bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accuracy Analysis of a Spectral Element Atmospheric Model Using a Fully Implicit Solution Framework
Authors: Evans Katherine J. , Taylor Mark A. , Drake John B. 
Published: March 2010

Abstract
A fully implicit (FI) time integration method has been implemented into a spectral finite-element shallow-water equation model on a sphere, and it is compared to existing fully explicit leapfrog and semi-implicit methods for a suite of test cases. This experiment is designed to determine the time step sizes that minimize simulation time while maintaining sufficient accuracy for these problems. For test cases without an analytical solution from which to compare, it is demonstrated that time step sizes 30–60 times larger than the gravity wave stability limits and 6–20 times larger than the advective-scale stability limits are possible using the FI method without a loss in accuracy, depending on the problem being solved. For a steady-state test case, the FI method produces error within machine accuracy limits as with existing methods, but using an arbitrarily large time step size.
Homeodomain-interacting protein kinase 2 plays an important role in normal terminal erythroid differentiation
Authors: Hattangadi Shilpa M. , Burke Karly A. , Lodish Harvey F. 
Published: March 2010

Abstract
Gene-targeting experiments report that the homeodomain-interacting protein kinases 1 and 2, Hipk1 and Hipk2, are essential but redundant in hematopoietic development because Hipk1/Hipk2 double-deficient animals exhibit severe defects in hematopoiesis and vasculogenesis, whereas the single knockouts do not. These serine-threonine kinases phosphorylate and consequently modify the functions of several important hematopoietic transcription factors and cofactors. Here we show that Hipk2 knockdown alone plays a significant role in terminal fetal liver erythroid differentiation. Hipk1 and Hipk2 are highly induced during primary mouse fetal liver erythropoiesis. Specific knockdown of Hipk2 inhibits terminal erythroid cell proliferation (explained in part by impaired cell-cycle progression as well as increased apoptosis) and terminal enucleation as well as the accumulation of hemoglobin. Hipk2 knockdown also reduces the transcription of many genes involved in proliferation and apoptosis as well as important, erythroid-specific genes involved in hemoglobin biosynthesis, such as α-globin and mitoferrin 1, demonstrating that Hipk2 plays an important role in some but not all aspects of normal terminal erythroid differentiation.
Complement receptor 2/CD21− human naive B cells contain mostly autoreactive unresponsive clones
Authors: Isnardi Isabelle , Ng Yen-Shing , Menard Laurence , Meyers Greta , Saadoun David , Srdanovic Iva , Samuels Jonathan , Berman Jessica , Buckner Jane H. , Cunningham-Rundles Charlotte , Meffre Eric 
Published: March 2010

AbstractComplement receptor 2–negative (CR2/CD21−) B cells have been found enriched in patients with autoimmune diseases and in common variable immunodeficiency (CVID) patients who are prone to autoimmunity. However, the physiology of CD21−/lo B cells remains poorly characterized. We found that some rheumatoid arthritis (RA) patients also display an increased frequency of CD21−/lo B cells in their blood. A majority of CD21−/lo B cells from RA and CVID patients expressed germline autoreactive antibodies, which recognized nuclear and cytoplasmic structures. In addition, these B cells were unable to induce calcium flux, become activated, or proliferate in response to B-cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. Moreover, gene array analyses of CD21−/lo B cells revealed molecules specifically expressed in these B cells and that are likely to induce their unresponsive stage. Thus, CD21−/lo B cells contain mostly autoreactive unresponsive clones, which express a specific set of molecules that may represent new biomarkers to identify anergic B cells in humans.
Genome-wide homozygosity signatures and childhood acute lymphoblastic leukemia risk
Authors: Hosking Fay J. , Papaemmanuil Elli , Sheridan Eammon , Kinsey Sally E. , Lightfoot Tracy , Roman Eve , Irving Julie A. E. , Allan James M. , Taylor Malcolm , Tomlinson Ian P. , Greaves Mel , Houlston Richard S. 
Published: March 2010

AbstractRecent studies have reported that regions of homozygosity (ROH) in the genome are detectable in outbred populations and can be associated with an increased risk of malignancy. To examine whether homozygosity is associated with an increased risk of developing childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we analyzed 824 ALL cases and 2398 controls genotyped for 292 200 tagging SNPs. Across the genome, cumulative distribution of ROH was not significantly different between cases and controls. Four common ROH at 10p11.2-10q11.21, 1p31.1, 19p13.2-3, and 20q11.1-23 were, however, associated with ALL risk at P less than .01 (including 1 ROH to which the erythropoietin receptor [EPOR] gene maps, P = .005) but were nonsignificant after adjusting for multiple testing. Our findings make it unlikely that levels of measured homozygosity, caused by autozygosity, uniparental isodisomy, or hemizygosity, play a major role in defining BCP-ALL risk in predominantly outbred populations.
High expression of AID and active class switch recombination might account for a more aggressive disease in unmutated CLL patients: link with an activated microenvironment in CLL disease
Authors: Palacios Florencia , Moreno Pilar , Morande Pablo , Abreu Cecilia , Correa Agustín , Porro Valentina , Landoni Ana Ines , Gabus Raul , Giordano Mirta , Dighiero Guillermo , Pritsch Otto , Oppezzo Pablo 
Published: March 2010

Abstract
Interaction of chronic lymphocytic leukemia (CLL) B cells with tissue microenvironment has been suggested to favor disease progression by promoting malignant B-cell growth. Previous work has shown expression in peripheral blood (PB) of CLL B cells of activation-induced cytidine deaminase (AID) among CLL patients with an unmutated (UM) profile of immunoglobulin genes and with ongoing class switch recombination (CSR) process. Because AID expression results from interaction with activated tissue microenvironment, we speculated whether the small subset with ongoing CSR is responsible for high levels of AID expression and could be derived from this particular microenvironment. In this work, we quantified AID expression and ongoing CSR in PB of 50 CLL patients and characterized the expression of different molecules related to microenvironment interaction. Our results show that among UM patients (1) high AID expression is restricted to the subpopulation of tumoral cells ongoing CSR; (2) this small subset expresses high levels of proliferation, antiapoptotic and progression markers (Ki-67, c-myc, Bcl-2, CD49d, and CCL3/4 chemokines). Overall, this work outlines the importance of a cellular subset in PB of UM CLL patients with a poor clinical outcome, high AID levels, and ongoing CSR, whose presence might be a hallmark of a recent contact with the microenvironment.
Quantitative evaluation of motor function before and after engraftment of dopaminergic neurons in a rat model of Parkinson's disease
Authors: Chuang Chieh-Sen , Su Hong-Lin , Cheng Fu-Chou , Hsu Shan-hui , Chuang Chi-Fen , Liu Chin-San 
Published: March 2010

Abstract
Although gait change is considered a useful indicator of severity in animal models of Parkinson's disease, systematic and extensive gait analysis in animal models of neurological deficits is not well established. The CatWalk-assisted automated gait analysis system provides a comprehensive way to assess a number of dynamic and static gait parameters simultaneously. In this study, we used the Catwalk system to investigate changes in gait parameters in adult rats with unilateral 6-OHDA-induced lesions and the rescue effect of dopaminergic neuron transplantation on gait function. Four weeks after 6-OHDA injection, the intensity and maximal area of contact were significantly decreased in the affected paws and the swing speed significantly decreased in all four paws. The relative distance between the hind paws also increased, suggesting that animals with unilateral 6-OHDA-induced lesions required all four paws to compensate for loss of balance function. At 8 weeks post-transplantation, engrafted dopaminergic neurons expressed tyrosine hydroxylase. In addition, the intensity, contact area, and swing speed of the four limbs increased and the distance between the hind paws decreased. Partial recovery of methamphetamine-induced rotational response was also noted.
A novel link between Sus1 and the cytoplasmic mRNA decay machinery suggests a broad role in mRNA metabolism
Authors: Cuenca-Bono Bernardo , García-Molinero Varinia , Pascual-García Pau , García-Oliver Encar , Llopis Ana , Rodríguez-Navarro Susana 
Published: March 2010

Abstract

Background
Gene expression is achieved by the coordinated action of multiple factors to ensure a perfect synchrony from chromatin epigenetic regulation through to mRNA export. Sus1 is a conserved mRNA export/transcription factor and is a key player in coupling transcription initiation, elongation and mRNA export. In the nucleus, Sus1 is associated to the transcriptional co-activator SAGA and to the NPC associated complex termed TREX2/THSC. Through these associations, Sus1 mediates the nuclear dynamics of different gene loci and facilitate the export of the new transcripts.

Results
In this study, we have investigated whether the yeast Sus1 protein is linked to factors involved in mRNA degradation pathways. We provide evidence for genetic interactions between SUS1 and genes coding for components of P-bodies such as PAT1, LSM1, LSM6 and DHH1. We demonstrate that SUS1 deletion is synthetic lethal with 5'→3' decay machinery components LSM1 and PAT1 and has a strong genetic interaction with LSM6 and DHH1. Interestingly, Sus1 overexpression led to an accumulation of Sus1 in cytoplasmic granules, which can co-localise with components of P-bodies and stress granules. In addition, we have identified novel physical interactions between Sus1 and factors associated to P-bodies/stress granules. Finally, absence of LSM1 and PAT1 slightly promotes the Sus1-TREX2 association.

Conclusions
In this study, we found genetic and biochemical association between Sus1 and components responsible for cytoplasmic mRNA metabolism. Moreover, Sus1 accumulates in discrete cytoplasmic granules, which partially co-localise with P-bodies and stress granules under specific conditions. These interactions suggest a role for Sus1 in gene expression during cytoplasmic mRNA metabolism in addition to its nuclear function.
Systematic analysis of off-target effects in an RNAi screen reveals microRNAs affecting sensitivity to TRAIL-induced apoptosis
Authors: Sudbery Ian , Enright Anton J , Fraser Andrew G , Dunham Ian 
Published: March 2010

Abstract

Background
RNA inhibition by siRNAs is a frequently used approach to identify genes required for specific biological processes. However RNAi screening using siRNAs is hampered by non-specific or off target effects of the siRNAs, making it difficult to separate genuine hits from false positives. It is thought that many of the off-target effects seen in RNAi experiments are due to siRNAs acting as microRNAs (miRNAs), causing a reduction in gene expression of unintended targets via matches to the 6 or 7 nt 'seed' sequence. We have conducted a careful examination of off-target effects during an siRNA screen for novel regulators of the TRAIL apoptosis induction pathway(s).

Results
We identified 3 hexamers and 3 heptamer seed sequences that appeared multiple times in the top twenty siRNAs in the TRAIL apoptosis screen. Using a novel statistical enrichment approach, we systematically identified a further 17 hexamer and 13 heptamer seed sequences enriched in high scoring siRNAs. The presence of one of these seeds sequences (which could explain 6 of 8 confirmed off-target effects) is sufficient to elicit a phenotype. Three of these seed sequences appear in the human miRNAs miR-26a, miR-145 and miR-384. Transfection of mimics of these miRNAs protects several cell types from TRAIL-induced cell death.

Conclusions
We have demonstrated a role for miR-26a, miR-145 and miR-26a in TRAIL-induced apoptosis. Further these results show that RNAi screening enriches for siRNAs with relevant off-target effects. Some of these effects can be identified by the over-representation of certain seed sequences in high-scoring siRNAs and we demonstrate the usefulness of such systematic analysis of enriched seed sequences.
Co-expression of neighbouring genes in Arabidopsis: separating chromatin effects from direct interactions
Authors: Chen Wei-Hua , de Meaux Juliette , Lercher Martin J 
Published: March 2010

Abstract

Background
In all eukaryotic species examined, genes that are chromosomal neighbours are more similar in their expression than random gene pairs. Currently, it is still unclear how much of this local co-expression is caused by direct transcriptional interactions, and how much is due to shared chromatin environments.

Results
We analysed neighbouring genes in Arabidopsis thaliana. At large intergenic distances (>400 bp), divergently and convergently transcribed gene pairs show very similar levels of co-expression, mediated most likely by shared chromatin environments. At gene distances below 400 bp, co-expression is strongly enhanced only for divergently transcribed gene pairs, indicating bi-directional transcription from a single promoter. Conversely, co-expression is suppressed for short convergently or uni-directionally transcribed pairs. This suppression points to transcriptional interference concentrated at the 3' end, e.g., in the context of transcription termination.

Conclusions
Classifying linked gene pairs by their orientation, we are able to partially tease apart the different levels of regional expression modulation. (i) Regional chromatin characteristics modulate the accessibility for regulation and transcription, regardless of gene orientation; the strength of this chromatin effect can be assessed from divergently or convergently transcribed distant neighbours. (ii) Shared promoter regions up to 400 bp in length enhance the co-expression of close bi-directional neighbours. (iii) Transcriptional interference of close neighbours is concentrated at the 3' ends of genes, and reduces co-expression on average by 40%.
Inter-country and ethnic variation in colorectal cancer survival: Comparisons between a Philippine population, Filipino-Americans and Caucasians
Authors: Redaniel Maria Theresa , Laudico Adriano , Mirasol-Lumague Maria Rica , Gondos Adam , Uy Gemma , Brenner Hermann 
Published: March 2010

Abstract

Background
Previous population-based studies showed differences in international and within country colorectal cancer survival estimates, but few investigated the role of prognostic factors. Using a "high resolution approach", we aimed to determine the effect of ethnicity and health care by comparing Filipino-Americans with Philippine residents, who have the same ethnicity, and with Caucasians living in the US, who have the same health care system.

Methods
Using databases from the Manila and Rizal Cancer Registries and the United States Surveillance, Epidemiology and End Results, age-adjusted five-year absolute and relative survival estimates were computed and compared between Filipino-American colorectal cancer patients, cancer patients from the Philippines and Caucasian patients. Cox proportional hazards modelling was used to determine factors affecting survival differences.

Results
Much lower 5-year relative survival estimates were obtained for Philippine residents (37%) as compared to those in Filipino-Americans (60.3%) and Caucasians (62.4%). Differences in age, stage and receipt of surgery explained a large proportion of the survival differences between Philippine residents and Filipino-Americans. However, strong excess risk of death for Philippine residents remained after controlling for these and other variables (relative risk, RR, 2.03, 95% confidence interval, 95% CI, 1.83-2.25).

Conclusions
Strong survival disadvantages of Philippine residents compared to Filipino-American patients were disclosed, which most likely reflect differences in access to and utilization of health care. Health education and advocacy, for both patients and health practitioners, should likewise be given priority.
A rapid, sensitive, reproducible and cost-effective method for mutation profiling of colon cancer and metastatic lymph nodes
Authors: Fumagalli Debora , Gavin Patrick G , Taniyama Yusuke , Kim Seung-Il , Choi Hyun-Joo , Paik Soonmyung , Pogue-Geile Katherine L 
Published: March 2010

Abstract

Background
An increasing number of studies show that genetic markers can aid in refining prognostic information and predicting the benefit from systemic therapy. Our goal was to develop a high throughput, cost-effective and simple methodology for the detection of clinically relevant hot spot mutations in colon cancer.

Methods
The Maldi-Tof mass spectrometry platform and OncoCarta panel from Sequenom were used to profile 239 colon cancers and 39 metastatic lymph nodes from NSABP clinical trial C-07 utilizing routinely processed FFPET (formalin-fixed paraffin-embedded tissue).

Results
Among the 238 common hot-spot cancer mutations in 19 genes interrogated by the OncoCarta panel, mutations were detected in 7 different genes at 26 different nucleotide positions in our colon cancer samples. Twenty-four assays that detected mutations in more than 1% of the samples were reconfigured into a new multiplexed panel, termed here as ColoCarta. Mutation profiling was repeated on 32 mutant samples using ColoCarta and the results were identical to results with OncoCarta, demonstrating that this methodology was reproducible. Further evidence demonstrating the validity of the data was the fact that the mutation frequencies of the most common colon cancer mutations were similar to the COSMIC (Catalog of Somatic Mutations in Cancer) database. The frequencies were 43.5% for KRAS, 20.1% for PIK3CA, and 12.1% for BRAF. In addition, infrequent mutations in NRAS, AKT1, ABL1, and MET were detected. Mutation profiling of metastatic lymph nodes and their corresponding primary tumors showed that they were 89.7% concordant. All mutations found in the lymph nodes were also found in the corresponding primary tumors, but in 4 cases a mutation was present in the primary tumor only.

Conclusions
This study describes a high throughput technology that can be used to interrogate DNAs isolated from routinely processed FFPET and identifies the specific mutations that are common to colon cancer. The development of this technology and the ColoCarta panel may provide a mechanism for rapid screening of mutations in clinically relevant genes like KRAS, PIK3CA, and BRAF.

Trial Registration

ClinicalTrials.gov: NSABP C-07: NCT00004931
Genetic and epigenetic silencing of the beclin 1gene in sporadic breast tumors
Authors: Li Zidong , Chen Bo , Wu Yiqing , Jin Feng , Xia Yongjing , Liu Xiangjun 
Published: March 2010

Abstract

Background
Beclin 1, an important autophagy-related protein in human cells, is involved in cell death and cell survival. Beclin 1 mapped to human chromosome 17q21. It is widely expressed in normal mammary epithelial cells. Although down-regulated expression with mono-allelic deletions of beclin 1 gene was frequently observed in breast tumors, whether there was other regulatory mechanism of beclin 1 was to be investigated. We studied the expression of beclin 1 and explored the possible regulatory mechanisms on its expression in breast tumors.

Methods
20 pairs of tumors and adjacent normal tissues from patients with sporadic breast invasive ductal cancer (IDCs) were collected. The mRNA expression of beclin 1 was detected by real-time quantitative RT-PCR. Loss of heterozygosity (LOH) was determined by real-time quantitative PCR and microsatellite methods. The protein expression of beclin 1, p53, BRCA1 and BRCA2 was assessed by immunohistochemistry. CpG islands in 5' genomic region of beclin 1 gene were identified using MethylPrimer Program. Sodium bisulfite sequencing was used in examining the methylation status of each CpG island.

Results
Decreased beclin 1 mRNA expression was detected in 70% of the breast tumors, and the protein levels were co-related to the mRNA levels. Expression of beclin 1 mRNA was demonstrated to be much higher in the BRCA1 positive tumors than that in the BRCA1 negative ones. Loss of heterozygosity was detected in more than 45% of the breast tumors, and a dense cluster of CpG islands was found from the 5' end to the intron 2 of the beclin 1 gene. Methylation analysis showed that the promoter and the intron 2 of beclin 1 were aberrantly methylated in the tumors with decreased expression.

Conclusions
These data indicated that LOH and aberrant DNA methylation might be the possible reasons of the decreased expression of beclin 1 in the breast tumors. The findings here shed some new light on the regulatory mechanisms of beclin 1 in breast cancer.
Socio-economic differences in life expectancy among persons with diabetes mellitus or myocardial infarction: results from the German MONICA/KORA study
Authors: Perna Laura , Thien-Seitz Uta , Ladwig Karl-Heinz , Meisinger Christa , Mielck Andreas 
Published: March 2010

Abstract

Background
Differences in life expectancy (LE) between social groups in a specific country are a fundamental measure of health inequalities within that country. Constant monitoring of these differences provides important information on the population's general health. The purpose of the present study is to explore and quantify the socio-economic differences in LE in Germany, focussing on a topic rarely assessed in other studies, the dependency of these LE differences on the presence of myocardial infarction or diabetes mellitus.

Methods
The dataset consists of 13,427 participants (6,725 men, 6,702 women) aged 25-74 years, recruited in the region of Augsburg in Germany through three independent cross-sectional representative surveys conducted in 1984/85, 1989/90, 1994/95, with a mortality follow up in 1998 and 2002. We use a parametric model for the survival function based on the Weibull distribution, in which the hazard function is described in terms of two parameters. We estimate these parameters with a maximum likelihood method that takes into account censoring and data truncation.

Results
The difference in LE between the lowest and the highest socio-economic group is estimated to be 3.79 years for men and 4.10 years for women. Diabetes mellitus reduces LE of men from the upper three income quartiles by 4.88 years, and LE of men belonging to the lowest income quartile by 7.97 years. For women, the corresponding figures are 5.79 and 5.72 years. Myocardial infarction reduces LE of men and women from the upper three income quartiles by 3.65 and 3.75 years, respectively, and LE of men and women belonging to the lowest income quartile by 5.11 and 10.95 years, respectively.

Conclusions
This study shows that in Germany the differences in LE by socio-economic status are comparable to those found in other European countries, and that these differences seem to increase when diabetes mellitus or myocardial infarction is present. The statistical method used allows estimates of LE with relatively small datasets.