bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction and Evolution of Cytomegalovirus-Specific CD4+ T Cell Clonotypes in Rhesus Macaques
Authors: Price David A. , Bitmansour Arlene D. , Edgar John B. , Walker Joshua M. , Axthelm Michael K. , Douek Daniel C. , Picker Louis J. 
Published: April 2014

Abstract
CMV infection induces robust CD4+ T cell responses in immunocompetent hosts that orchestrate immune control of viral replication, dissemination, and disease. In this study, we characterized the clonotypic composition of CD4+ T cell populations specific for rhesus CMV (RhCMV) in chronically infected adult rhesus macaques (RM) and in juvenile RM undergoing primary RhCMV infection and subsequent secondary challenge with RhCMV. In adult RM with established chronic infection, RhCMV-specific CD4+ T cell populations exhibited stable, pauciclonal structures with skewed hierarchies dominated by two or three clonotypes. During primary infection, in contrast, the initial RhCMV-specific CD4+ T cell populations were highly polyclonal and progressive evolution to the chronic pattern manifest in adults occurred over the ensuing 2–3 years. Clear patterns of clonal succession were observed during this maturation process, such that clonotypes present in the acute phase were largely replaced over time. However, rechallenge with RhCMV expanded virus-specific CD4+ T cell clonotypes identified solely during acute infection. These findings indicate that, during persistent viral infection, substantial selection pressures and ongoing clonotype recruitment shape the specific CD4+ T cell repertoire and that rapidly exhausted or superseded clonotypes often remain within the memory T cell pool.
Differential Contribution of NFATc2 and NFATc1 to TNF-α Gene Expression in T Cells
Authors: Kaminuma Osamu , Kitamura Fujiko , Kitamura Noriko , Hiroi Takachika , Miyoshi Hiroyuki , Miyawaki Atsushi , Miyatake Shoichiro 
Published: April 2014

AbstractThe NFAT family transcription factors play crucial roles in immunological and other biological events; however, the functional differences among NFAT members have not been fully elucidated. This study investigated the relative contribution of NFATc2 and NFATc1 to the transactivation of cytokine genes in T cells. Ectopic expression of NFATc2 but not NFATc1, especially its short isoform, enhanced TNF-α synthesis in human T cells at the gene transcription level, whereas both NFATs augmented IL-2 expression. In addition, a reduction of the shortest NFATc1 isoform using RNA interference technology failed to suppress TNF-α expression. The promoter/enhancer activity of the NFAT-binding site in the TNF-α gene was up-regulated by NFATc2 but not by NFATc1, whereas both NFATs associated similarly with this region. A study of mRNA expression using NFATc2/NFATc1 chimeric molecules revealed that the enhancing activity of NFAT on the TNF-α gene was lost by truncation of its C-terminal transactivation domain. In addition, this domain derived from NFATc2 behaved as a dominant negative against the NFAT site in TNF-α promoter-dependent transcriptional activity in T cells. We conclude that the C-terminal transactivation domain in NFAT is crucial for TNF-α gene expression in human T cells.
Systemic, but Not Intestinal, IL-7 Is Essential for the Persistence of Chronic Colitis
Authors: Tomita Takayuki , Kanai Takanori , Nemoto Yasuhiro , Totsuka Teruji , Okamoto Ryuichi , Tsuchiya Kiichiro , Sakamoto Naoya , Watanabe Mamoru 
Published: April 2014

Abstract
We previously demonstrated that IL-7 is produced by intestinal goblet cells and is essential for the persistence of colitis. It is well known, however, that goblet cells are decreased or depleted in the chronically inflamed mucosa of animal colitis models or human inflammatory bowel diseases. Thus, in this study, we assess whether intestinal IL-7 is surely required for the persistence of colitis using a RAG-1/2−/− colitis model induced by the adoptive transfer of CD4+CD45RBhigh T cells in combination with parabiosis system. Surprisingly, both IL-7−/− × RAG-1−/− and IL-7+/+ × RAG-1−/− host mice developed colitis 4 wk after parabiosis to a similar extent of colitic IL-7+/+ × RAG-1−/− donor mice that were previously transferred with CD4+CD45RBhigh T cells. Of note, although the number of CD4+ T cells recovered from the spleen or the bone marrow of IL-7−/− × RAG-1−/− host mice was significantly decreased compared with that of IL-7+/+ × RAG-1−/− host mice, an equivalent number of CD4+ T cells was recovered from the lamina propria of both mice, indicating that the expansion of CD4+ T cells in the spleen or in the bone marrow is dependent on IL-7, but not in the lamina propria. Development of colitis was never observed in parabionts between IL-7+/+ × RAG-1−/− host and noncolitic IL-7−/− × RAG-1−/− donor mice that were transferred with CD4+CD45RBhigh T cells. Collectively, systemic, but not intestinal, IL-7 is essential for the persistence of colitis, suggesting that therapeutic approaches targeting the systemic IL-7/IL-7R signaling pathway may be feasible in the treatment of inflammatory bowel diseases.
Cutting Edge: Guillain-Barré Syndrome-Associated IgG Responses to Gangliosides Are Generated Independently of CD1 Function in Mice
Authors: Matsumoto Yukie , Yuki Nobuhiro , Van Kaer Luc , Furukawa Koichi , Hirata Koichi , Sugita Masahiko 
Published: April 2014

Abstract
CD1 molecules present a variety of microbial glycolipids and self-glycolipids to T cells, but their potential role in humoral responses to glycolipid Ags remains to be established. To address this issue directly, we used GM1/GD1a-deficient mice, which, upon immunization with heat-killed Campylobacter jejuni, develop Guillain-Barré syndrome-associated IgG Abs against the GM1/GD1a sugar chain epitopes of bacterial lipo-oligosaccharides (LOS). Our results showed that anti-ganglioside Abs of the IgG1, IgG2b, and IgG3 isotypes were produced in the absence of group 2 CD1 (CD1d) expression. Unlike mouse and human group 2 CD1 molecules that specifically bound LOS, none of the group 1 CD1 molecules (CD1a, CD1b, and CD1c in humans) were capable of interacting with LOS. Thus, these results indicate CD1-independent pathways for anti-ganglioside Ab production.
Neutrophil Microbicides Induce a Pathogen Survival Response in Community-Associated Methicillin-Resistant Staphylococcus aureus
Authors: Palazzolo-Ballance Amy M. , Reniere Michelle L. , Braughton Kevin R. , Sturdevant Daniel E. , Otto Michael , Kreiswirth Barry N. , Skaar Eric P. , DeLeo Frank R. 
Published: April 2014

Abstract
In recent years, there has been a dramatic increase in the incidence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections. MW2 (pulsed-field type USA400), the prototype CA-MRSA strain, is highly virulent and has enhanced ability to evade killing by neutrophils. Although progress has been made, the molecular basis for enhanced virulence of CA-MRSA remains incompletely defined. To that end, we studied resistance of MW2 to key microbicides of human neutrophils. Hydrogen peroxide (H2O2), hypochlorous acid, and azurophilic granule proteins had significant bacteriostatic but limited staphylocidal activity toward MW2 under the conditions tested. An MW2-specific microarray revealed common changes in S. aureus gene expression following exposure to each microbicide, such as up-regulation of transcripts involved in gene regulation (e.g., saeRS and kdpDE) and stress response. Azurophilic granule proteins elicited the greatest number of changes in MW2 transcripts, including up-regulation of mRNAs encoding multiple toxins and hemolysins (e.g., hlgA, hlgB, hlgC, hla, lukS-PV, lukF-PV, sec4, and set17–26). Notably, H2O2 triggered up-regulation of transcripts related to heme/iron uptake (e.g., isdA, isdB, and isdCDEFsrtBisdG), and an isogenic isdAB-negative strain of MW2 had increased susceptibility to H2O2 (p &lt; 0.001) and human neutrophils (p &lt; 0.05) compared with the wild-type parental strain. These findings reveal a S. aureus survival response wherein Iron-regulated surface determinant (Isd) proteins are important for resistance to innate host defense. Collectively, the data provide an enhanced view of the mechanisms used by S. aureus to circumvent destruction by the innate immune system.
Extracellular HIV-Tat Induces Cyclooxygenase-2 in Glial Cells through Activation of Nuclear Factor of Activated T Cells
Authors: Blanco Almudena , Álvarez Susana , Fresno Manuel , Muñoz-Fernández María Ángeles 
Published: April 2014

Abstract
Both the HIV-1 protein Tat and cyclooxygenase-2 (COX-2) have been involved in the neuropathogenesis associated with HIV-1 infection. However, the relationship among them has not been addressed. Here, we found that extracellular Tat was able to induce COX-2 mRNA and protein expression and PGE2 synthesis in astrocytoma cell lines and primary human astrocytes. Moreover, Tat induced COX-2 promoter transcription. Deletion of NF-κB sites of the promoter did not diminish Tat-dependent transcription. Interestingly, Tat did not induce NF-κB activity, suggesting that NF-κB was not necessary to control COX-2 transcription induced by Tat. In contrast, deletion or mutation of the NFAT and/or AP-1 site abrogated COX-2 induction by Tat. Moreover, Tat induced transcription of NFAT- and AP-1-dependent reporter genes. Transfection of a dominant negative c-Jun mutant protein, TAM-67, or of a dominant negative version of NFAT, efficiently blocked the induction of COX-2 promoter by Tat, confirming the requirement of both transcription factors. Moreover, Tat induced NFAT translocation to the nucleus and binding to the distal site of the COX-2 promoter. The importance of NFAT and AP-1 in COX-2 induction and PGE2 synthesis by Tat was corroborated by using pharmacological inhibitors of the NFΑΤ, ERK, and JNK pathways. In summary, our results indicate that HIV-1 Tat was able to induce COX-2 and PGE2 synthesis in astrocytic cells through an NFAT/AP-1-dependent mechanism.
Cyclooxygenase-2/Prostaglandin D2/CRTH2 Pathway Mediates Double-Stranded RNA-Induced Enhancement of Allergic Airway Inflammation
Authors: Shiraishi Yoshiki , Asano Koichiro , Niimi Kyoko , Fukunaga Koichi , Wakaki Misa , Kagyo Junko , Takihara Takahisa , Ueda Soichiro , Nakajima Takeshi , Oguma Tsuyoshi , Suzuki Yusuke , Shiomi Tetsuya , Sayama Koichi , Kagawa Shizuko , Ikeda Eiji , Hirai Hiroyuki , Nagata Kinya , Nakamura Masataka , Miyasho Taku , Ishizaka Akitoshi 
Published: April 2014

Abstract
Respiratory RNA viruses responsible for the common cold often worsen airway inflammation and bronchial responsiveness, two characteristic features of human asthma. We studied the effects of dsRNA, a nucleotide synthesized during viral replication, on airway inflammation and bronchial hyperresponsiveness in murine models of asthma. Intratracheal instillation of poly I:C, a synthetic dsRNA, increased the airway eosinophilia and enhanced bronchial hyperresponsiveness to methacholine in OVA-sensitized, exposed rats. These changes were associated with induction of cyclooxygenase-2 (COX-2) expression and COX-2-dependent PGD2 synthesis in the lungs, particularly in alveolar macrophages. The direct intratracheal instillation of PGD2 enhanced the eosinophilic inflammation in OVA-exposed animals, whereas pretreatment with a dual antagonist against the PGD2 receptor-(CRTH2) and the thromboxane A2 receptor, but not with a thromboxane A2 receptor-specific antagonist, nearly completely eliminated the dsRNA-induced worsening of airway inflammation and bronchial hyperresponsiveness. CRTH2-deficient mice had the same degree of allergen-induced airway eosinophilia as wild-type mice, but they did not exhibit a dsRNA-induced increase in eosinophil accumulation. Our data demonstrate that COX-2-dependent production of PGD2 followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenetic factors responsible for the dsRNA-induced enhancement of airway inflammation and responsiveness.
Activation of Rho Kinase by TNF-α Is Required for JNK Activation in Human Pulmonary Microvascular Endothelial Cells
Authors: Mong Phyllus Y. , Petrulio Christian , Kaufman Howard L. , Wang Qin 
Published: April 2014

Abstract
TNF-α induces complex signaling events in endothelial cells (ECs), leading to inflammatory gene transcription and junctional permeability increases. This study examined the activation of RhoA and Rho kinase induced by TNF-α in primary human pulmonary microvascular ECs and its role in regulating EC responses to TNF-α. TNF-α induced a time-dependent activation of RhoA and Rho kinase in these ECs. TNF-α also induced activation of JNK that peaked at 15 min and lasted for at least 3 h. Inhibition of Rho kinase using a specific pharmacological inhibitor, Y27632, prevented TNF-α-induced early and late JNK activation. Inhibition of RhoA protein expression using small-interfering RNA, however, did not prevent TNF-α-induced Rho kinase activation or JNK activation. Studies using MAPK kinase 4 (MKK4) small-interfering RNA showed that MKK4 was not required for TNF-α-induced early JNK activation and that Rho kinase modulated early JNK activation through MKK4-independent mechanisms. Rho kinase, however, modulated TNF-α-induced late JNK activation mainly through MKK4-dependent mechanisms. Activation of Rho kinase was required for JNK-dependent IL-6 secretion induced by TNF-α. Moreover, inhibition of Rho kinase prevented TNF-α-induced cytoskeletal changes and permeability increases. Inhibition of JNK activation, however, did not prevent TNF-α-induced cytoskeletal changes, suggesting that Rho kinase did not modulate cytoskeletal changes through JNK activation. Therefore, Rho kinase plays important roles in EC responses to TNF-α by regulating permeability increases and JNK-dependent IL-6 production during pulmonary inflammation.
Targeting Immune Complex-Mediated Hypersensitivity with Recombinant Soluble Human FcγRIA (CD64A)
Authors: Ellsworth Jeff L. , Maurer Mark , Harder Brandon , Hamacher Nels , Lantry Megan , Lewis Kenneth B. , Rene Shirley , Byrnes-Blake Kelly , Underwood Sara , Waggie Kimberly S. , Visich Jennifer , Lewis Katherine E. 
Published: April 2014

Abstract
Binding of Ag-Ab immune complexes to cellular FcγR promotes cell activation, release of inflammatory mediators, and tissue destruction characteristic of autoimmune disease. To evaluate whether a soluble FcγR could block the proinflammatory effects of immune complexes, recombinant human (rh) versions of FcγRIA, FcγRIIA, and FcγRIIIA were prepared. Binding of rh-FcγRIA to IgG was of high affinity (KD = 1.7 × 10−10 M), whereas rh-FcγRIIA and rh-FcγRIIIA bound with low affinity (KD = 0.6–1.9 × 10−6 M). All rh-FcγR reduced immune complex precipitation, blocked complement-mediated lysis of Ab-sensitized RBC, and inhibited immune complex-mediated production of IL-6, IL-13, MCP-1, and TNF-α by cultured mast cells. Local or systemic delivery only of rh-FcγRIA, however, reduced edema and neutrophil infiltration in the cutaneous Arthus reaction in mice. 125I-labeled rh-FcγRIA was cleared from mouse blood with a rapid distribution phase followed by a slow elimination phase with a t1/2γ of ∼130 h. The highest percentage of injected radioactivity accumulated in blood ∼ liver ∼ carcass &gt; kidney. s.c. dosing of rh-FcγRIA resulted in lower serum levels of inflammatory cytokines and prevented paw swelling and joint damage in a murine model of collagen Ab-induced arthritis. These data demonstrate that rh-FcγRIA is an effective inhibitor of type III hypersensitivity.
Prostaglandin E2 Mediates IL-1β-Related Fibroblast Mitogenic Effects in Acute Lung Injury through Differential Utilization of Prostanoid Receptors
Authors: White Kimberly E. , Ding Qiang , Moore Bethany B. , Peters-Golden Marc , Ware Lorraine B. , Matthay Michael A. , Olman Mitchell A. 
Published: April 2014

Abstract
The fibroproliferative response to acute lung injury (ALI) results in severe, persistent respiratory dysfunction. We have reported that IL-1β is elevated in pulmonary edema fluid in those with ALI and mediates an autocrine-acting, fibroblast mitogenic pathway. In this study, we examine the role of IL-1β-mediated induction of cyclooxygenase-2 and PGE2, and evaluate the significance of individual E prostanoid (EP) receptors in mediating the fibroproliferative effects of IL-1β in ALI. Blocking studies on human lung fibroblasts indicate that IL-1β is the major cyclooxygenase-2 mRNA and PGE2-inducing factor in pulmonary edema fluid and accounts for the differential PGE2 induction noted in samples from ALI patients. Surprisingly, we found that PGE2 produced by IL-1β-stimulated fibroblasts enhances fibroblast proliferation. Further studies revealed that the effect of fibroblast proliferation is biphasic, with the promitogenic effect of PGE2 noted at concentrations close to that detected in pulmonary edema fluid from ALI patients. The suppressive effects of PGE2 were mimicked by the EP2-selective receptor agonist, butaprost, by cAMP activation, and were lost in murine lung fibroblasts that lack EP2. Conversely, the promitogenic effects of mid-range concentrations of PGE2 were mimicked by the EP3-selective agent, sulprostone, by cAMP reduction, and lost upon inhibition of Gi-mediated signaling with pertussis toxin. Taken together, these data demonstrate that PGE2 can stimulate or inhibit fibroblast proliferation at clinically relevant concentrations, via preferential signaling through EP3 or EP2 receptors, respectively. Such mechanisms may drive the fibroproliferative response to ALI.
Memory CD8+ T Cell Responses Expand When Antigen Presentation Overcomes T Cell Self-Regulation
Authors: Cockburn Ian A. , Chakravarty Sumana , Overstreet Michael G. , García-Sastre Adolfo , Zavala Fidel 
Published: April 2014

Abstract
Antimicrobial memory CD8+ T cell responses are not readily expanded by either repeated infections or immunizations. This is a major obstacle to the development of T cell vaccines. Prime-boost immunization with heterologous microbes sharing the same CD8+ epitope can induce a large expansion of the CD8+ response; however, different vectors vary greatly in their ability to boost for reasons that are poorly understood. To investigate how efficient memory T cell expansion can occur, we evaluated immune regulatory events and Ag presentation after secondary immunization with strong and weak boosting vectors. We found that dendritic cells were essential for T cell boosting and that Ag presentation by these cells was regulated by cognate memory CD8+ T cells. When weak boosting vectors were used for secondary immunization, pre-established CD8+ T cells were able to effectively curtail Ag presentation, resulting in limited CD8+ T cell expansion. In contrast, a strong boosting vector, vaccinia virus, induced highly efficient Ag presentation that overcame regulation by cognate T cells and induced large numbers of memory CD8+ T cells to expand. Thus, efficient targeting of Ag to dendritic cells in the face of cognate immunity is an important requirement for T cell expansion.
Breast carcinoma in young females below the age of 40 years: A histopathological perspective
Authors: Thangjam Shitalmala , Laishram Rajesh Singh , Debnath Kaushik 
Published: April 2014

Abstract
Background: Breast cancer among young women is a rare pathology, but is known to have a more aggressive behavior and poorer outcome. Aims: The objective of this study was to evaluate the clinicopathological characteristics of breast carcinoma below 40 years in comparison to that over 40 years in Manipur, India. Settings and Design: This retrospective study from the period of January 2005-December 2010 was conducted in the Department of Pathology, Regional Institute of Medical Sciences, Imphal, Manipur. Materials and Methods: All cases of mastectomy specimens of carcinoma breast from the period of January 2005-December 2010 were included in the study. Clinical and histopathological data of all cases were reviewed and correlated. Results: A total of 507 mastectomy specimens were received, among which, 160 cases (31.56%) were below 40 years; whereas 347 cases (68.44%) were above 40 years of age. Stage III was the commonest stage (47% versus 18%) in the younger group; while in the older group, Stage II was the commonest (64% versus 34%). Conclusion: This study shows that young females with breast cancer have higher stage of tumor.
Evaluation of protective effect of myricetin, a bioflavonoid in dimethyl benzanthracene-induced breast cancer in female Wistar rats
Authors: Jayakumar J. K. , Nirmala P. , Kumar B.A. Praveen , Kumar Ashok P. 
Published: April 2014

Abstract
Background: Breast cancer is one of the most common cancers worldwide. Alarmingly, the incidence of breast cancer is rising rapidly in India. Aim: The present research was focused to assess the role of myricetin; a bioflavonoid in 7,12-dimethylbenzanthracene (DMBA)-induced breast cancer in female Wistar rats. Materials and Methods: A total of 36 female Wistar rats (total 6 groups, n = 6 per group) 6 - 8 weeks old, weighing 150 gm were used in the study. DMBA was given at the dose of 7.5 mg/kg subcutaneously in the mammary region once a week for 4 consecutive weeks in group 2. Vincristine was given in the dose of 500 μg/kg intraperitonially every week for 4 consecutive weeks in group 3. Myricetin was given orally in a dose of 50, 100, and 200 mg/kg in group 4, 5, and 6 respectively. The statistical significance of the data was determined using one way analysis of variance and Duncan’s multiple range test. Results: The result showed that myricetin increased the antioxidant levels in plasma, erythrocyte lysate, and breast tissue and was effective in preventing the oxidative damage induced by the carcinogen DMBA. Myricetin 50, 100, and 200 mg/kg/oral for 120 days treated animal resulted comparable results to that of standard vincristine and control groups. Conclusions: Myricetin was found to be either equieffective or more effective than vincristine in all the parameters studied. Myricetin proved the capacity of flavonols to act as antioxidant in cells represents a potential treatment in the field of oncology.
Convergence Analysis of an Iterative Targeting Method for Keyhole Robotic Surgery
Authors: Comparetti Mirko Daniele , De Momi Elena , Beyl Tim , Kunze Mirko , Raczkowsky Jörg , Ferrigno Giancarlo 
Published: April 2014

In surgical procedures, robots can accurately position and orient surgical instruments. Intraoperatively, external sensors can localize the instrument and compute the targeting movement of the robot, based on the transformation between the coordinate frame of the robot and the sensor. This paper addresses the assessment of the robustness of an iterative targeting algorithm in perturbed conditions. Numerical simulations and experiments (with a robot with seven degrees of freedom and an optical tracking system) were performed for computing the maximum error of the rotational part of the calibration matrix, which allows for convergence, as well as the number of required iterations. The algorithm converges up to 50 degrees of error within a large working space. The study confirms the clinical relevance of the method because it can be applied on commercially available robots without modifying the internal controller, thus improving the targeting accuracy and meeting surgical accuracy requirements.