bluuebunny/crossref_metadata_2025_split huggingface dataset:
CRTH2 Is A Critical Regulator of Neutrophil Migration and Resistance to Polymicrobial Sepsis
Authors: Ishii Makoto , Asano Koichiro , Namkoong Ho , Tasaka Sadatomo , Mizoguchi Kosuke , Asami Takahiro , Kamata Hirofumi , Kimizuka Yoshifumi , Fujiwara Hiroshi , Funatsu Yohei , Kagawa Shizuko , Miyata Jun , Ishii Ken , Nakamura Masataka , Hirai Hiroyuki , Nagata Kinya , Kunkel Steven L. , Hasegawa Naoki , Betsuyaku Tomoko 
Published: April 2012

Abstract
Although arachidonic acid cascade has been shown to be involved in sepsis, little is known about the role of PGD2 and its newly found receptor, chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2), on the septic response. Severe sepsis is associated with the failure of neutrophil migration. To investigate whether CRTH2 influences neutrophil recruitment and the lethality during sepsis, sepsis was induced by cecal ligation and puncture (CLP) surgery in mice. CRTH2 knockout (CRTH2−/−) mice were highly resistant to CLP-induced sepsis, which was associated with lower bacterial load and lower production of TNF-α, IL-6, and CCL3. IL-10, an anti-inflammatory cytokine, was higher in CRTH2−/− mice, blunting CLP-induced lethality in CRTH2−/− mice. Neutrophil accumulation in the peritoneum was more pronounced after CLP in CRTH2−/− mice, which was associated with higher CXCR2 levels in circulating neutrophils. Furthermore, sepsis caused a decrease in the level of acetylation of histone H3, an activation mark, at the CXCR2 promoter in wild-type neutrophils, suggesting that CXCR2 expression levels are epigenetically regulated. Finally, both pharmacological depletion of neutrophils and inhibition of CXCR2 abrogated the survival benefit in CRTH2−/− mice. These results demonstrate that genetic ablation of CRTH2 improved impaired neutrophil migration and survival during severe sepsis, which was mechanistically associated with epigenetic-mediated CXCR2 expression. Thus, CRTH2 is a potential therapeutic target for polymicrobial sepsis.
Incorporation of Transmembrane Hydrophobic Mutations in the TCR Enhance Its Surface Expression and T Cell Functional Avidity
Authors: Haga-Friedman Astar , Horovitz-Fried Miryam , Cohen Cyrille J. 
Published: April 2012

Abstract
TCR-gene transfer represents an effective way to redirect the specificity of T lymphocytes for therapeutic purposes. Recent successful clinical trials have underscored the potential of this approach in which efficient expression of the exogenous TCR has been directly linked to the efficacy of T cell activity. It has been also demonstrated that the TCR exhibits a lack of stability associated with the presence of positively charged residues in its transmembrane (TM) region. In this study, we designed an original approach selectively to improve exogenous TCR stability by increasing the hydrophobic nature of the TCRα TM region. Incorporation of hydrophobic residues at evolutionarily permissive positions resulted in an enhanced surface expression of the TCR chains, leading to an improved cellular avidity and anti-tumor TCR activity. Furthermore, this strategy was successfully applied to different TCRs, enabling the targeting of human tumors from different histologies. We also show that the combination of these hydrophobic mutations with another TCR-enhancing approach further improved TCR expression and function. Overall, these findings provide information regarding TCR TM composition that can be applied for the improvement of TCR-gene transfer-based treatments.
Mycobacterium tuberculosisModulates Macrophage Lipid-Sensing Nuclear Receptors PPARγ and TR4 for Survival
Authors: Mahajan Sahil , Dkhar H. Kitdorlang , Chandra Vemika , Dave Sandeep , Nanduri Ravikanth , Janmeja Ashok Kumar , Agrewala Javed N. , Gupta Pawan 
Published: April 2012

AbstractMycobacterium tuberculosis–macrophage interactions are key to pathogenesis and clearance of these bacteria. Although interactions between M. tuberculosis-associated lipids and TLRs, non-TLRs, and opsonic receptors have been investigated, interactions of these lipids and infected macrophage lipid repertoire with lipid-sensing nuclear receptors expressed in macrophages have not been addressed. In this study, we report that M. tuberculosis–macrophage lipids can interact with host peroxisome proliferator-activated receptor γ and testicular receptor 4 to ensure survival of the pathogen by modulating macrophage function. These two lipid-sensing nuclear receptors create a foamy niche within macrophage by modulating oxidized low-density lipoprotein receptor CD36, phagolysosomal maturation block by induction of IL-10, and a blunted innate response by alternative polarization of the macrophages, which leads to survival of M. tuberculosis. These results also suggest possible heterologous ligands for peroxisome proliferator-activated receptor γ and testicular receptor 4 and are suggestive of adaptive or coevolution of the host and pathogen. Relative mRNA expression levels of these receptors in PBMCs derived from clinical samples convincingly implicate them in tuberculosis susceptibility. These observations expose a novel paradigm in the pathogenesis of M. tuberculosis amenable for pharmacological modulation.
Prostaglandin E2 Affects T Cell Responses through Modulation of CD46 Expression
Authors: Kickler Karoline , Maltby Kathryn , Ni Choileain Siobhán , Stephen Jillian , Wright Sheila , Hafler David A. , Jabbour Henry N. , Astier Anne L. 
Published: April 2012

Abstract
The ubiquitous protein CD46, a regulator of complement activity, promotes T cell activation and differentiation toward a regulatory Tr1-like phenotype. The CD46-mediated differentiation pathway is defective in several chronic inflammatory diseases, underlying the importance of CD46 in controlling T cell function and the need to understand its regulatory mechanisms. Using an RNA interference-based screening approach in primary T cells, we have identified that two members of the G protein-coupled receptor kinases were involved in regulating CD46 expression at the surface of activated cells. We have investigated the role of PGE2, which binds to the E-prostanoid family of G protein-coupled receptors through four subtypes of receptors called EP 1–4, in the regulation of CD46 expression and function. Conflicting roles of PGE2 in T cell functions have been reported, and the reasons for these apparent discrepancies are not well understood. We show that addition of PGE2 strongly downregulates CD46 expression in activated T cells. Moreover, PGE2 differentially affects T cell activation, cytokine production, and phenotype depending on the activation signals received by the T cells. This was correlated with a distinct pattern of the PGE2 receptors expressed, with EP4 being preferentially induced by CD46 activation. Indeed, addition of an EP4 antagonist could reverse the effects observed on cytokine production after CD46 costimulation. These data demonstrate a novel role of the PGE2–EP4 axis in CD46 functions, which might at least partly explain the diverse roles of PGE2 in T cell functions.
Ceramide Synthase 6 Plays a Critical Role in the Development of Experimental Autoimmune Encephalomyelitis
Authors: Schiffmann Susanne , Ferreiros Nerea , Birod Kerstin , Eberle Max , Schreiber Yannick , Pfeilschifter Waltraud , Ziemann Ulf , Pierre Sandra , Scholich Klaus , Grösch Sabine , Geisslinger Gerd 
Published: April 2012

Abstract
Ceramides are mediators of apoptosis and inflammatory processes. In an animal model of multiple sclerosis (MS), the experimental autoimmune encephalomyelitis (EAE) model, we observed a significant elevation of C16:0-Cer in the lumbar spinal cord of EAE mice. This was caused by a transiently increased expression of ceramide synthase (CerS) 6 in monocytes/macrophages and astroglia. Notably, this corresponds to the clinical finding that C16:0-Cer levels were increased 1.9-fold in cerebrospinal fluid of MS patients. NO and TNF-α secreted by IFN-γ–activated macrophages play an essential role in the development of MS. In murine peritoneal and mouse-derived RAW 264.7 macrophages, IFN-γ–mediated expression of inducible NO synthase (iNOS)/TNF-α and NO/TNF-α release depends on upregulation of CerS6/C16:0-Cer. Downregulation of CerS6 by RNA interference or endogenous upregulation of C16:0-Cer mediated by palmitic acid in RAW 264.7 macrophages led to a significant reduction or increase in NO/TNF-α release, respectively. EAE/IFN-γ knockout mice showed a significant delay in disease onset accompanied by a significantly less pronounced increase in CerS6/C16:0-Cer, iNOS, and TNF-α compared with EAE/wild-type mice. Treatment of EAE mice with l-cycloserine prevented the increase in C16:0-Cer and iNOS/TNF-α expression and caused a remission of the disease. In conclusion, CerS6 plays a critical role in the onset of MS, most likely by regulating NO and TNF-α synthesis. CerS6 may represent a new target for the inhibition of inflammatory processes promoting MS development.
IRF5 Risk Polymorphisms Contribute to Interindividual Variance in Pattern Recognition Receptor-Mediated Cytokine Secretion in Human Monocyte-Derived Cells
Authors: Hedl Matija , Abraham Clara 
Published: April 2012

Abstract
Monocyte-derived cells display highly variable cytokine secretion upon pattern recognition receptor (PRR) stimulation across individuals; such variability likely affects interindividual inflammatory/autoimmune disease susceptibility. To define mechanisms for this heterogeneity, we examined PRR-induced monocyte-derived cell cytokine secretion from a large cohort of healthy individuals. Although cytokine secretion ranged widely among individuals, the magnitude of cytokine induction after individual nucleotide-binding oligomerization domain 2 (Nod2) and TLR2 stimulation (a cohort of 86 individuals) or stimulation of multiple TLRs (a cohort of 77 individuals), either alone or in combination with Nod2, was consistent intraindividually across these stimuli. Nod2 and TLRs signal through IFN regulatory factor 5 (IRF5), and common IRF5 polymorphisms confer risk for autoimmunity. We find that cells from rs2004640 IRF5 risk-associated allele carriers secrete increased cytokines upon individual or synergistic PRR stimulation in a gene dose- and ligand dose-dependent manner in both monocyte-derived dendritic cells and monocyte-derived macrophages. IRF5 expression knockdown in IRF5 risk allele carrier cells significantly decreases PRR-induced cytokines. Moreover, we find that IRF5 knockdown profoundly decreases Nod2-mediated MAPK and NF-κB pathway activation, whereas the PI3K and mammalian target of rapamycin pathways are not impaired. Finally, the IRF5 rs2004640 polymorphism is a major determinant of the variance (r2 = 0.53) in Nod2-induced cytokine secretion by monocyte-derived cells from different individuals. We therefore show a profound contribution of a single gene to the variance in interindividual PRR-induced cytokines. The hyperresponsiveness of IRF5 disease-associated polymorphisms to a wide spectrum of microbial triggers has broad implications on global immunological responses, host defenses against pathogens, and inflammatory/autoimmune disease susceptibility.
TLR9 Provokes Inflammation in Response to Fetal DNA: Mechanism for Fetal Loss in Preterm Birth and Preeclampsia
Authors: Scharfe-Nugent Andrea , Corr Sinéad C. , Carpenter Susan B. , Keogh Louise , Doyle Brendan , Martin Cara , Fitzgerald Katherine A. , Daly Sean , O’Leary John J. , O’Neill Luke A. J. 
Published: April 2012

Abstract
Preterm birth, the major cause of neonatal mortality in developed countries, is associated with intrauterine infections and inflammation, although the exact mechanisms underlying this event are unclear. In this study, we show that circulating fetal DNA, which is elevated in pregnancies complicated by preterm labor or preeclampsia, triggers an inflammatory reaction that results in spontaneous preterm birth. Fetal DNA activates NF-κB, shown by IκBα degradation in human PBMCs resulting in production of proinflammatory IL-6. We show that fetal resorption and preterm birth are rapidly induced in mice after i.p. injection of CpG or fetal DNA (300 μg/dam) on gestational day 10–14. In contrast, TLR9−/− mice were protected from these effects. Furthermore, this effect was blocked by oral administration of the TLR9 inhibitor chloroquine. Our data therefore provide a novel mechanism for preterm birth and preeclampsia, highlighting TLR9 as a potential therapeutic target for these common disorders of pregnancy.
CD13 Regulates Dendritic Cell Cross-Presentation and T Cell Responses by Inhibiting Receptor-Mediated Antigen Uptake
Authors: Ghosh Mallika , McAuliffe Beata , Subramani Jaganathan , Basu Sreyashi , Shapiro Linda H. 
Published: April 2012

Abstract
Dendritic cell (DC) Ag cross-presentation is generally associated with immune responses to tumors and viral Ags, and enhancement of this process is a focus of tumor vaccine design. In this study, we found that the myeloid cell surface peptidase CD13 is highly and specifically expressed on the subset of DCs responsible for cross-presentation, the CD8+ murine splenic DCs. In vivo studies indicated that lack of CD13 significantly enhanced T cell responses to soluble OVA Ag, although development, maturation, and Ag processing and presentation of DCs are normal in CD13KO mice. In vitro studies showed that CD13 regulates receptor-mediated, dynamin-dependent endocytosis of Ags such as OVA and transferrin but not fluid-phase or phagocytic Ag uptake. CD13 and Ag are cointernalized in DCs, but CD13 did not coimmunoprecipitate with Ag receptors, suggesting that CD13 does not control internalization of specific receptors but regulates endocytosis at a more universal level. Mechanistically, we found that phosphorylation of the endocytic regulators p38MAPK and Akt was dysregulated in CD13KO DCs, and blocking of these kinases perturbed CD13-dependent endocytic uptake. Therefore, CD13 is a novel endocytic regulator that may be exploited to enhance Ag uptake and T cell activation to improve the efficacy of tumor-targeted vaccines.
MicroRNA-494 Is Required for the Accumulation and Functions of Tumor-Expanded Myeloid-Derived Suppressor Cells via Targeting of PTEN
Authors: Liu Yang , Lai Lihua , Chen Qingyun , Song Yinjing , Xu Sheng , Ma Feng , Wang Xiaojian , Wang Jianli , Yu Hai , Cao Xuetao , Wang Qingqing 
Published: April 2012

Abstract
Myeloid-derived suppressor cells (MDSCs) potently suppress the anti-tumor immune responses and also orchestrate the tumor microenvironment that favors tumor angiogenesis and metastasis. The molecular networks regulating the accumulation and functions of tumor-expanded MDSCs are largely unknown. In this study, we identified microRNA-494 (miR-494), whose expression was dramatically induced by tumor-derived factors, as an essential player in regulating the accumulation and activity of MDSCs by targeting of phosphatase and tensin homolog (PTEN) and activation of the Akt pathway. TGF-β1 was found to be the main tumor-derived factor responsible for the upregulation of miR-494 in MDSCs. Expression of miR-494 not only enhanced CXCR4-mediated MDSC chemotaxis but also altered the intrinsic apoptotic/survival signal by targeting of PTEN, thus contributing to the accumulation of MDSCs in tumor tissues. Consequently, downregulation of PTEN resulted in increased activity of the Akt pathway and the subsequent upregulation of MMPs for facilitation of tumor cell invasion and metastasis. Knockdown of miR-494 significantly reversed the activity of MDSCs and inhibited the tumor growth and metastasis of 4T1 murine breast cancer in vivo. Collectively, our findings reveal that TGF-β1–induced miR-494 expression in MDSCs plays a critical role in the molecular events governing the accumulation and functions of tumor-expanded MDSCs and might be identified as a potential target in cancer therapy.
Cutting Edge: In the Absence of Regulatory T Cells, a Unique Th Cell Population Expands and Leads to a Loss of B Cell Anergy
Authors: Leonardo Steven M. , De Santis Jessica L. , Malherbe Laurent P. , Gauld Stephen B. 
Published: April 2012

Abstract
The absence of regulatory T cells (Tregs) results in significant immune dysregulation that includes autoimmunity. The mechanism(s) by which Tregs suppress autoimmunity remains unclear. We have shown that B cell anergy, a major mechanism of B cell tolerance, is broken in the absence of Tregs. In this study, we identify a unique subpopulation of CD4+ Th cells that are highly supportive of Ab production and promote loss of B cell anergy. Notably, this novel T cell subset was shown to express the germinal center Ag GL7 and message for the B cell survival factor BAFF, yet failed to express markers of the follicular Th cell lineage. We propose that the absence of Tregs results in the expansion of a unique nonfollicular Th subset of helper CD4+ T cells that plays a pathogenic role in autoantibody production.
Severe Impairment of Leukocyte Recruitment in ppGalNAcT-1–Deficient Mice
Authors: Block Helena , Ley Klaus , Zarbock Alexander 
Published: April 2012

Abstract
P-selectin glycoprotein ligand-1 plays an important role in leukocyte recruitment. Its binding affinity to selectins is modulated by posttranslational modifications. The polypeptide N-acetylgalactosamine transferase-1 (ppGalNAcT-1) initiates core-type protein O-glycosylation. To address whether the glycosylation of P-selectin glycoprotein ligand-1 by ppGalNAcT-1 is important for leukocyte recruitment in vivo, we investigated leukocyte recruitment in untreated and TNF-α–treated cremaster muscles comparing ppGalNAcT-1–deficient mice (Galnt1−/−) and wild-type mice. In untreated and TNF-α–treated Galnt1−/− mice, leukocyte rolling, adhesion, and transmigration were significantly reduced, with markedly increased rolling velocity compared with control mice. L-selectin–dependent leukocyte rolling was completely abolished in Galnt1−/− mice compared with wild-type mice. Thioglycollate-induced peritonitis experiments with chimeric mice revealed that hematopoietic ppGalNAcT-1 is important for leukocyte recruitment. These data show that the loss of ppGalNAcT-1 led to reduced leukocyte rolling and recruitment and increased rolling velocity, suggesting a predominant role for ppGalNAcT-1 in attaching functionally relevant O-linked glycans to selectin ligands.
La investigación en Comunicación. Análisis bibliométrico de las revistas de mayor impacto del ISI
Authors: Castillo Esparcia Antonio , Rubio Moraga Ángel , Almansa Martínez Ana 
Published: April 2012

Mediante el presente artículo se pretenden analizar algunos de los problemas metodológicos más comunes que se presentan a la hora de evaluar las revistas científicas de comunicación y para ello se han tomado como referencia las 10 publicaciones indexadas en el Social Sciences Citation Index con mayor impacto. Mediante el análisis de contenido se estudiará la procedencia y vinculación académico-investigadora de los autores que aparecen reflejados en estas publicaciones, así como las temáticas de los artículos, los géneros y las metodologías utilizadas. Con todo ello se pretenden dos objetivos principales: por un lado analizar el papel de la evaluación de las publicaciones científicas en el ámbito de la comunicación en los procesos de valoración de la investigación lo que nos permitirá poner de manifiesto las dificultades de aplicación de los métodos bibliométricos de repercusión aplicados por la base de datos de Thomson Scientific y, por otro lado, establecer un marco de desarrollo de las publicaciones científicas españolas en el ámbito de la comunicación que cumplen algunos de los requisitos indicados pero que, bien porque su factor de impacto es aún bajo, o bien porque carecen de difusión internacional aún no han sido registradas en el Social Sciences Citation Index. Está investigación ha contado con financiación del Instituto de Investigación en Relaciones Públicas de la Universidad de Málaga.
Medicolegal Issues in Obstetric and Gynecologic Ultrasound
Authors: Chervenak Frank A , Chervenak Judith L 
Published: May 2012

ABSTRACT
Professional liability risks exist in the practice of ultrasound. In this article, basic aspects of medical negligence are reviewed. The guidelines published by ACOG and AIUM are presented and discussed relating to the importance of instrumentation and safety, documentation, and indications for first, second and third trimester ultrasound examinations as well at the content of these examinations. Litigation related to ultrasound is presented and the controversial nonmedical use of ultrasonography is discussed.

How to cite this article
Chervenak FA, Chervenak JL. Medicolegal Issues in Obstetric and Gynecologic Ultrasound. Donald School J Ultrasound Obstet Gynecol 2012;6(1):9-13.
Effect of Maternal Fever on Fetal Behavior Assessed by KANET Test
Authors: Honemeyer Ulrich , Talic Amira 
Published: May 2012

ABSTRACT
Objective of the study was to assess the possible effect of maternal fever without clinical chorioamnionitis on fetal behavior. In a period of 18 months, in a prospective longitudinal cohort study, Kurjak antenatal neurological test (KANET) was applied to assess fetal behavior in both normal pregnancies and pregnancies complicated by maternal fever. According to the primary localization of the infection, maternal fever group was divided into four groups: Respiratory tract infection, urinary tract infection, malaria and gastrointestinal tract infection. According to KANET test, fetuses with scores >14 were considered normal, 6 to 13 borderline and abnormal, if KANET scores were <5. Differences between groups were examined by Mann-Whitney U-test, differences between subgroups by Steel test. KANET scores differed statistically significant between two main groups. The largest proportion of abnormal KANET scores was found in pregnancies complicated by malaria, while the largest proportion of borderline scores showed fetuses from pregnancies complicated by urinary tract infection. There was no statistical significant difference in KANET scores between the control group and fetuses from pregnancies complicated by respiratory tract infection. KANET test has been shown to be a reliable means to distinguish normal and abnormal fetal behavior. Postnatal follow-up should confirm the data from prenatal assessment of fetal behavior.

How to cite this article
Talic A, Kurjak A, Honemeyer U. Effect of Maternal Fever on Fetal Behavior Assessed by KANET Test. Donald School J Ultrasound Obstet Gynecol 2012;6(2):160-165.
Role of Ultrasound in the Assessment of Postmenopausal Bleeding
Authors: Appleton Kallie 
Published: May 2012

ABSTRACT
Uterine bleeding is a symptom seen by gynecologists in approximately 70% of their visits with women of peri and postmenopausal age. A common symptom, postmenopausal bleeding sometimes can be indicative of malignant pathology. While traditional diagnosis took place via endometrial biopsy, diagnosis is trending toward the use of ultrasound. Benefits of ultrasound include its noninvasive nature, decreased cost, and increased accuracy in diagnosis of postmenopausal bleeding. We present a case-based approach to the usage of various ultrasonography techniques including 2D and color Doppler ultrasound, saline infusion sonography (SIS), 3D and 3D power Doppler ultrasound, as complements to traditional diagnosis of endometrial biopsy. In each of the cases, ultrasonography reveals the diagnosis of postmenopausal pathologies, including atrophic endometrium, endometrial polyps, endometrial hyperplasia, and the malignant pathology, such as endometrial carcinoma, uterine leiomyosarcoma and cervical carcinoma. By the end of our case-based discussion, learners are encouraged to test their knowledge in self-assessment quiz.

How to cite this article
Appleton K, Plavsic SK. Role of Ultrasound in the Assessment of Postmenopausal Bleeding. Donald School J Ultrasound Obstet Gynecol 2012;6(2):197-206.