bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Receptor for Advanced Glycation End Products Impairs Host Defense in Pneumococcal Pneumonia
Authors: van Zoelen Marieke A. D. , Schouten Marcel , de Vos Alex F. , Florquin Sandrine , Meijers Joost C. M. , Nawroth Peter P. , Bierhaus Angelika , van der Poll Tom 
Published: March 2009

Abstract
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. The receptor for advanced glycation end products (RAGE) is a multiligand receptor that is expressed ubiquitously in the lungs. Engagement of RAGE leads to activation of multiple intracellular signaling pathways, including NF-κB and subsequent transcription of several proinflammatory mediators. To determine the role of RAGE in the innate immune response to S. pneumoniae pneumonia, RAGE-deficient (RAGE−/−) and wild-type mice were intranasally inoculated with S. pneumoniae. S. pneumoniae pneumonia resulted in an up-regulation of constitutively present RAGE expression in lung tissue, especially in the interalveolar septae. RAGE−/− mice showed an improved survival, which was accompanied by a lower bacterial load in the lungs at 16 h and a decreased dissemination of the bacteria to blood and spleen at 16 and 48 h after inoculation. RAGE−/− macrophages showed an improved killing capacity of S. pneumoniae in vitro. Lung inflammation was attenuated in RAGE−/− mice at 48 h after inoculation, as indicated by histopathology and cytokine/chemokine levels. Neutrophil migration to the lungs was mitigated in the RAGE−/− mice. In addition, in RAGE−/− mice, activation of coagulation was diminished. Additional studies examining the effect of RAGE deficiency on the early (6-h) inflammatory response to S. pneumoniae did not reveal an early accelerated or enhanced immune response. These data suggest that RAGE plays a detrimental role in the host response to S. pneumoniae pneumonia by facilitating the bacterial growth and dissemination and concurrently enhancing the pulmonary inflammatory and procoagulant response.
Reduced c-myc Expression Levels Limit Follicular Mature B Cell Cycling in Response to TLR Signals
Authors: Meyer-Bahlburg Almut , Bandaranayake Ashok D. , Andrews Sarah F. , Rawlings David J. 
Published: March 2009

Abstract
The splenic B cell compartment is comprised of two major, functionally distinct, mature B cell subsets, i.e., follicular mature (FM) and marginal zone (MZ) B cells. Whereas MZ B cells exhibit a robust proliferative response following stimulation with the TLR4 ligand LPS, FM B cells display markedly delayed and reduced levels of proliferation to the identical stimulus. The current study was designed to identify a potential mechanism(s) accounting for this differential responsiveness. In contrast to the delay in cell cycle entry, FM and MZ B cells exhibited nearly identical LPS-driven alterations in the expression level of cell surface activation markers. Furthermore, both the NF-κB and mTOR signaling cascades were similarly activated by LPS stimulation in FM vs MZ B cells, while inducible activation of ERK and AKT were nearly absent in both subsets. MZ B cells, however, exhibited higher basal levels of phospho-AKT and pS6, consistent with a preactivated status. Importantly, both basal and LPS activation-induced c-myc expression was markedly reduced in FM vs MZ B cells and enforced c-myc expression fully restored the defective proliferative response in FM B cells. These data support a model wherein TLR responses in FM B cells are tightly regulated by limiting c-myc levels, thereby providing an important checkpoint to control nonspecific FM B cell activation in the absence of cognate Ag.
Bacterial DNA Activates Endothelial Cells and Promotes Neutrophil Adherence through TLR9 Signaling
Authors: El Kebir Driss , József Levente , Pan Wanling , Wang Lili , Filep János G. 
Published: March 2009

Abstract
TLR9 detects bacterial DNA (CpG DNA) and elicits both innate and adoptive immunity. Recent evidence indicates that TLR9 is expressed in more diverse cell types than initially thought. In this study, we report that HUVECs constitutively express TLR9 and selectively recognize unmethylated CpG motifs in bacterial DNA and synthetic immune stimulatory CpG oligodeoxynucleotides. HUVECs respond to CpG DNA with rapid phosphorylation of IκB-α and NF-κB-mediated gene transcription and surface expression of the adhesion molecules ICAM-1 and E-selectin independent of MAPK signaling. The telomere-derived TLR9 inhibitory oligonucleotide 5′-TTT AGG GTT AGG GTT AGG G-3′, agents that block endosomal acidification such as chloroquine and bafilomycin A, and NF-κB inhibitors abrogated CpG DNA-induced signaling. HUVEC activation by CpG DNA led to markedly enhanced neutrophil adhesion under nonstatic conditions that was further enhanced when neutrophils were stimulated with CpG DNA. The adhesive interactions were blocked by Abs against CD18 and, to a lesser degree, by anti-E-selectin and anti-L-selectin Abs. Our findings demonstrate that bacterial DNA promotes β2 integrin and E-selectin-mediated HUVEC-neutrophil adherence, and indicate the ability of CpG DNA to initiate and/or maintain the inflammatory response.
TLR3 Ligand Induces NF-κB Activation and Various Fates of Multiple Myeloma Cells Depending on IFN-α Production
Authors: Chiron David , Pellat-Deceunynck Catherine , Amiot Martine , Bataille Régis , Jego Gaëtan 
Published: March 2009

Abstract
Multiple myeloma (MM) cells express TLR. It has been shown that TLR ligands induce the proliferation, survival, and immune surveillance escape of MM cells through MyD88-TLR pathways. Deciphering TLR function in MM cells will help in understanding the mechanisms of tumor cell growth. In this study, we examined the response of MM cells to the MyD88-independent/TIR-domain-containing adapter-inducing IFN-β-dependent TLR3. Deregulation of NF-κB pathway is a feature of MM cells, and we wondered whether TLR3 activation could mobilize the NF-κB pathway. We show that five of seven human myeloma cell line (HMCL) cells expressed TLR3. In the presence of the synthetic TLR3 ligand (poly(I:C)), activation of NF-κB pathway was observed in three of five selected TLR3+ HMCL, NCI-H929, RPMI 8226, and KMM1. In agreement with NF-κB activation, only these three HMCL responded to poly(I:C), although by either an increase (KMM1) or a decrease (NCI-H929, RPMI 8226) of proliferation. We show that KMM1 increase of proliferation was prevented by NF-κB inhibitor. In contrast, inhibition of proliferation in both NCI-H929 and RPMI 8226 was due to IFN-α-induced apoptosis. We next demonstrated that p38 MAPK pathway controlled both IFN-α secretion and IFN-α-mediated cell death. Moreover, cell death also involved activation of ERK1/2 pathway. In conclusion, our results show that TLR3 ligand induces NF-κB pathway activation in MM and support a switching function of type I IFN in the functional outcome of TLR3 triggering in tumor cells.
Interactions between Human NK Cells and Macrophages in Response to Salmonella Infection
Authors: Lapaque Nicolas , Walzer Thierry , Méresse Stéphane , Vivier Eric , Trowsdale John 
Published: March 2009

Abstract
NK cells play a key role in host resistance to a range of pathogenic microorganisms, particularly during the initial stages of infection. NK cell interactions with cells infected with viruses and parasites have been studied extensively, but human bacterial infections have not been given the same attention. We studied crosstalk between human NK cells and macrophages infected with intracellular Salmonella. These macrophages activated NK cells, resulting in secretion of IFN-γ and degranulation. Reciprocally, NK cell activation led to a dramatic reduction in numbers of intramacrophagic live bacteria. We identified three elements in the interaction of NK cells with infected macrophages. First, communication between NK cells and infected macrophages was contact-dependent. The second requirement was IL-2- and/or IL-15-dependent priming of NK cells to produce IFN-γ. The third was activation of NK cells by IL-12 and IL-18, which were secreted by the Salmonella-infected macrophages. Adhesion molecules and IL-12Rβ2 were enriched in the contact zone between NK cells and macrophages, consistent with contact- and IL-12/IL-18-dependent NK activation. Our results suggest that, in humans, bacterial clearance is consistent with a model invoking a “ménage à trois” involving NK cells, IL-2/IL-15-secreting cells, and infected macrophages.
Identification and Characterization of a Human CD5+ Pre-Naive B Cell Population
Authors: Lee Jisoo , Kuchen Stefan , Fischer Randy , Chang Sooghee , Lipsky Peter E. 
Published: March 2009

Abstract
We have identified a distinct pre-naive B cell population circulating in human peripheral blood that exhibits an intermediate phenotype between transitional and naive B cells. Like human transitional B cells, these cells express CD5 but have intermediate densities of CD38, CD10, CD9, and the ABCB1 transporter compared with transitional and naive B cells. These pre-naive B cells account for a majority of circulating human CD5+ B cells. Importantly, CD5+ pre-naive B cells could be induced to differentiate into cells with a naive phenotype in vitro. CD5+ pre-naive B cells show only partial responses to BCR stimulation and CD40 ligation and undergo more spontaneous apoptosis and cell death than do naive B cells, whereas BAFF/BLyS (B cell-activating factor belonging to the TNF family) did not enhance their survival compared with naive B cells. In contrast, CD5+ pre-naive B cells carry out certain functions comparable to naive B cells, including the capacity to differentiate into plasma cells and the ability to function as APCs. Notably, an increased proportion of CD5+ pre-naive B cells were found in peripheral blood of patients with systemic lupus erythematosus. These results have identified a unique intermediate in human naive B cell development within the peripheral blood and derangements of its homeostasis in patients with systemic lupus erythematosus.
Early NK Cell-Derived IFN-γ Is Essential to Host Defense in Neutropenic Invasive Aspergillosis
Authors: Park Stacy J. , Hughes Molly A. , Burdick Marie , Strieter Robert M. , Mehrad Borna 
Published: March 2009

Abstract
Invasive aspergillosis is among the most common human fungal infections and occurs in patients with severe and complex defects in immune responses. NK cells have previously been found to be important in host defense against this infection, but the mechanism of this effect is not known. We hypothesized that NK cells mediate their protective effect in invasive aspergillosis by acting as the major source of IFN-γ during early infection. We found that, in the lungs of neutropenic mice with invasive aspergillosis, NK cells were the major population of cells capable of generating IFN-γ during early infection. Depletion of NK cells resulted in reduced lung IFN-γ levels and increased lung fungal load that was independent of T and B cell subsets. Depletion of NK cells and absence of IFN-γ resulted in a similar increase in susceptibility to the infection, but depletion of NK cells in IFN-γ-deficient hosts did not result in further increase in severity of the infection. NK cell-derived IFN-γ caused enhanced macrophage antimicrobial effects in vitro and also resulted in greater expression of IFN-inducible chemokines in the lungs. Finally, transfer of activated NK cells from wild-type, but not IFN-γ-deficient hosts, resulted in greater pathogen clearance from the lungs of both IFN-γ-deficient and wild-type recipients. Taken together, these data indicate that NK cells are the main source of early IFN-γ in the lungs in neutropenic invasive aspergillosis, and this is an important mechanism in the defense against this infection.
Protective Antigen-Independent CD8 T Cell Memory Is Maintained during γ-Herpesvirus Persistence
Authors: Cush Stephanie S. , Flaño Emilio 
Published: March 2009

Abstract
Ag persistence during high-titer chronic viral infections induces CD8 T cell dysfunction and lack of Ag-independent CD8 T cell memory formation. However, we have a poor understanding of the generation and maintenance of CD8 T cell memory during asymptomatic persistent viral infections, particularly γ-herpesvirus infections. In this study, we demonstrate that the continuous presence of cognate Ag in the host is not required for the maintenance of CD8 T cell memory during a persistent γ-herpesvirus infection. Importantly, the Ag-independent CD8 T cell memory that is maintained during γ-herpesvirus persistence has the capacity to survive long-term under homeostatic conditions and to mount a protective recall response to a secondary encounter with the pathogen. These data highlight the ability of the immune system to maintain a population of protective memory CD8 T cells with capacity for long-term Ag-independent survival in the presence of systemic virus persistence.
Isoforms of Vitamin E Have Opposing Immunoregulatory Functions during Inflammation by Regulating Leukocyte Recruitment
Authors: Berdnikovs Sergejs , Abdala-Valencia Hiam , McCary Christine , Somand Michelle , Cole Rokeisha , Garcia Alex , Bryce Paul , Cook-Mills Joan M. 
Published: March 2009

Abstract
Reports indicate contradictory outcomes for anti-inflammatory functions of the α-tocopherol isoform of vitamin E in clinical studies of asthma and atherosclerosis. These seemingly disparate clinical results are consistent with novel unrecognized properties of isoforms of vitamin E reported in this study. We demonstrate that the isoform d-γ-tocopherol elevates inflammation in experimental asthma. Moreover, d-γ-tocopherol, at as little as 10% the concentration of d-α-tocopherol, ablates the anti-inflammatory benefit of the d-α-tocopherol isoform. A mechanism for these opposing immunoregulatory functions of purified tocopherols at physiological concentrations is not through modulation of expression of several cytokines, chemokines, or adhesion molecules, but is, at least in part, by regulation of endothelial cell signals during leukocyte recruitment. These opposing regulatory functions of vitamin E isoforms have impact on interpretations of vitamin E studies. In summary, our studies with purified tocopherol isoforms alter our understanding of vitamin E regulation of vascular function and asthma.
Human IgG4 Binds to IgG4 and Conformationally Altered IgG1 via Fc-Fc Interactions
Authors: Rispens Theo , Ooievaar-De Heer Pleuni , Vermeulen Ellen , Schuurman Janine , van der Neut Kolfschoten Marijn , Aalberse Rob C. 
Published: March 2009

Abstract
The Fc fragment of IgG4 can interact with the Fc fragment of another IgG molecule. This interaction is a confounding factor when measuring IgG4 rheumatoid factor levels. Recently, we demonstrated that half-molecules of IgG4 can exchange to form a bispecific Ab. We expected these two phenomena to be related and investigated the physicochemical aspects of IgG4 Fc-Fc interactions. We found that IgG4 is &gt;99% monomeric by size-exclusion chromatography; therefore, IgG4 Fc-Fc interactions in the fluid phase (if any) would be short-lived. However, 125I-labeled IgG4 does bind to IgG1 and IgG4 coupled to a solid phase. By contrast, IgG1 does not bind to coupled IgG4. Furthermore, conditions that induce partial unfolding/dissociation of the CH3 domains enhance IgG4 Fc binding, suggesting that Fc binding is primarily CH3 mediated. IgG4 slowly associates with both IgG4 and IgG1 coupled to a biosensor chip. Remarkably, subsequent dissociation was much faster for IgG4 than for IgG1. Moreover, after binding of an IgG4 mAb to Sepharose-coupled Ag, we observed additional binding of IgG4 with irrelevant specificity, whereas similar binding was not observed with Ag-bound IgG1. We propose that the IgG4-IgG4 Fc interaction resembles an intermediate of the Fab-arm (half-molecule) exchange reaction that is stabilized because one of the IgG4 molecules is coupled to a solid phase. By contrast, IgG4 Fc recognizes IgG1 only after a conformational change that renders CH3(IgG1) accessible to an interaction with the CH3(IgG4). Such Fc interactions may enhance Ag binding of IgG4 in vivo.
TLR-Induced Local Metabolism of Vitamin D3 Plays an Important Role in the Diversification of Adaptive Immune Responses
Authors: Enioutina Elena Yu , Bareyan Diana , Daynes Raymond A. 
Published: March 2009

Abstract
The addition of monophosphoryl lipid A, a minimally toxic derivative of LPS, to nonmucosally administered vaccines induced both systemic and mucosal immune responses to coadministered Ags. This was dependent on an up-regulated expression of 1α-hydroxylase (CYP27B1, 1αOHase), the enzyme that converts 25-hydroxycholecalciferol, a circulating inactive metabolite of vitamin D3, into 1,25(OH)2D3 (calcitriol). In response to locally produced calcitriol, myeloid dendritic cells (DCs) migrated from cutaneous vaccination sites into multiple secondary lymphoid organs, including classical inductive sites of mucosal immunity, where they effectively stimulated B and T cell immune responses. The endogenous production of calcitriol by monophosphoryl lipid A-stimulated DCs appeared to be Toll-IL-1R domain-containing adapter-inducing IFN-β-dependent, mediated through a type 1 IFN-induced expression of 1αOHase. Responsiveness to calcitriol was essential to promote the trafficking of mobilized DCs to nondraining lymphoid organs. Collectively, these studies help to expand our understanding of the physiologically important roles played by locally metabolized vitamin D3 in the initiation and diversification of adaptive immune responses. The influences of locally produced calcitriol on the migration of activated DCs from sites of vaccination/infection into both draining and nondraining lymphoid organs create a condition whereby Ag-responsive B and T cells residing in multiple lymphoid organs are able to simultaneously engage in the induction of adaptive immune responses to peripherally administered Ags as if they were responding to an infection of peripheral or mucosal tissues they were designed to protect.
Multipurpose On‐the‐Spot Peptide‐Based Hydrogels for Skin, Cornea, and Heart Repair
Authors: Ross Alex , Guo Xixi , Salazar German A. Mercado , Schejtman Sergio David Garcia , El‐Hage Jinane , Comtois‐Bona Maxime , Macadam Aidan , Guzman‐Soto Irene , Takaya Hiroki , Hu Kevin , Liu Bryan , Tu Ryan , Siddiqi Bilal , Anderson Erica , Muñoz Marcelo , Briones‐Rebolledo Patricio , Ning Tianqin , Griffith May , Rotsein Benjamin , Poblete Horacio , Li Jianyu , Ruel Marc , Suuronen Erik J. , Alarcon Emilio I. 
Published: April 2024

AbstractBioinspired synthetic materials can be designed as reliable, cost‐effective, and fully controlled alternatives to natural biomaterials for treating damaged tissues and organs. However, several hurdles need to be overcome for clinical translation, particularly for biomaterials gelled in situ. These include the potential toxicity of chemical crosslinkers used in the materials' assembly or breakdown products they generate and the challenges of fine‐tuning the mechanical properties of the materials. Here, a minimalistic, adhesive soft material is developed by screening hundreds of potential formulations of self‐assembling, custom‐designed collagen‐like peptide sequences for the in situ formation of tissue‐bonding 3D hydrogels. Nine promising formulations for tissue repair are identified using a low‐volume and rapid combinatory screening approach. It is shown that simply varying the ratio of the two key components promotes adhesion and fine‐tunes the material's mechanical properties. The materials' skin and heart repair capabilities are assessed in vitro and clinically relevant animal models. The materials are also tested for corneal applications using ex vivo pig cornea models complemented by in vitro cell compatibility assays.
Deep Learning Prediction of Triplet–Triplet Annihilation Parameters in Blue Fluorescent Organic Light‐Emitting Diodes
Authors: Lim Junseop , Kim Jae‐Min , Lee Jun Yeob 
Published: April 2024

AbstractThe triplet–triplet annihilation (TTA) ratio and the rate coefficient (kTT) of TTA are key factors in estimating the contribution of triplet excitons to radiative singlet excitons in fluorescent TTA organic light‐emitting diodes. In this study, deep learning models are implemented to predict key factors from transient electroluminescence (trEL) data using new numerical equations. A new TTA model is developed that considers both polaron and exciton dynamics, enabling the distinction between prompt and delayed singlet decays with a fundamental understanding of the mechanism. In addition, deep learning models for predicting the kinetic coefficients and TTA ratio are established. After comprehensive optimization inspired by photophysics, determination coefficient values of 0.992 and 0.999 are achieved in the prediction of kTT and TTA ratio, respectively, indicating a nearly perfect prediction. The contribution of each kinetic parameter of polaron and exciton dynamics to the trEL curve is discussed using various deep‐learning models.
Boosting Contact Electrification by Amorphous Polyvinyl Alcohol Endowing Improved Contact Adhesion and Electrochemical Capacitance
Authors: Serairi Lisa , Santillo Chiara , Basset Philippe , Lavorgna Marino , Pace Giuseppina 
Published: April 2024

AbstractIon conductive hydrogels are relevant components in wearable, biocompatible, and biodegradable electronics. Polyvinyl‐alcohol (PVA) homopolymer is often the favored choice for integration into supercapacitors and energy harvesters as in sustainable triboelectric nanogenerators (TENGs). However, to further improve hydrogel‐based TENGs, a deeper understanding of the impact of their composition and structure on devices performance is necessary. Here, it is shown how ionic hydrogels based on an amorphous‐PVA (a‐PVA) allow to fabricate TENGs that outperform the one based on the homopolymer. When used as tribomaterial, the Li‐doped a‐PVA allows to achieve a twofold higher pressure sensitivity compared to PVA, and to develop a conformable e‐skin. When used as an ionic conductor encased in an elastomeric tribomaterial, 100 mW cm−2 average power is obtained, providing 25% power increase compared to PVA. At the origin of such enhancement is the increased softness, stronger adhesive contact, higher ionic mobility (> 3,5‐fold increase), and long‐term stability achieved with Li‐doped a‐PVA. These improvements are attributed to the high density of hydroxyl groups and amorphous structure present in the a‐PVA, enabling a strong binding to water molecules. This work discloses novel insights on those parameters allowing to develop easy‐processable, stable, and highly conductive hydrogels for integration in conformable, soft, and biocompatible TENGs.
Regioselective C6‐Arylation of Thieno[3,2‐c]pyrazole Heterocycles with Aryl Iodides
Authors: Ait Lfakir Noura , Jismy Badr , Guillaumet Gérald , Akssira Mohamed , El Hakmaoui Ahmed , Guillot Régis , Tikad Abdellatif , Abarbri Mohamed 
Published: April 2024

AbstractRegioselective C6‐arylation of thieno[3,2‐c]pyrazoles with aryl iodides as coupling partners has been developed. This strategy was performed in the presence of Pd(OAc)2 as catalyst in combination with AgOTf as an oxidant and TFA in dimethylacetamide. In all experiments, only the C6‐arylated thieno[3,2‐c]pyrazole was isolated since its C5‐regioisomer was not observed, indicating the high regioselectivity of this approach. The catalytic system used is compatible with a variety of 3‐functionalized thieno[3,2‐c]pyrazoles and iodoaryl electrophiles, providing access to 3,6‐disubstituted thieno[3,2‐c]pyrazoles in yields ranging from 49% to 94%.