bluuebunny/crossref_metadata_2025_split huggingface dataset:
Putative GTPase GIMAP1 is critical for the development of mature B and T lymphocytes
Authors: Saunders Amy , Webb Louise M. C. , Janas Michelle L. , Hutchings Amanda , Pascall John , Carter Christine , Pugh Nicholas , Morgan Geoff , Turner Martin , Butcher Geoffrey W. 
Published: March 2010

AbstractThe guanosine triphosphatases (GTPases) of the immunity-associated protein (GIMAP) family of putative GTPases has been implicated in the regulation of T-lymphocyte development and survival. A mouse conditional knockout allele was generated for the immune GTPase gene GIMAP1. Homozygous loss of this allele under the influence of the lymphoid-expressed hCD2-iCre recombinase transgene led to severe (> 85%) deficiency of mature T lymphocytes and, unexpectedly, of mature B lymphocytes. By contrast there was little effect of GIMAP1 deletion on immature lymphocytes in either B or T lineages, although in vitro studies showed a shortening of the survival time of both immature and mature CD4+ single-positive thymocytes. These findings show a vital requirement for GIMAP1 in mature lymphocyte development/survival and draw attention to the nonredundant roles of members of the GIMAP GTPase family in these processes.
Ribosomopathies: human disorders of ribosome dysfunction
Authors: Narla Anupama , Ebert Benjamin L. 
Published: March 2010

Abstract
Ribosomopathies compose a collection of disorders in which genetic abnormalities cause impaired ribosome biogenesis and function, resulting in specific clinical phenotypes. Congenital mutations in RPS19 and other genes encoding ribosomal proteins cause Diamond-Blackfan anemia, a disorder characterized by hypoplastic, macrocytic anemia. Mutations in other genes required for normal ribosome biogenesis have been implicated in other rare congenital syndromes, Schwachman-Diamond syndrome, dyskeratosis congenita, cartilage hair hypoplasia, and Treacher Collins syndrome. In addition, the 5q− syndrome, a subtype of myelodysplastic syndrome, is caused by a somatically acquired deletion of chromosome 5q, which leads to haploinsufficiency of the ribosomal protein RPS14 and an erythroid phenotype highly similar to Diamond-Blackfan anemia. Acquired abnormalities in ribosome function have been implicated more broadly in human malignancies. The p53 pathway provides a surveillance mechanism for protein translation as well as genome integrity and is activated by defects in ribosome biogenesis; this pathway appears to be a critical mediator of many of the clinical features of ribosomopathies. Elucidation of the mechanisms whereby selective abnormalities in ribosome biogenesis cause specific clinical syndromes will hopefully lead to novel therapeutic strategies for these diseases.
Deadly allies: the fatal interplay between platelets and metastasizing cancer cells
Authors: Erpenbeck Luise , Schön Michael P. 
Published: March 2010

Abstract
The general notion that functional platelets are important for successful hematogenous tumor metastasis has been inaugurated more than 4 decades ago and has since been corroborated in numerous experimental settings. Thorough preclinical investigations have, at least in part, clarified some specifics regarding the involvement of platelet adhesion receptors, such as thrombin receptors or integrins, in the metastasis cascade. Pivotal preclinical experiments have demonstrated that hematogenous tumor spread was dramatically diminished when platelets were depleted from the circulation or when functions of platelet surface receptors were inhibited pharmacologically or genetically. Such insight has inspired researchers to devise novel antitumoral therapies based on targeting platelet receptors. However, several mechanistic aspects underlying the impact of platelet receptors on tumor metastasis are not fully understood, and agents directed against platelet receptors have not yet found their way into the clinic. In addition, recent results suggesting that targeted inhibition of certain platelet surface receptors may even result in enhanced experimental tumor metastasis have demonstrated vividly that the role of platelets in tumor metastasis is more complex than has been anticipated previously. This review gives a comprehensive overview on the most important platelet receptors and their putative involvement in hematogenous metastasis of malignant tumors.
R-Ras regulates β1-integrin trafficking via effects on membrane ruffling and endocytosis
Authors: Conklin Matthew W , Ada-Nguema Aude , Parsons Maddy , Riching Kristin M , Keely Patricia J 
Published: March 2010

AbstractBackgroundIntegrin-mediated cell adhesion and spreading is dramatically enhanced by activation of the small GTPase, R-Ras. Moreover, R-Ras localizes to the leading edge of migrating cells, and regulates membrane protrusion. The exact mechanisms by which R-Ras regulates integrin function are not fully known. Nor is much known about the spatiotemporal relationship between these two molecules, an understanding of which may provide insight into R-Ras regulation of integrins.ResultsGFP-R-Ras localized to the plasma membrane, most specifically in membrane ruffles, in Cos-7 cells. GFP-R-Ras was endocytosed from these ruffles, and trafficked via multiple pathways, one of which involved large, acidic vesicles that were positive for Rab11. Cells transfected with a dominant negative form of GFP-R-Ras did not form ruffles, had decreased cell spreading, and contained numerous, non-trafficking small vesicles. Conversely, cells transfected with the constitutively active form of GFP-R-Ras contained a greater number of ruffles and large vesicles compared to wild-type transfected cells. Ruffle formation was inhibited by knock-down of endogenous R-Ras with siRNA, suggesting that activated R-Ras is not just a component of, but also an architect of ruffle formation. Importantly, β1-integrin co-localized with endogenous R-Ras in ruffles and endocytosed vesicles. Expression of dominant negative R-Ras or knock down of R-Ras by siRNA prevented integrin accumulation into ruffles, impaired endocytosis of β1-integrin, and decreased β1-integrin-mediated adhesion. Knock-down of R-Ras also perturbed the dynamics of another membrane-localized protein, GFP-VSVG, suggesting a more global role for R-Ras on membrane dynamics. However, while R-Ras co-internalized with integrins, it did not traffic with VSVG, which instead moved laterally out of ruffles within the plane of the membrane, suggesting multiple levels of regulation of and by R-Ras.ConclusionsOur results suggest that integrin function involves integrin trafficking via a cycle of membrane protrusion, ruffling, and endocytosis regulated by R-Ras, providing a novel mechanism by which integrins are linked to R-Ras through control of membrane dynamics.
An unedited 1.1 kb mitochondrial orfB gene transcript in the Wild Abortive Cytoplasmic Male Sterility (WA-CMS) system of Oryza sativa L. subsp. indica
Authors: Das Srirupa , Sen Supriya , Chakraborty Anirban , Chakraborti Papia , Maiti Mrinal K , Basu Asitava , Basu Debabrata , Sen Soumitra K 
Published: March 2010

Abstract

Background
The application of hybrid rice technology has significantly increased global rice production during the last three decades. Approximately 90% of the commercially cultivated rice hybrids have been derived through three-line breeding involving the use of WA-CMS lines. It is believed that during the 21st century, hybrid rice technology will make significant contributions to ensure global food security. This study examined the poorly understood molecular basis of the WA-CMS system in rice.

Results
RFLPs were detected for atp6 and orfB genes in sterile and fertile rice lines, with one copy of each in the mt-genome. The RNA profile was identical in both lines for atp6, but an additional longer orfB transcript was identified in sterile lines. 5' RACE analysis of the long orfB transcript revealed it was 370 bp longer than the normal transcript, with no indication it was chimeric when compared to the genomic DNA sequence. cDNA clones of the longer orfB transcript in sterile lines were sequenced and the transcript was determined unedited. Sterile lines were crossed with the restorer and maintainer lines, and fertile and sterile F1 hybrids were respectively generated. Both hybrids contained two types of orfB transcripts. However, the long transcript underwent editing in the fertile F1 hybrids and remained unedited in the sterile lines. Additionally, the editing of the 1.1 kb orfB transcript co-segregated with fertility restoring alleles in a segregating population of F2 progeny; and the presence of unedited long orfB transcripts was detected in the sterile plants from the F2 segregating population.

Conclusion
This study helped to assign plausible operative factors responsible for male-sterility in the WA cytoplasm of rice. A new point of departure to dissect the mechanisms governing the CMS-WA system in rice has been identified, which can be applied to further harness the opportunities afforded by hybrid vigor in rice.
Dual effect of Plasmodium-infected erythrocytes on dendritic cell maturation
Authors: Bettiol Esther , Carapau Daniel , Galan-Rodriguez Cristina , Ocaña-Morgner Carlos , Rodriguez Ana 
Published: March 2010

Abstract

Background
Infection with Plasmodium is the cause of malaria, a disease characterized by a high inflammatory response in the blood. Dendritic cells (DC) participate in both adaptive and innate immune responses, influencing the generation of inflammatory responses. DC can be activated through different receptors, which recognize specific molecules in microbes and induce the maturation of DC.

Methods
Using Plasmodium yoelii, a rodent malaria model, the effect of Plasmodium-infected erythrocytes on DC maturation and TLR responses have been analysed.

Results
It was found that intact erythrocytes infected with P. yoelii do not induce maturation of DC unless they are lysed, suggesting that accessibility of parasite inflammatory molecules to their receptors is a key issue in the activation of DC by P. yoelii. This activation is independent of MyD88. It was also observed that pre-incubation of DC with intact P. yoelii-infected erythrocytes inhibits the maturation response of DC to other TLR stimuli. The inhibition of maturation of DC is reversible, parasite-specific and increases with the stage of parasite development, with complete inhibition induced by schizonts (mature infected erythrocytes). Plasmodium yoelii-infected erythrocytes induce a broad inhibitory effect rendering DC non-responsive to ligands for TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9.

Conclusions
Despite the presence of inflammatory molecules within Plasmodium-infected erythrocytes, which are probably responsible for DC maturation induced by lysates, intact Plasmodium-infected erythrocytes induce a general inhibition of TLR responsiveness in DC. The observed effect on DC could play an important role in the pathology and suboptimal immune response observed during the disease. These results help to explain why immune functions are altered during malaria, and provide a system for the identification of a parasite-derived broad inhibitor of TLR-mediated signaling pathways.
Computational analysis of binding between malarial dihydrofolate reductases and anti-folates
Authors: Choowongkomon Kiattawee , Theppabutr Sasikrit , Songtawee Napat , Day Nicholas PJ , White Nicholas J , Woodrow Charles J , Imwong Mallika 
Published: March 2010

Abstract

Background

Plasmodium falciparum readily develops resistance to the anti-folates pyrimethamine and proguanil via a characteristic set of mutations in the dihydrofolate reductase (PfDHFR) gene that leads to reduced competitive drug binding at the enzyme's active site. Analogous mutations can be found in the DHFR gene in isolates of Plasmodium vivax (PvDHFR) although anti-folates have not been widely used for the treatment of this infection. Here the interactions between DHFR inhibitors and modelled structures of the DHFR enzymes of Plasmodium malariae (PmDHFR) and Plasmodium ovale (PoDHFR) are described, along with an investigation of the effect of recently reported mutations within PmDHFR.

Methods
DHFR models for PmDHFR and PoDHFR were constructed using the solved PfDHFR-TS and PvDHFR structures respectively as templates. The modelled structures were docked with three DHFR inhibitors as ligands and more detailed interactions were explored via simulation of molecular dynamics.

Results
Highly accurate models were obtained containing sets of residues that mediate ligand binding which are highly comparable to those mediating binding in known crystal structures. Within this set, there were differences in the relative contribution of individual residues to inhibitor binding. Modelling of PmDHFR mutant sequences revealed that PmDHFR I170M was associated with a significant reduction in binding energy to all DHFR inhibitors studied, while the other predicted resistance mutations had lesser or no effects on ligand binding.

Conclusions
Binding of DHFR inhibitors to the active sites of all four Plasmodium enzymes is broadly similar, being determined by an analogous set of seven residues. PmDHFR mutations found in field isolates influenced inhibitor interactions to a varying extent. In the case of the isolated I170M mutation, the loss of interaction with pyrimethamine suggests that DHFR-inhibitor interactions in P. malariae are different to those seen for DHFRs from P. falciparum and P. vivax.
PEEP titration guided by ventilation homogeneity: a feasibility study using electrical impedance tomography
Authors: Zhao Zhanqi , Steinmann Daniel , Frerichs Inéz , Guttmann Josef , Möller Knut 
Published: March 2010

Abstract
Introduction
Lung protective ventilation requires low tidal volume and suitable positive end-expiratory pressure (PEEP). To date, few methods have been accepted for clinical use to set the appropriate PEEP. The aim of this study was to test the feasibility of PEEP titration guided by ventilation homogeneity using the global inhomogeneity (GI) index based on electrical impedance tomography (EIT) images.

Methods
In a retrospective study, 10 anesthetized patients with healthy lungs mechanically ventilated under volume-controlled mode were investigated. Ventilation distribution was monitored by EIT. A standardized incremental PEEP trial (PEEP from 0 to 28 mbar, 2 mbar per step) was conducted. During the PEEP trial, "optimal" PEEP level for each patient was determined when the air was most homogeneously distributed in the lung, indicated by the lowest GI index value. Two published methods for setting PEEP were included for comparison based on the maximum global dynamic compliance and the intra-tidal compliance-volume curve.

Results
No significant differences in the results were observed between the GI index method (12.2 ± 4.6 mbar) and the dynamic compliance method (11.4 ± 2.3 mbar, P > 0.6), or between the GI index and the compliance-volume curve method (12.2 ± 4.9 mbar, P > 0.6).

Conclusions
According to the results, it is feasible and reasonable to use the GI index to select the PEEP level with respect to ventilation homogeneity. The GI index may provide new insights into the relationship between lung mechanics and tidal volume distribution and may be used to guide ventilator settings.
High-resolution transcription atlas of the mitotic cell cycle in budding yeast
Authors: Granovskaia Marina V , Jensen Lars J , Ritchie Matthew E , Toedling Joern , Ning Ye , Bork Peer , Huber Wolfgang , Steinmetz Lars M 
Published: March 2010

Abstract
Background
Extensive transcription of non-coding RNAs has been detected in eukaryotic genomes and is thought to constitute an additional layer in the regulation of gene expression. Despite this role, their transcription through the cell cycle has not been studied; genome-wide approaches have only focused on protein-coding genes. To explore the complex transcriptome architecture underlying the budding yeast cell cycle, we used 8 bp tiling arrays to generate a 5 minute-resolution, strand-specific expression atlas of the whole genome.

Results
We discovered 523 antisense transcripts, of which 80 cycle or are located opposite periodically expressed mRNAs, 135 unannotated intergenic non-coding RNAs, of which 11 cycle, and 109 cell-cycle-regulated protein-coding genes that had not previously been shown to cycle. We detected periodic expression coupling of sense and antisense transcript pairs, including antisense transcripts opposite of key cell-cycle regulators, like FAR1 and TAF2.

Conclusions
Our dataset presents the most comprehensive resource to date on gene expression during the budding yeast cell cycle. It reveals periodic expression of both protein-coding and non-coding RNA and profiles the expression of non-annotated RNAs throughout the cell cycle for the first time. This data enables hypothesis-driven mechanistic studies concerning the functions of non-coding RNAs.
Prognostic Value of Changes in Health-Related Quality of Life Scores During Curative Treatment for Esophagogastric Cancer
Authors: Djärv Therese , Metcalfe Chris , Avery Kerry N.L. , Lagergren Pernilla , Blazeby Jane M. 
Published: March 2010

Purpose Accumulating evidence suggests that health-related quality of life (HRQL) data before treatment predict survival, but the prognostic value of changes in HRQL scores after treatment is unknown. The aim of this study was to explore whether changes in HRQL scores in esophagogastric cancer predict survival. Patients and Methods Consecutive patients undergoing curative treatment completed HRQL questionnaires (EORTC QLQ-C30) at baseline and after six months and were followed up for at least five years. Cox proportional hazard models with adjustments assessed associations between baseline HRQL and survival and between changes in HRQL before and after treatment and survival. Results Overall, 216 patients initiated curative therapy, of whom169 completed treatment and survived 6 months. Of these, 132 (7%) had two complete HRQL assessments. Analyses adjusted for age, sex, performance status, tumor stage, and disease site revealed that a 10-point poorer dyspnea score at baseline was significantly associated with an 18% higher risk of death. Additional analyses to adjust for baseline HRQL and treatment showed that a 10-point change in physical function (hazard ratio [HR], 0.85; 95% CI, 0.76 to 0.96; P = .007), pain (HR, 1.20; 95% CI, 1.09 to 1.33; P < .001), and fatigue (HR, 1.16; 95% CI, 1.04 to 1.30; P = .009) scores was associated with better survival. Conclusion This exploratory study found longer survival beyond the 6 months after starting treatment to be associated with fewer problems with dyspnea before treatment and better recovery of physical function, pain, and fatigue after treatment. More research to confirm these findings and understand the results is needed.
Serum MicroRNA Signatures Identified in a Genome-Wide Serum MicroRNA Expression Profiling Predict Survival of Non–Small-Cell Lung Cancer
Authors: Hu Zhibin , Chen Xi , Zhao Yang , Tian Tian , Jin Guangfu , Shu Yongqian , Chen Yijiang , Xu Lin , Zen Ke , Zhang Chenyu , Shen Hongbing 
Published: March 2010

Purpose Recent findings that human serum contains stably expressed microRNA (miRNA) have revealed a great potential of serum miRNA signature as disease fingerprints to predict survival. We used genome-wide serum miRNA expression analysis to investigate the role of serum miRNA in predicting prognosis of non–small-cell lung cancer (NSCLC). Patients and Methods To control disease heterogeneity, we used patients with stages I to IIIa lung adenocarcinoma and squamous cell carcinoma, who were treated with both operation and adjuvant chemotherapies. In the discovery stage, Solexa sequencing followed by individual quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assays was used to test the difference in levels of serum miRNAs between 30 patients with longer survival (alive and mean survival time, 49.54 months) and 30 patients with shorter survival matched by age, sex, and stage (dead and mean survival time, 9.54 months). The detected serum miRNAs then were validated in 243 patients (randomly classified into two subgroups: n = 120 for the training set, and n = 123 for the testing set). Results Eleven serum miRNAs were found to be altered more than five-fold by Solexa sequencing between longer-survival and shorter-survival groups, and levels of four miRNAs (ie, miR-486, miR-30d, miR-1 and miR-499) were significantly associated with overall survival. The four-miRNA signature also was consistently an independent predictor of overall survival for both training and testing samples. Conclusion The four-miRNA signature from the serum may serve as a noninvasive predictor for the overall survival of NSCLC.
Immunitätsversprechen. Wie SS-Obergruppenführer Karl Wolff der Strafverfolgung entging
Authors: von Lingen Kerstin 
Published: March 2010

Zusammenfassung
Am Fall des SS-Obergruppenführers und Generals der Waffen SS, Karl Wolff, der mit Allen Dulles die deutsche Kapitulation in der Schweiz verhandelte und dafür vor Strafverfolgung geschützt wurde, lässt sich beispielhaft zeigen, wie im Zerfallsprozess der alliierten Allianz zu Kriegsende politische Erwägungen zu dominieren begannen, die dann im Kalten Krieg direkten Einfluss auf die Strafverfolgungsmechanismen ausübten. Exemplarisch wird hier eine wichtige Facette der westalliierten Kriegs- und Nachkriegsstrategie deutlich, die statt »unconditional surrender« eher auf »unconditional agreements« setzte. Die Ergebnisse im Fall Wolff zeigen, dass die Kriegsverbrecherpolitik hinter politischen Erwägungen rangierte und zur Erreichung eigener strategischer oder politischer Ziele auch Kompromisse denkbar waren, die der offiziellen politischen Linie der Westmächte widersprachen und auf der Basis ideologischer Übereinstimmungen mit den deutschen Kriegsgegnern und gegen Stalin getroffen wurden.
The waved with open eyelids (woe) Locus Is a Hypomorphic Mouse Mutation in Adam17
Authors: Hassemer E L , Le Gall S M , Liegel R , McNally M , Chang B , Zeiss C J , Dubielzig R D , Horiuchi K , Kimura T , Okada Y , Blobel C P , Sidjanin D J 
Published: March 2010

Abstract
The waved with open eyes (woe) locus is a spontaneous recessive mouse mutation that exhibits wavy fur, eyelids open at birth, and enlarged heart and esophagus. In this study, we confirmed the previously identified woe phenotypes and additionally identified anterior eye segment defects, absence of the meibomian glands, and defects in the semilunar cardiac valves. Positional cloning identified a C794T substitution in the Adam17 gene that ablates a putative exonic splicing enhancer (ESE) sequence in exon 7 resulting in aberrant Adam17 splicing. The predominant woe transcript, Adam17Δexon7, lacks exon 7 resulting in an in-frame deletion of 90 bp and a putative Adam17Δ252-281 protein lacking residues 252–281 from the metalloprotease domain. Western blot analysis in woe identified only the precursor form of Adam17Δ252-281 protein. Absence of cleavage of the prodomain renders Adam17Δ252-281 functionally inactive; however, constitutive and stimulated shedding of Adam17 substrates was detected in woe at significantly reduced levels. This residual Adam17 shedding activity in woe most likely originates from full-length Adam17T265M encoded by the Adam17C794T transcript identified expressed at severely reduced levels. These results show that even small amounts of functional Adam17 allow woe mice to survive into adulthood. In contrast to Adam17−/− mice that die at birth, the viability of woe mice provides an excellent opportunity for studying the role of Adam17 throughout postnatal development and homeostasis.