bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Neonatal Microbial Recognition: TLR-Mediated Innate Immune Responses Are Specifically and Differentially Modulated by Human Milk
Authors: LeBouder Emmanuel , Rey-Nores Julia E. , Raby Anne-Catherine , Affolter Michael , Vidal Karine , Thornton Catherine A. , Labéta Mario O. 
Published: April 2014

AbstractThe mechanisms controlling innate microbial recognition in the neonatal gut are still to be fully understood. We have sought specific regulatory mechanisms operating in human breast milk relating to TLR-mediated microbial recognition. In this study, we report a specific and differential modulatory effect of early samples (days 1–5) of breast milk on ligand-induced cell stimulation via TLRs. Although a negative modulation was exerted on TLR2 and TLR3-mediated responses, those via TLR4 and TLR5 were enhanced. This effect was observed in human adult and fetal intestinal epithelial cell lines, monocytes, dendritic cells, and PBMC as well as neonatal blood. In the latter case, milk compensated for the low capacity of neonatal plasma to support responses to LPS. Cell stimulation via the IL-1R or TNFR was not modulated by milk. This, together with the differential effect on TLR activation, suggested that the primary effect of milk is exerted upstream of signaling proximal to TLR ligand recognition. The analysis of TLR4-mediated gene expression, used as a model system, showed that milk modulated TLR-related genes differently, including those coding for signal intermediates and regulators. A proteinaceous milk component of ≥80 kDa was found to be responsible for the effect on TLR4. Notably, infant milk formulations did not reproduce the modulatory activity of breast milk. Together, these findings reveal an unrecognized function of human milk, namely, its capacity to influence neonatal microbial recognition by modulating TLR-mediated responses specifically and differentially. This in turn suggests the existence of novel mechanisms regulating TLR activation.
Epitope Enhancement of a CD4 HIV Epitope toward the Development of the Next Generation HIV Vaccine
Authors: Okazaki Takahiro , Pendleton C. David , Sarobe Pablo , Thomas Elaine K. , Iyengar Sujatha , Harro Clayton , Schwartz David , Berzofsky Jay A. 
Published: April 2014

Abstract
Virus-specific CD4+ T cell help and CD8+ cytotoxic T cell responses are critical for maintenance of effective immunity in chronic viral infections. The importance of CD4+ T cells has been documented in HIV infection. To investigate whether a stronger CD4+ T cell response can be induced by modifications to enhance the T1 epitope, the first CD4+ T cell epitope discovered in HIV-1-gp120, we developed a T1-specific CD4+ T cell line from a healthy volunteer immunized with a canarypox vector expressing gp120 and boosted with recombinant gp120. This T1-specific CD4+ T cell line was restricted to DR13, which is common in U.S. Caucasians and African-Americans and very frequent in Africans. Peptides with certain amino acid substitutions in key positions induced enhanced specific CD4+ T cell proliferative responses at lower peptide concentration than the original epitope. This relatively conserved CD4 epitope improved by the epitope enhancement strategy could be a component of a more effective second generation vaccine construct for HIV infection.
Genome-Wide Analysis Reveals a Highly Diverse CD8 T Cell Response to Murine Cytomegalovirus
Authors: Munks Michael W. , Gold Marielle C. , Zajac Allison L. , Doom Carmen M. , Morello Christopher S. , Spector Deborah H. , Hill Ann B. 
Published: April 2014

Abstract
Human CMV establishes a lifelong latent infection in the majority of people worldwide. Although most infections are asymptomatic, immunocompetent hosts devote an extraordinary amount of immune resources to virus control. To increase our understanding of CMV immunobiology in an animal model, we used a genomic approach to comprehensively map the C57BL/6 CD8 T cell response to murine CMV (MCMV). Responses to 27 viral proteins were detectable directly ex vivo, the most diverse CD8 T cell response yet described within an individual animal. Twenty-four peptide epitopes were mapped from 18 Ags, which together account for most of the MCMV-specific response. Most Ags were from genes expressed at early times, after viral genes that interfere with Ag presentation are expressed, consistent with the hypothesis that the CD8 T cell response to MCMV is largely driven by cross-presented Ag. Titration of peptide epitopes in a direct ex vivo intracellular cytokine staining assay revealed a wide range of functional avidities, with no obvious correlation between functional avidity and the strength of the response. The immunodominance hierarchy varied only slightly between mice and between experiments. However, H-2b-expressing mice with different genetic backgrounds responded preferentially to different epitopes, indicating that non-MHC-encoded factors contribute to immunodominance in the CD8 T cell response to MCMV.
A Quantitative Trait Loci Analysis to Map Genes Involved in Lipopolysaccharide-Induced Inflammatory Response: Identification of Macrophage Scavenger Receptor 1 as a Candidate Gene
Authors: Fulton William B. , Reeves Roger H. , Takeya Motohiro , De Maio Antonio 
Published: April 2014

Abstract
Septic shock, which is a major complication observed after trauma and other human diseases, is likely the product of a prolonged and poorly controlled systemic inflammatory response. Symptoms of sepsis can be partially reproduced by injection of bacterial LPS in mice. Differences in mortality between C57BL/6Jhigh and A/Jlow mice after LPS injection have been previously observed and correlated with differences in the inflammatory response between these two inbred strains. In the present study, we have mapped four loci responsible for differences in levels of LPS-induced IL-10, named modifier of IL-10, between the two strains. A locus within mouse chromosome 8 was confirmed using chromosome 8 consomic mice. This locus was further reduced in size by haplotype analysis and evaluated by the presence of potential candidate genes. The macrophage scavenger receptor 1 (Msr1) within this locus emerged as a candidate gene based on differences at the expression and structural levels between C57BL/6J and A/J mice. In comparison with wild-type (C57BL/6J) mice, Msr1 knockout mice displayed reduced levels of LPS-induced IL-10, but not of TNF-α or IL-6, confirming a specific role for this gene in the regulation of IL-10. These results suggest that Msr1 is involved in the regulation of the anti-inflammatory process, thus offering a new perspective on the molecular mechanisms involved in endotoxemia and sepsis.
Pancreatitis-Associated Protein I Suppresses NF-κB Activation through a JAK/STAT-Mediated Mechanism in Epithelial Cells
Authors: Folch-Puy Emma , Granell Susana , Dagorn Jean C. , Iovanna Juan L. , Closa Daniel 
Published: April 2014

Abstract
Pancreatitis-associated protein I (PAP I), also known as HIP, p23, or Reg2 protein, has recently been implicated in the endogenous regulation of inflammation. Although it was initially characterized as a protein that is overexpressed in acute pancreatitis, PAP I has also been associated with a number of inflammatory diseases, such as Crohn’s disease. Knowing that PAP I and IL-10 responses share several features, we have used a pancreatic acinar cell line (AR42J) to assess the extent to which their expression is reciprocally regulated, and whether the JAK/STAT and NF-κB signaling pathways are involved in the suppression of inflammation mediated by PAP I. We observed that PAP I is induced in epithelial cells by IL-10 and by PAP I itself. In contrast, we found phosphorylation and nuclear translocation of STAT3 and induction of suppressor of cytokine signaling 3 in response to PAP I exposure. Finally, a JAK-specific inhibitor, tyrphostin AG490, markedly prevented PAP I-induced NF-κB inhibition, pointing to a cross-talk between JAK/STAT3 and NF-κB signaling pathways. Together, these findings indicate that PAP I inhibits the inflammatory response by blocking NF-κB activation through a STAT3-dependent mechanism. Important functional similarities to the anti-inflammatory cytokine IL-10 suggest that PAP I could play a role similar to that of IL-10 in epithelial cells.
Regulation of IL-1 Family Cytokines IL-1α, IL-1 Receptor Antagonist, and IL-18 by 1,25-Dihydroxyvitamin D3 in Primary Keratinocytes
Authors: Kong Juan , Grando Sergei A. , Li Yan Chun 
Published: April 2014

Abstract
IL-1 family cytokines are key mediators of inflammatory response. Excessive production of these cytokines by keratinocytes has been implicated in inflammatory and hyperproliferative skin diseases. Given the immunosuppressive role of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and its clinical application in treatment of psoriasis, we investigated the effect of 1,25(OH)2D3 on the expression of IL-1α, intracellular IL-1 receptor antagonist (icIL-1Ra), and IL-18 in mouse primary keratinocytes. Treatment of keratinocytes with 1,25(OH)2D3 increased the expression of IL-1α and icIL-1Ra and decreased the expression of IL-18 in dose- and time-dependent manners. The magnitude of icIL-1Ra induction was much greater than that of IL-1α so that the ratio of icIL-1Ra to IL-1α was markedly increased, leading to repression of IL-1 activity. The regulation of these three cytokines by 1,25(OH)2D3 was mediated by vitamin D receptor (VDR), as 1,25(OH)2D3 had no effect in VDR−/− keratinocytes, whereas the effect was restored in cells derived from VDR−/− mice expressing human VDR. 1,25(OH)2D3 appeared to use different mechanisms to regulate the biosynthesis of IL-1α and icIL-1Ra: it increased IL-1α mRNA stability whereas it enhanced icIL-1Ra gene transcription. The basal IL-18 expression and activity were much higher in VDR−/− keratinocytes and skin, underscoring the importance of the repressive role of vitamin D in IL-18 production. Similar regulation of these cytokines was also seen in primary human keratinocytes. Collectively, these results suggest that vitamin D modulates cutaneous inflammatory reactions, at least in part, by increasing the IL-1Ra to IL-1α ratio and suppressing IL-18 synthesis in keratinocytes.
Mast Cell β-Tryptase Selectively Cleaves Eotaxin and RANTES and Abrogates Their Eosinophil Chemotactic Activities
Authors: Pang Linhua , Nie Mei , Corbett Lisa , Sutcliffe Amy , Knox Alan J. 
Published: April 2014

Abstract
Recent studies have shown that a lack of eosinophils in asthmatic airway smooth muscle (ASM) bundles in contrast to the large number of mast cells is a key feature of asthma. We hypothesized that this is caused by β-tryptase, the predominant mast cell-specific protease, abrogating the eosinophil chemotactic activities of ASM cell-derived eosinophil chemoattractants such as eotaxin and RANTES. We studied the effect of β-tryptase on the immunoreactivities of human ASM cell-derived and recombinant eotaxin and other recombinant chemokines that are known to be produced by human ASM cells. We report in this study that purified β-tryptase markedly reduced the immunoreactivity of human ASM cell-derived and recombinant eotaxin, but had no effect on eotaxin mRNA expression. The effect was mimicked by recombinant human β-tryptase in the presence of heparin and was reversed by heat inactivation and the protease inhibitor leupeptin, suggesting that the proteolytic activity of tryptase is required. β-Tryptase also exerted similar effects on recombinant RANTES, but not on the other chemokines and cytokines that were screened. Furthermore, a chemotaxis assay revealed that recombinant eotaxin and RANTES induced eosinophil migration concentration-dependently, which was abrogated by pretreatment of these chemokines with β-tryptase. Another mast cell protease chymase also markedly reduced the immunoreactivity of eotaxin, but had no effect on RANTES and other chemokines and did not affect the influence of β-tryptase on RANTES. These findings suggest that mast cell β-tryptase selectively cleaves ASM-derived eotaxin and RANTES and abrogates their chemotactic activities, thus providing an explanation for the eosinophil paucity in asthmatic ASM bundles.
MyD88 and TNF Receptor-Associated Factor 6 Are Critical Signal Transducers in Helicobacter pylori-Infected Human Epithelial Cells
Authors: Hirata Yoshihiro , Ohmae Tomoya , Shibata Wataru , Maeda Shin , Ogura Keiji , Yoshida Haruhiko , Kawabe Takao , Omata Masao 
Published: April 2014

Abstract
Helicobacter pylori induces NF-κB activation, leading to mucosal inflammation via cag pathogenicity island. Although recent studies have implicated several candidate proteins of both H. pylori and host, the molecular mechanism by which H. pylori activates NF-κB remains unclear. The aim of this study was to analyze the mechanism of cag pathogenicity island-mediated NF-κB activation in epithelial cells. The responses of human cell lines and mouse embryonic fibroblasts to infection with wild-type H. pylori or cagE mutant were investigated. The effect of small interfering RNAs (siRNAs) for several NF-κB signaling intermediate molecules was evaluated in H. pylori-induced IκBα phosphorylation and IL-8 production. Protein interactions of exogenously expressed TNFR-associated factor 6 (TRAF6) and MyD88 or receptor-interacting protein 2 and nucleotide-binding oligomerization domain 1 or those of endogenous IκB kinase, TGF-β-activated kinase 1 (TAK1), and TRAF6 were assessed by immunoprecipitation. Cag pathogenicity island-dependent NF-κB activation was observed in human cell lines, but not in mouse fibroblasts. In human epithelial cells, H. pylori-induced IκBα phosphorylation and IL-8 production were severely inhibited by siRNAs directed against TAK1, TRAF6, and MyD88. In contrast, siRNAs for TRAF2, IL-1R-associated kinases 1 and 4, and cell surface receptor proteins did not affect these responses. H. pylori infection greatly enhanced MyD88 and TRAF6 complex formation in a cag-dependent manner, but did not enhance Nod1 and receptor-interacting protein 2 complex formation. H. pylori also induced TAK1 and TRAF6 complexes. These results suggest that the cag pathogenicity island of H. pylori is a cell type-specific NF-κB activator. TAK1, TRAF6, and MyD88 are important signal transducers in H. pylori-infected human epithelial cells.
Microglia Recognize Double-Stranded RNA via TLR3
Authors: Town Terrence , Jeng David , Alexopoulou Lena , Tan Jun , Flavell Richard A. 
Published: April 2014

Abstract
Microglia are CNS resident innate immune cells of myeloid origin that become activated and produce innate proinflammatory molecules upon encountering bacteria or viruses. TLRs are a phylogenetically conserved diverse family of sensors for pathogen-associated molecular patterns that drive innate immune responses. We have recently shown that mice deficient in TLR3 (TLR3−/− mice) are resistant to lethal encephalitis and have reduced microglial activation after infection with West Nile virus, a retrovirus that produces dsRNA. We wished to determine whether microglia recognize dsRNA through the TLR3 pathway. In vitro, murine wild-type primary cultured microglia responded to synthetic dsRNA polyinosinic-polycytidylic acid (poly(I:C)) by increasing TLR3 and IFN-β mRNA and by morphologic activation. Furthermore, wild-type microglia dose dependently secreted TNF-α and IL-6 after poly(I:C) challenge, whereas TLR3−/− microglia produced diminished cytokines. Activation of MAPK occurred in a time-dependent fashion following poly(I:C) treatment of wild-type microglia, but happened with delayed kinetics in TLR3−/− microglia. As an in vivo model of encephalitis, wild-type or TLR3−/− mice were injected intracerebroventricularly with poly(I:C) or LPS, and microglial activation was assessed by cell surface marker or phospho-MAPK immunofluorescence. After intracerebroventricular injection of poly(I:C), microgliosis was clearly evident in wild-type mice but was nearly absent in TLR3−/− animals. When taken together, our results demonstrate that microglia recognize dsRNA through TLR3 and associated signaling molecules and suggest that these cells are key sensors of dsRNA-producing viruses that may invade the CNS.
Preprotachykinin-A Gene Products Are Key Mediators of Lung Injury in Polymicrobial Sepsis
Authors: Puneet Padmam , Hegde Akhil , Ng Siaw Wei , Lau Hon Yen , Lu Jia , Moochhala Shabbir M. , Bhatia Madhav 
Published: April 2014

Abstract
Preprotachykinin-A (PPT-A) gene products substance P and neurokinin-A have been shown to play an important role in neurogenic inflammation. To investigate the role of PPT-A gene products in lung injury in sepsis, polymicrobial sepsis was induced by cecal ligation and puncture in PPT-A gene-deficient mice (PPT-A−/−) and the wild-type control mice (PPT-A+/+). PPT-A gene deletion significantly protected against mortality, delayed the onset of lethality, and improved the long-term survival following cecal ligation and puncture-induced sepsis. PPT-A−/− mice also had significantly attenuated inflammation and damage in the lungs. The data suggest that deletion of the PPT-A gene may have contributed to the disruption in recruitment of inflammatory cells resulting in protection against tissue damage, as in these mice the sepsis-associated increase in chemokine levels is significantly attenuated.
T Cell Responses in Dengue Hemorrhagic Fever: Are Cross-Reactive T Cells Suboptimal?
Authors: Mongkolsapaya Juthathip , Duangchinda Thaneeya , Dejnirattisai Wanwisa , Vasanawathana Sirijit , Avirutnan Panisadee , Jairungsri Aroonroong , Khemnu Nuanpan , Tangthawornchaikul Nattaya , Chotiyarnwong Pojchong , Sae-Jang Kanokwan , Koch Michael , Jones Yvonne , McMichael Andrew , Xu Xiaoning , Malasit Prida , Screaton Gavin 
Published: April 2014

Abstract
Dengue virus infection poses a growing public health and economic burden in a number of tropical and subtropical countries. Dengue circulates as a number of quasispecies, which can be divided by serology into four groups or serotypes. An interesting feature of Dengue, recognized over five decades ago, is that most severe cases that show hemorrhagic fever are not suffering from a primary infection. Instead, they are reinfected with a virus of different serotype. This observation poses considerable problems in vaccine design, and it is therefore imperative to gain a full understanding of the mechanisms underlying this immunological enhancement of disease. In this study, we examined a T cell epitope restricted by HLA-A*24, a major MHC class I allele, in Southeast Asia in a cohort of children admitted to a hospital with acute Dengue infection. The cytokine profiles and the degranulation capacity of T cells generated to this epitope are defined and compared across different viral serotypes. Cross-reactive Dengue-specific T cells seem to show suboptimal degranulation but high cytokine production, which may contribute to the development of the vascular leak characteristic of Dengue hemorrhagic fever.
Sensitization of IL-2 Signaling through TLR-7 Enhances B Lymphoma Cell Immunogenicity
Authors: Tomic Jelena , White Dionne , Shi Yonghong , Mena Jenny , Hammond Caitlin , He Liwei , Miller Richard L. , Spaner David E. 
Published: April 2014

Abstract
The innate ability of B lymphoma cells to escape control by tumor-reactive T cells must be overcome to develop effective immunotherapies for these diseases. Because signals from both the innate and adaptive immune systems direct the acquisition of strong immunogenicity by professional APCs, the effects of IL-2 and the TLR-7 agonist, S28690, on the immunogenic properties of chronic lymphocytic leukemia (CLL) B cells were studied. IL-2 with S28690 caused CLL cells to proliferate and increased their expression of B7-family members, production of TNF-α and IL-10, and levels of tyrosine-phosphorylated STAT-1 and STAT-3 proteins. S28690 increased CD25 expression on CLL cells and sensitized them to IL-2 signaling. However, IL-2 did not change TLR-7 expression or signaling in CLL cells. The ability to stimulate T cell proliferation required additional activation of protein kinase C, which inhibited tumor cell proliferation, “switched off” IL-10 production, and caused essentially all CLL cells (regardless of clinical stage) to acquire a CD83highCD80highCD86highCD54high surface phenotype marked by the activation of STAT-1 without STAT-3. These findings suggest that TLR-7 “licenses” human B cells to respond to cytokines of the adaptive immune system (such as IL-2) and provide a strategy to increase the immunogenicity of lymphoma cells for therapeutic purposes.
Should Smaller Commercial Trucks Be Subject to Safety Regulations?
Authors: Corsi Thomas M. , Grimm Curtis , Cantor David , Wright Donald 
Published: April 2014

Abstract
Motor-carrier safety is a critical and challenging issue in the US motor-carrier industry. Despite the vast safety improvements in the industry, a continuing challenge is the economic costs associated with regulatory oversight of safety inspection programs. The purpose of this article is to compute the costs and associated benefits of the Federal Motor Carrier Safety Administration's driver and vehicle inspection program of commercial motor vehicles in the 10,001- to 26,000-lb category. Our analysis reveals that for every dollar spent in program costs, the benefits are $8.86.
Heat transport in hyporheic zones due to bedforms: An experimental study
Authors: Norman Francis A. , Cardenas M. Bayani 
Published: April 2014

AbstractHeat transport in hyporheic zones is critical for many temperature‐sensitive physical, chemical, and biological processes. It also plays a role in the energy balance of rivers. To complement previous theoretical studies, we investigated the effects of hyporheic flow due to bed topography on hyporheic thermal dynamics through flume experiments. Diel temperature cycles were imposed in the channel and propagation of temperature signals into the sediment was examined for three different bed morphologies (flat bed, pool‐riffle‐pool, and rippled bed), three‐channel flow rates, and two sediment grain sizes. Results show that the downwelling upstream and downstream of the bedforms and upwelling focused near the crest caused substantial advective heat transport and distinct thermal patterns in the sediment, with downwelling zones reflecting most of the surface water diel thermal range whereas upwelling zones were more buffered. Increasing permeability and channel flow rates increased advective transport. The results corroborate previous theoretical models further showing that hyporheic flow distinctly affects thermal patchiness in sediment. The results also have implications for heat tracing using analytical models which work well for flow fields without pronounced divergence and convergence and minimal dispersion, features atypical of hyporheic flow.
Debates—the future of hydrological sciences: A (common) path forward? Using models and data to learn: A systems theoretic perspective on the future of hydrological science
Authors: Gupta Hoshin V. , Nearing Grey S. 
Published: April 2014

Key Points

Discovery can be advanced by taking a perspective based in Information Theory
Much can be gained by focusing on the a priori role of Process Modeling
System Parameterization can result in information loss