgensen Helle F. , Soza-Ried Jorge , Terry Anna V. , Pearson Stella , Lacaud Georges , Kouskoff Valerie , Merkenschlager Matthias , Fisher Amanda G.
Published: September 2010

Many lineage-specific developmental regulator genes are transcriptionally primed in embryonic stem (ES) cells; RNA PolII is bound at their promoters but is prevented from productive elongation by the activity of polycomb repressive complexes (PRC) 1 and 2. This epigenetically poised state is thought to enable ES cells to rapidly execute multiple differentiation programs and is recognized by a simultaneous enrichment for trimethylation of lysine 4 and trimethylation of lysine 27 of histone H3 (bivalent chromatin) across promoter regions. Here we show that the chromatin profile of this important cohort of genes is progressively modified as ES cells differentiate toward blood-forming precursors. Surprisingly however, neural specifying genes, such as Nkx2-2, Nkx2-9, and Sox1, remain bivalent and primed even in committed hemangioblasts, as conditional deletion of PRC1 results in overt and inappropriate expression of neural genes in hemangioblasts. These data reinforce the importance of PRC1 for normal hematopoietic differentiation and reveal an unexpected epigenetic plasticity of mesoderm-committed hemangioblasts.
Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy
Authors: Finn Jonathan D. , Ozelo Margareth C. , Sabatino Denise E. , Franck Helen W. G. , Merricks Elizabeth P. , Crudele Julie M. , Zhou Shangzhen , Kazazian Haig H. , Lillicrap David , Nichols Timothy C. , Arruda Valder R.
Published: September 2010

Inhibitory antibodies to factor VIII (FVIII) are a major complication in the treatment of hemophilia A, affecting approximately 20% to 30% of patients. Current treatment for inhibitors is based on long-term, daily injections of large amounts of FVIII protein. Liver-directed gene therapy has been used to induce antigen-specific tolerance, but there are no data in hemophilic animals with pre-existing inhibitors. To determine whether sustained endogenous expression of FVIII could eradicate inhibitors, we injected adeno-associated viral vectors encoding canine FVIII (cFVIII) in 2 strains of inhibitor hemophilia A dogs. In 3 dogs, a transient increase in inhibitor titers (up to 7 Bethesda Units [BU]) at 2 weeks was followed by continuous decline to complete disappearance within 4-5 weeks. Subsequently, an increase in cFVIII levels (1.5%-8%), a shortening of clotting times, and a reduction (> 90%) of bleeding episodes were observed. Immune tolerance was confirmed by lack of antibody formation after repeated challenges with cFVIII protein and normal protein half-life. A fourth dog exhibited a strong early anamnestic response (216 BU), with slow decline to 0.8 BU and cFVIII antigen detection by 18 months after vector delivery. These data suggest that liver gene therapy has the potential to eradicate inhibitors and could improve the outcomes of hemophilia A patients.
Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies
Authors: Rosenthal Joseph , Wong Jeffrey , Stein Anthony , Qian Dajun , Hitt Debbie , Naeem Hossameldin , Dagis Andrew , Thomas Sandra H. , Forman Stephen
Published: September 2010

This phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m2 per day for 5 days, melphalan 140 mg/m2 for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non–relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non–relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC.
Non-coding RNA detection methods combined to improve usability, reproducibility and precision
Authors: Raasch Peter , Schmitz Ulf , Patenge Nadja , Vera Julio , Kreikemeyer Bernd , Wolkenhauer Olaf
Published: September 2010

Background

Non-coding RNAs gain more attention as their diverse roles in many cellular processes are discovered. At the same time, the need for efficient computational prediction of ncRNAs increases with the pace of sequencing technology. Existing tools are based on various approaches and techniques, but none of them provides a reliable ncRNA detector yet. Consequently, a natural approach is to combine existing tools. Due to a lack of standard input and output formats combination and comparison of existing tools is difficult. Also, for genomic scans they often need to be incorporated in detection workflows using custom scripts, which decreases transparency and reproducibility.

Results

We developed a Java-based framework to integrate existing tools and methods for ncRNA detection. This framework enables users to construct transparent detection workflows and to combine and compare different methods efficiently. We demonstrate the effectiveness of combining detection methods in case studies with the small genomes of Escherichia coli, Listeria monocytogenes and Streptococcus pyogenes. With the combined method, we gained 10% to 20% precision for sensitivities from 30% to 80%. Further, we investigated Streptococcus pyogenes for novel ncRNAs. Using multiple methods--integrated by our framework--we determined four highly probable candidates. We verified all four candidates experimentally using RT-PCR.

Conclusions

We have created an extensible framework for practical, transparent and reproducible combination and comparison of ncRNA detection methods. We have proven the effectiveness of this approach in tests and by guiding experiments to find new ncRNAs. The software is freely available under the GNU General Public License (GPL), version 3 at http://www.sbi.uni-rostock.de/moses along with source code, screen shots, examples and tutorial material.
Cell-specific occupancy of an extended repertoire of CREM and CREB binding loci in male germ cells
Authors: Martianov Igor , Choukrallah Mohamed-Amin , Krebs Arnaud , Ye Tao , Legras Stephanie , Rijkers Erikjan , Van Ijcken Wilfred , Jost Bernard , Sassone-Corsi Paolo , Davidson Irwin
Published: September 2010

Background

CREB and CREM are closely related factors that regulate transcription in response to various stress, metabolic and developmental signals. The CREMτ activator isoform is selectively expressed in haploid spermatids and plays an essential role in murine spermiogenesis.

Results

We have used chromatin immunoprecipitation coupled to sequencing (ChIP-seq) to map CREM and CREB target loci in round spermatids from adult mouse testis and spermatogonia derived GC1-spg cells respectively. We identify more than 9000 genomic loci most of which are cell-specifically occupied. Despite the fact that round spermatids correspond to a highly specialised differentiated state, our results show that they have a remarkably accessible chromatin environment as CREM occupies more than 6700 target loci corresponding not only to the promoters of genes selectively expressed in spermiogenesis, but also of genes involved in functions specific to other cell types. The expression of only a small subset of these target genes are affected in the round spermatids of CREM knockout animals. We also identify a set of intergenic binding loci some of which are associated with H3K4 trimethylation and elongating RNA polymerase II suggesting the existence of novel CREB and CREM regulated transcripts.

Conclusions

We demonstrate that CREM and CREB occupy a large number of promoters in highly cell specific manner. This is the first study of CREM target promoters directly in a physiologically relevant tissue in vivo and represents the most comprehensive experimental analysis of CREB/CREM regulatory potential to date.
The core genome of the anaerobic oral pathogenic bacterium Porphyromonas gingivalis
Authors: Brunner Jorg , Wittink Floyd RA , Jonker Martijs J , de Jong Mark , Breit Timo M , Laine Marja L , de Soet Johannes J , Crielaard Wim
Published: September 2010

Background

The Gram negative anaerobic bacteriumPorphyromonas gingivalishas long been recognized as a causative agent of periodontitis. Periodontitis is a chronic infectious disease of the tooth supporting tissues eventually leading to tooth-loss. Capsular polysaccharide (CPS) ofP. gingivalishas been shown to be an important virulence determinant. Seven capsular serotypes have been described. Here, we used micro-array based comparative genomic hybridization analysis (CGH) to analyze a representative of each of the capsular serotypes and a non-encapsulated strain against the highly virulent and sequenced W83 strain. We defined absent calls usingArabidopsis thaliananegative control probes, with the aim to distinguish between aberrations due to mutations and gene gain/loss.

Results

Our analyses allowed us to call aberrant genes, absent genes and divergent regions in each of the test strains. A conserved coreP. gingivalisgenome was described, which consists of 80% of the analyzed genes from the sequenced W83 strain. The percentage of aberrant genes between the test strains and control strain W83 was 8.2% to 13.7%. Among the aberrant genes many CPS biosynthesis genes were found. Most other virulence related genes could be found in the conserved core genome. Comparing highly virulent strains with less virulent strains indicates thathmuS,a putative CobN/Mg chelatase involved in heme uptake, may be a more relevant virulence determinant than previously expected. Furthermore, the description of the 39 W83-specific genes could give more insight in why this strain is more virulent than others.

Conclusion

Analyses of the genetic content of theP. gingivaliscapsular serotypes allowed the description of aP. gingivaliscore genome. The high resolution data from three types of analysis of triplicate hybridization experiments may explain the higher divergence betweenP. gingivalisstrains than previously recognized.
A prevalent mutation with founder effect in Spanish Recessive Dystrophic Epidermolysis Bullosa families
Authors: Cuadrado-Corrales Natividad , Sánchez-Jimeno Carolina , García Marta , Escámez María-José , Illera Nuria , Hernández-Martín Ángela , Trujillo-Tiebas María-José , Ayuso Carmen , Del Rio Marcela
Published: September 2010

Background

Recessive Dystrophic Epidermolysis Bullosa (RDEB) is a genodermatosis caused by more than 500 different mutations in the COL7A1 gene and characterized by blistering of the skin following a minimal friction or mechanical trauma.

The identification of a cluster of RDEB pedigrees carrying the c.6527insC mutation in a specific area raises the question of the origin of this mutation from a common ancestor or as a result of a hotspot mutation. The aim of this study was to investigate the origin of the c.6527insC mutation.

Methods

Haplotypes were constructed by genotyping nine single nucleotides polymorphisms (SNPs) throughout the COL7A1 gene. Haplotypes were determined in RDEB patients and control samples, both of Spanish origin.

Results

Sixteen different haplotypes were identified in our study. A single haplotype cosegregated with the c.6527insC mutation.

Conclusion

Haplotype analysis showed that all alleles carrying the c.6527insC mutation shared the same haplotype cosegregating with this mutation (
CCGCTCAAA_6527insC
), thus suggesting the presence of a common ancestor.
MicroRNA-146a expresses in interleukin-17 producing T cells in rheumatoid arthritis patients
Authors: Niimoto Takuya , Nakasa Tomoyuki , Ishikawa Masakazu , Okuhara Atsushi , Izumi Bunichiro , Deie Masataka , Suzuki Osami , Adachi Nobuo , Ochi Mitsuo
Published: September 2010

Background

Interleukin (IL)-17 is an important factor in rheumatoid arthritis (RA) pathogenesis. MicroRNA (miRNA)s are a family of non coding RNAs and associated with human diseases including RA. The purpose of this study is to identify the miRNAs in the differentiation of IL-17 producing cells, and analyze their expression pattern in the peripheral blood mononuclear cells (PBMC) and synovium from RA patients.

Methods

IL-17 producing cells were expanded from CD4+T cell. MiRNA microarray was performed to identify the miRNAs in the differentiation of IL-17 producing cells. Quantitative polymerase chain reaction was performed to examine the expression patterns of the identified miRNAs in the PBMC and synovium from RA and osteoarthritis (OA) patients. Double staining combining in situ hybridization and immunohistochemistry of IL-17 was performed to analyze the expression pattern of identified miRNA in the synovium.

Results

Six miRNAs, let-7a, miR-26, miR-146a/b, miR-150, and miR-155 were significantly up regulated in the IL-17 producing T cells. The expression of miR-146a and IL-17 was higher than in PBMC in the patients with low score of Larsen grade and short disease duration. MiR-146a intensely expressed in RA synovium in comparison to OA. MiR-146a expressed intensely in the synovium with hyperplasia and high expression of IL-17 from the patients with high disease activity. Double staining revealed that miR-146a expressed in IL-17 expressing cells.

Conclusion

These results indicated that miR-146a was associated with IL-17 expression in the PBMC and synovium in RA patients. There is the possibility that miR-146a participates in the IL-17 expression.
Cardiovascular and inflammatory effects of intratracheally instilled ambient dust from Augsburg, Germany, in spontaneously hypertensive rats (SHRs)
Authors: Upadhyay Swapna , Ganguly Koustav , Stoeger Tobias , Semmler-Bhenke Manuela , Takenaka Shinji , Kreyling Wolfgang G , Pitz Mike , Reitmeir Peter , Peters Annette , Eickelberg Oliver , Wichmann H Erich , Schulz Holger
Published: September 2010

Rationale

Several epidemiological studies associated exposure to increased levels of particulate matter in Augsburg, Germany with cardiovascular mortality and morbidity. To elucidate the mechanisms of cardiovascular impairments we investigated the cardiopulmonary responses in spontaneously hypertensive rats (SHR), a model for human cardiovascular diseases, following intratracheal instillation of dust samples from Augsburg.

Methods

250 μg, 500 μg and 1000 μg of fine ambient particles (aerodynamic diameter <2.5 μm, PM2.5-AB) collected from an urban background site in Augsburg during September and October 2006 (PM2.518.2 μg/m3, 10,802 particles/cm3) were instilled in 12 months old SHRs to assess the inflammatory response in bronchoalveolar lavage fluid (BALF), blood, lung and heart tissues 1 and 3 days post instillation. Radio-telemetric analysis was performed to investigate the cardiovascular responses following instillation of particles at the highest dosage based on the inflammatory response observed.

Results

Exposure to 1000 μg of PM2.5-AB was associated with a delayed increase in delta mean blood pressure (ΔmBP) during 2nd-4thday after instillation (10.0 ± 4.0 vs. -3.9 ± 2.6 mmHg) and reduced heart rate (HR) on the 3rdday post instillation (325.1 ± 8.8 vs. 348.9 ± 12.5 bpm). BALF cell differential and inflammatory markers (osteopontin, interleukin-6, C-reactive protein, and macrophage inflammatory protein-2) from pulmonary and systemic level were significantly induced, mostly in a dose-dependent way. Protein analysis of various markers indicate that PM2.5-AB instillation results in an activation of endothelin system (endothelin1), renin-angiotensin system (angiotensin converting enzyme) and also coagulation system (tissue factor, plasminogen activator inhibitor-1) in pulmonary and cardiac tissues during the same time period when alternation in ΔmBP and HR have been detected.

Conclusions

Our data suggests that high concentrations of PM2.5-AB exposure triggers low grade PM mediated inflammatory effects in the lungs but disturbs vascular homeostasis in pulmonary tissues and on a systemic level by affecting the renin angiotensin system, the endothelin system and the coagulation cascade. These findings are indicative for promotion of endothelial dysfunction, atherosclerotic lesions, and thrombogeneis and, thus, provide plausible evidence that susceptible-predisposed individuals may develop acute cardiac events like myocardial infarction when repeatedly exposed to high pollution episodes as observed in epidemiological studies in Augsburg, Germany.
DNA methylation epigenotypes in breast cancer molecular subtypes
Authors: Bediaga Naiara G , Acha-Sagredo Amelia , Guerra Isabel , Viguri Amparo , Albaina Carmen , Ruiz Diaz Irune , Rezola Ricardo , Alberdi María Jesus , Dopazo Joaquín , Montaner David , de Renobales Mertxe , Fernández Agustín F , Field John K , Fraga Mario F , Liloglou Triantafillos , de Pancorbo Marian M
Published: September 2010

Introduction

Identification of gene expression-based breast cancer subtypes is considered a critical means of prognostication. Genetic mutations along with epigenetic alterations contribute to gene-expression changes occurring in breast cancer. So far, these epigenetic contributions to sporadic breast cancer subtypes have not been well characterized, and only a limited understanding exists of the epigenetic mechanisms affected in those particular breast cancer subtypes. The present study was undertaken to dissect the breast cancer methylome and to deliver specific epigenotypes associated with particular breast cancer subtypes.

Methods

By using a microarray approach, we analyzed DNA methylation in regulatory regions of 806 cancer-related genes in 28 breast cancer paired samples. We subsequently performed substantial technical and biologic validation by pyrosequencing, investigating the top qualifying 19 CpG regions in independent cohorts encompassing 47 basal-like, 44 ERBB2+ overexpressing, 48 luminal A, and 48 luminal B paired breast cancer/adjacent tissues. With the all-subset selection method, we identified the most subtype-predictive methylation profiles in multivariable logistic regression analysis.

Results

The approach efficiently recognized 15 individual CpG loci differentially methylated in breast cancer tumor subtypes. We further identified novel subtype-specific epigenotypes that clearly demonstrate the differences in the methylation profiles of basal-like and human epidermal growth factor 2 (HER2)-overexpressing tumors.

Conclusions

Our results provide evidence that well-defined DNA methylation profiles enable breast cancer subtype prediction and support the utilization of this biomarker for prognostication and therapeutic stratification of patients with breast cancer.
Multi-species integrative biclustering
Authors: Waltman Peter , Kacmarczyk Thadeous , Bate Ashley R , Kearns Daniel B , Reiss David J , Eichenberger Patrick , Bonneau Richard
Published: September 2010

We describe an algorithm, multi-species cMonkey, for the simultaneous biclustering of heterogeneous multiple-species data collections and apply the algorithm to a group of bacteria containing Bacillus subtilis, Bacillus anthracis, and Listeria monocytogenes. The algorithm reveals evolutionary insights into the surprisingly high degree of conservation of regulatory modules across these three species and allows data and insights from well-studied organisms to complement the analysis of related but less well studied organisms.
Identification of putative dental epithelial stem cells in a lizard with life-long tooth replacement
Authors: Handrigan Gregory R. , Leung Kelvin J. , Richman Joy M.
Published: September 2010

Most dentate vertebrates, including humans, replace their teeth and yet the process is poorly understood. Here, we investigate whether dental epithelial stem cells exist in a polyphyodont species, the leopard gecko (Eublepharis macularius). Since the gecko dental epithelium lacks a histologically distinct site for stem cells analogous to the mammalian hair follicle bulge, we performed a pulse-chase experiment on juvenile geckos to identify label-retaining cells (LRCs). We detected LRCs exclusively on the lingual side of the dental lamina, which exhibits low proliferation rates and is not involved in tooth morphogenesis. Lingual LRCs were organized into pockets of high density close to the successional lamina. A subset of the LRCs expresses Lgr5 and other genes that are markers of adult stem cells in mammals. Also similar to mammalian stem cells, the LRCs appear to proliferate in response to gain of function of the canonical Wnt pathway. We suggest that the LRCs in the lingual dental lamina represent a population of stem cells, the immediate descendents of which form the successional lamina and, ultimately, the replacement teeth in the gecko. Furthermore, their location on the non-tooth-forming side of the dental lamina implies that dental stem cells are sequestered from signals that might otherwise induce them to differentiate.
Serpent, Suppressor of Hairless and U-shaped are crucial regulators of hedgehog niche expression and prohemocyte maintenance during Drosophila larval hematopoiesis
Authors: Tokusumi Yumiko , Tokusumi Tsuyoshi , Stoller-Conrad Jessica , Schulz Robert A.
Published: September 2010

The lymph gland is a specialized organ for hematopoiesis, utilized during larval development in Drosophila. This tissue is composed of distinct cellular domains populated by blood cell progenitors (the medullary zone), niche cells that regulate the choice between progenitor quiescence and hemocyte differentiation [the posterior signaling center (PSC)], and mature blood cells of distinct lineages (the cortical zone). Cells of the PSC express the Hedgehog (Hh) signaling molecule, which instructs cells within the neighboring medullary zone to maintain a hematopoietic precursor state while preventing hemocyte differentiation. As a means to understand the regulatory mechanisms controlling Hh production, we characterized a PSC-active transcriptional enhancer that drives hh expression in supportive niche cells. Our findings indicate that a combination of positive and negative transcriptional inputs program the precise PSC expression of the instructive Hh signal. The GATA factor Serpent (Srp) is essential for hh activation in niche cells, whereas the Suppressor of Hairless [Su(H)] and U-shaped (Ush) transcriptional regulators prevent hh expression in blood cell progenitors and differentiated hemocytes. Furthermore, Srp function is required for the proper differentiation of niche cells. Phenotypic analyses also indicated that the normal activity of all three transcriptional regulators is essential for maintaining the progenitor population and preventing premature hemocyte differentiation. Together, these studies provide mechanistic insights into hh transcriptional regulation in hematopoietic progenitor niche cells, and demonstrate the requirement of the Srp, Su(H) and Ush proteins in the control of niche cell differentiation and blood cell precursor maintenance.
WUSCHEL mediates stem cell homeostasis by regulating stem cell number and patterns of cell division and differentiation of stem cell progenitors
Authors: Yadav Ram Kishor , Tavakkoli Montreh , Reddy G. Venugopala
Published: September 2010

Plant stem cell populations, unlike their animal counterparts, do not use cell migration and oriented cell divisions to maintain their size, and therefore require a precise coordination between self-renewing divisions of stem cells, and rates of cell division and differentiation among stem cell progenitors. Shoot apical meristems (SAMs) of higher plants harbor a set of stem cells within the central zone (CZ) that divide infrequently. Stem cell daughters that are displaced towards the surrounding peripheral zone (PZ) divide at a faster rate and enter into differentiation at specific locations to form leaves or flowers. The relative ratios of cells in the CZ and the PZ are maintained, despite a constant displacement of cells from the CZ into the PZ, and subsequent allocation of cells within the PZ to form organ primordia. The mechanisms that mediate this homeostatic balance are not well understood. A homeodomain transcription factor WUSCHEL, expressed in the rib meristem (RM), located beneath the CZ, has been shown to provide nonautonomous cues for stem cell specification. By employing transient spatial manipulation and live imaging, we show that an elevated level of WUS not only induces expansion of the CZ, but also results in increased cell division rates in cells of the PZ; conversely, decreases in WUS level lead to a smaller CZ and are associated with a reduction in cell division rate. Moreover, low levels of WUS lead to enlarged organ primordia, by elevating the responsiveness of the PZ cells to the plant hormone auxin. This reveals a function of WUS in mediating the balance between differentiating and non-differentiating cells of the PZ. Regulation of stem cell numbers, growth and differentiation patterns by a single transcription factor forms a interconnected and self-correcting feedback loop to provide robustness to stem cell homeostasis in a dynamic cellular environment.
Schwann cells reposition a peripheral nerve to isolate it from postembryonic remodeling of its targets
Authors: Raphael Alya R. , Perlin Julie R. , Talbot William S.
Published: September 2010

Although much is known about the initial construction of the peripheral nervous system (PNS), less well understood are the processes that maintain the position and connections of nerves during postembryonic growth. Here, we show that the posterior lateral line nerve in zebrafish initially grows in the epidermis and then rapidly transitions across the epidermal basement membrane into the subepidermal space. Our experiments indicate that Schwann cells, which myelinate axons in the PNS, are required to reposition the nerve. In mutants lacking Schwann cells, the nerve is mislocalized and the axons remain in the epidermis. Transplanting wild-type Schwann cells into these mutants rescues the position of the nerve. Analysis of chimeric embryos suggests that the process of nerve relocalization involves two discrete steps – the degradation and recreation of the epidermal basement membrane. Although the outgrowth of axons is normal in mutants lacking Schwann cells, the nerve becomes severely disorganized at later stages. In wild-type embryos, exclusion of the nerve from the epidermis isolates axons from migration of their targets (sensory neuromasts) within the epidermis. Without Schwann cells, axons remain within the epidermis and are dragged along with the migrating neuromasts. Our analysis of the posterior lateral line system defines a new process in which Schwann cells relocate a nerve beneath the epidermal basement membrane to insulate axons from the postembryonic remodeling of their targets.
A novel mRNA affinity purification technique for the identification of interacting proteins and transcripts in ribonucleoprotein complexes
Authors: Slobodin Boris , Gerst Jeffrey E.
Published: September 2010

Intracellular mRNA targeting and localized translation are potential determinants for protein localization. To facilitate targeting, mRNAs possess specific cis-acting sequence motifs that are recognized by trans-acting RNA-binding proteins (RBPs). While many mRNAs are trafficked, our knowledge of the RBPs involved and presence of additional transcripts within these ribonucleoprotein (RNP) complexes is limited. To facilitate the identification of RBPs and transcripts that bind to specific mRNAs, we developed RNA-binding protein purification and identification (RaPID), a novel technique that allows for the affinity purification of MS2 aptamer-tagged mRNAs and subsequent detection of bound RBPs and transcripts using mass-spectometry and RT–PCR, respectively. RaPID effectively isolated specific mRNAs from both yeast and mammalian cells, and identified known mRNA–RBP interactions (e.g., ASH1-She2; β-Actin-IMP1). By isolating tagged OXA1 mRNA using RaPID, we could identify a yeast COPI subunit (i.e., Sec27) as a candidate interacting protein. This finding was strengthened by the observation that a portion of OXA1 mRNA was delocalized in a sec27-1 temperature-sensitive mutant at restrictive temperatures. Finally, RaPID could also be used to show biochemically the coexistence of different RNA species within the same RNP complex (e.g., coprecipitation of the yeast SRO7, WSC2, SEC3, and IST2 mRNAs with ASH1 mRNA) for the first time.
Myocarditis During Lenalidomide Therapy
Authors: Carver Joseph R , Nasta Sunita , Chong Elise A , Stonecypher Mark , Wheeler James E , Ahmadi Tahamtan , Schuster Stephen J
Published: September 2010

Objective:

To report the first case of pathologically confirmed myocarditis in a patient receiving treatment with lenalidomide for non-Hodgkin's lymphoma.

Case Summary:

An 85-year-old woman with recurrent follicular lymphoma was treated with lenalidomide 10 mg daily and low-dose dexamethasone 8 mg once weekly in a clinical trial. She had a past medical history of hypertension and breast cancer. Within 17 days of starting lenalidomide and dexamethasone, she developed symptoms and signs of congestive heart failure. Despite aggressive supportive care, she had progressive and refractory multiorgan failure and died. Postmortem examination of the heart confirmed the absence of coronary artery disease, and histopathological examination of the myocardium revealed a diffuse lymphocytic/eosinophilic inflammatory infiltrate with associated acute and chronic myocardial injury affecting al 4 chambers of the heart, consistent with myocarditis.

Discussion:

Lenalidomide is an immunomodulatory agent derived from thalidomide and is approved for the treatment of multiple myeloma and myelodysplastic syndromes. The efficacy of lenalidomide has been reported in B-cell malignancies. Common toxicities are myelosuppression, fatigue, diarrhea, skin rash, venous thromboembolism, peripheral neuropathy, and tumor flare reaction. Cardiovascular toxicity has been limited to atrial fibrillation and an increased risk for venous thromboembolism. Autoimmune hemolytic anemia, pneumonitis, and dermatitis have been described with lenalidomide. We propose an immunological mechanism for myocarditis based on the predominantly T-cell infiltration of the myocardium.

Conclusions:

Our findings suggest that lenalidomide may be a cause of drug-induced myocarditis. When patients treated with lenalidomide present with signs and symptoms of heart failure in the absence of other obvious causes, lenalidomide hypersensitivity should be considered in the differential diagnosis and a myocardial biopsy should be considered when other common causes of heart failure have been excluded. A reasonable management approach is drug discontinuation and early institution of corticosteroid therapy. An objective causality assessment, using the Naranjo probability scale, revealed that the adverse drug event was probable.
Ranolazine-Tacrolimus Interaction
Authors: Pierce Dwayne A , Reeves-Daniel Amber M
Published: September 2010

Objective:

To report the case of a kidney allograft recipient on a stable regimen of tacrolimus who exhibited increased tacrolimus concentrations within 24 hours of initiating ranolazine.

Case Summary:

A 64-year-old kidney allograft recipient on a stable dose of tacrolimus (10 mg twice daily) was admitted for recent worsening of her chronic anginal pain. The patient was initiated on ranolazine 500 mg twice daily on hospital day 2. Tacrolimus concentrations rose from 7.0-10.1 ng/mL preadmission to 17.8 ng/mL within 24 hours of ranolazine initiation. Ranolazine therapy was continued due to the patient's beneficial response; therefore, the tacrolimus dose was eventually decreased by 70% to 3 mg twice daily to maintain steady-state trough concentrations between 6.6 and 7.9 ng/mL with ranolazine therapy. Ranolazine dechallenge on a subsequent admission produced subtherapeutic tacrolimus concentrations requiring dosage increases.

Discussion:

Ranolazine, an antianginal agent, is both a substrate and a weak inhibitor of CYP3A as well as a substrate and moderate inhibitor of the P-glycoprotein (P-GP) efflux transport system. Tacrolimus, an immunosuppressant, is also a substrate of CYP3A and P-GP. Through possible inhibition of both P-GP– and CYP3A-mediated first-pass metabolism and CYP3A systemic metabolism, ranolazine may have significantly increased serum concentrations of tacrolimus necessitating an eventual 70% decrease in the tacrolimus dose. Based on the Horn Drug Interaction Probability Scale, this interaction is possible.

Conclusions:

We suggest that the eventual 70% decrease in tacrolimus dose after ranolazine initiation may indicate that ranolazine decreases the metabolism and clearance of tacrolimus, causing an elevation in tacrolimus concentrations and the potential for tacrolimus toxicity. Clinicians should be aware of this possible interaction when initiating ranolazine in patients on tacrolimus.
Cold‐blooded lie catchers? An investigation of psychopathy, emotional processing, and deception detection
Authors: Peace Kristine A. , Sinclair Sarah M.
Published: September 2010

Purpose. The process of catching liars is challenging, though evidence suggests that deception detection abilities are influenced by the characteristics of the judge. This study examined individual differences in emotional processing and levels of psychopathic traits on the ability to judge the veracity of written narratives varying in emotional valence.

Methods. Undergraduate participants (N= 251) judged the veracity of 12 written narratives (truthful/deceptive) across three emotional categories: positive, negative, and neutral events. Levels of psychopathy were assessed to investigate its relation to accuracy and cue use.

Results. Overall accuracy was close to chance, although participants were more accurate in determining the veracity of truthful relative to deceptive narratives. Accuracy was impaired for emotional (positive and negative) relative to neutral narratives. Psychopathy was not associated with levels of overall accuracy, but related to discriminative ability, and differential use of cues in decision making. Reported cue use also differed across emotional narrative conditions.

Conclusions. We speculated that an emotive truth bias may have detracted judges from attending to valid cues that are indicative of the deceptive nature of stimuli because they were distracted by the emotional content of the report. Implications for deception detection in forensic settings are discussed.