bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Secreted Antigenic Target of 6-kDa Protein ofMycobacterium tuberculosisPrimes Dendritic Cells To Stimulate Th17 and Inhibit Th1 Immune Responses
Authors: Wang Xisheng , Barnes Peter F. , Huang Fangfang , Alvarez Ivana B. , Neuenschwander Pierre F. , Sherman David R. , Samten Buka 
Published: August 2012

AbstractEarly secreted antigenic target of 6 kDa (ESAT-6) of Mycobacterium tuberculosis is a T cell Ag that is a potential vaccine candidate, but it is also a virulence factor that mediates pathogenicity. To better understand the effects of ESAT-6 on the immune response, we studied the effect of ESAT-6 on human dendritic cells (DCs). Peripheral blood monocytes were treated with GM-CSF and IL-4 to yield immature DCs, which were matured by addition of LPS and CD40 ligand (CD40L), with or without ESAT-6. ESAT-6 inhibited LPS/CD40L-induced DC expression of costimulatory molecules, reduced DC-stimulated allogeneic T cell proliferation and IL-2 and IFN-γ production, and enhanced IL-17 production. ESAT-6–treated DCs also increased IL-17 and reduced IFN-γ production by M. tuberculosis-specific autologous T cells. ESAT-6 inhibited LPS/CD40L-induced DC production of IL-12 and enhanced that of IL-23 and IL-1β, without affecting secretion of TNF-α, IL-6, or IL-8 through specific interaction with immature DCs. The effects of ESAT-6 were not mediated through cAMP or p38 MAPK. Medium from ESAT-6–conditioned DCs increased IL-17 and reduced IFN-γ production by T cells stimulated with anti-CD3 plus anti-CD28, and ESAT-6–induced IL-17 production was blocked by neutralizing both IL-23 and IL-1β. ESAT-6 reduced LPS/CD40L-stimulated transcription of IL-12p35 and enhanced that of IL-23p19 through inhibition of IFN regulatory factor-1 and upregulation of activating transcription factor-2 and c-Jun, transcriptional regulators of IL-12p35 and IL-23p19, respectively. We conclude that ESAT-6 increases DC production of IL-23 and IL-1β while inhibiting that of IL-12, thus enhancing Th17 at the expense of protective Th1 responses.
Cutting Edge: TLR13 Is a Receptor for Bacterial RNA
Authors: Hidmark Asa , von Saint Paul Antonia , Dalpke Alexander H. 
Published: August 2012

Abstract
Bacterial RNA (bRNA) can induce cytokine production in macrophages and dendritic cells (DCs) through a previously unidentified receptor. Gene expression analysis of murine DCs showed that bRNA induced gene regulation similar to that induced by stimulation of TLR7 with R848. Although TLR7 was dispensable for cytokine induction by bRNA, TLR-associated proteins MyD88 and UNC93B were required. TLR13 is an endosomal murine TLR that has been described to interact with UNC93B with, so far, no characterized ligand. Small interfering RNA against TLR13 reduced cytokine induction by bRNA in DCs. Moreover, Chinese hamster ovary cells transfected with TLR13, but not with TLR7 or 8, could activate NF-κB in response to bRNA or Streptococcus pyogenes in an RNA-specific manner. TLR7 antagonist IRS661 could, in addition, inhibit TLR13 signaling and reduced recognition of whole Gram-positive bacteria by DCs, also in the absence of TLR7. The results identify TLR13 as a receptor for bRNA.
Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses
Authors: Procaccini Claudio , De Rosa Veronica , Galgani Mario , Carbone Fortunata , Cassano Silvana , Greco Dario , Qian Kui , Auvinen Petri , Calì Gaetano , Stallone Giovanni , Formisano Luigi , La Cava Antonio , Matarese Giuseppe 
Published: August 2012

Abstract
The sensing by T cells of metabolic and energetic changes in the microenvironment can determine the differentiation, maturation, and activation of these cells. Although it is known that mammalian target of rapamycin (mTOR) gauges nutritonal and energetic signals in the extracellular milieu, it is not known how mTOR and metabolism influence CD4+CD25−FOXP3− effector T cell (Teff) responses. In this article, we show that leptin-induced activation of mTOR, which, in turn, controls leptin production and signaling, causes a defined cellular, biochemical, and transcriptional signature that determine the outcome of Teff responses, both in vitro and in vivo. The blockade of leptin/leptin receptor signaling, induced by genetic means or by starvation, leads to impaired mTOR activity that inhibits the proliferation of Teffs in vivo. Notably, the transcriptional signature of Teffs in the presence of leptin blockade appears similar to that observed in rapamycin-treated Teffs. These results identify a novel link between nutritional status and Teff responses through the leptin–mTOR axis and define a potential target for Teff modulation in normal and pathologic conditions.
Semaphorin 7A Contributes to West Nile Virus Pathogenesis through TGF-β1/Smad6 Signaling
Authors: Sultana Hameeda , Neelakanta Girish , Foellmer Harald G. , Montgomery Ruth R. , Anderson John F. , Koski Raymond A. , Medzhitov Ruslan M. , Fikrig Erol 
Published: August 2012

Abstract
Semaphorin 7A (Sema7A) is a membrane-associated/secreted protein that plays an essential role in connecting the vertebrate neuronal and immune systems. However, the role of Sema7A has not been elucidated in viral pathogenesis. In this study, we show that abrogation of Sema7A protects mice from lethal West Nile virus (WNV) infection. Mice lacking Sema7A showed increased survival, reduced viral burden, and less blood–brain barrier permeability upon WNV infection. Increased Sema7A levels were evident in murine tissues, as well as in murine cortical neurons and primary human macrophages upon WNV infection. Treatment with Sema7A Ab blocked WNV infection in both of these cell types. Furthermore, Sema7A positively regulates the production of TGF-β1 and Smad6 to facilitate WNV pathogenesis in mice. Collectively, these data elucidate the role of Sema7A in shared signaling pathways used by the immune and nervous systems during viral pathogenesis that may lead to the development of Sema7A-blocking therapies for WNV and possibly other flaviviral infections.
Retention of Anergy and Inhibition of Antibody Responses during Acute Gammaherpesvirus 68 Infection
Authors: Getahun Andrew , Smith Mia J. , Kogut Igor , van Dyk Linda F. , Cambier John C. 
Published: August 2012

Abstract
The majority of the human population becomes infected early in life by the gammaherpesvirus EBV. Some findings suggest that there is an association between EBV infection and the appearance of pathogenic Abs found in lupus. Gammaherpesvirus 68 infection of adult mice (an EBV model) was shown to induce polyclonal B cell activation and hypergammaglobulinemia, as well as increased production of autoantibodies. In this study, we explored the possibility that this breach of tolerance reflects loss of B cell anergy. Our findings show that, although anergic B cells transiently acquire an activated phenotype early during infection, they do not become responsive to autoantigen, as measured by the ability to mobilize Ca2+ following AgR cross-linking or mount Ab responses following immunization. Indeed, naive B cells also acquire an activated phenotype during acute infection but are unable to mount Ab responses to either T cell-dependent or T cell-independent Ags. In acutely infected animals, Ag stimulation leads to upregulation of costimulatory molecules and relocalization of Ag-specific B cells to the B–T cell border; however, these cells do not proliferate or differentiate into Ab-secreting cells. Adoptive-transfer experiments show that the suppressed state is reversible and is dictated by the environment in the infected host. Finally, B cells in infected mice deficient of CD4+ T cells are not suppressed, suggesting a role for CD4+ T cells in enforcing unresponsiveness. Thus, rather than promoting loss of tolerance, gammaherpesvirus 68 infection induces an immunosuppressed state, reminiscent of compensatory anti-inflammatory response syndrome.
Chemical Chaperones Curcumin and 4-Phenylbutyric Acid Improve Secretion of Mutant Factor H R127H by Fibroblasts from a Factor H-Deficient Patient
Authors: Albuquerque José Antonio T. , Lamers Marcelo L. , Castiblanco-Valencia Mónica M. , dos Santos Marinilce , Isaac Lourdes 
Published: August 2012

Abstract
Factor H (FH) is one of the most important regulatory proteins of the alternative pathway of the complement system. Patients with FH deficiency have a higher risk for development of infections and kidney diseases because of the uncontrolled activation and subsequent depletion of the central regulatory component C3 of the complement system. In this study, we investigated the consequences of the Arg127His mutation in FH (FHR127H) previously described in an FH-deficient patient, on the secretion of this protein by skin fibroblasts in vitro. We observed that, although the patient cells stimulated with IFN-γ were able to synthesize FHR127H, the mutant protein was largely retained within the endoplasmic reticulum (ER), whereas normal human fibroblasts stimulated with IFN-γ secrete FH without retention in the ER. Moreover, the retention of FHR127H provoked enlargement of ER cisterns after treatment with IFN-γ. A similar ER retention was observed in Cos-7 cells expressing the mutant FHR127H protein. Despite this deficiency in secretion, we show that the FHR127H mutant is capable of functioning as a cofactor in the Factor I-mediated cleavage of C3. We then evaluated whether a treatment could increase the secretion of FH, and observed that the patient’s fibroblasts treated with the chemical chaperones 4-phenylbutiric acid or curcumin increased the secretion rate of FH. We propose that these chemical chaperones could be used as alternative therapeutic agents to increase FH plasma levels in FH-deficient patients caused by secretion delay of this regulatory protein.
Gcn5 Is Required for PU.1-Dependent IL-9 Induction in Th9 Cells
Authors: Goswami Ritobrata , Kaplan Mark H. 
Published: August 2012

Abstract
Naive CD4+ T cells differentiate into various effector Th subsets depending on the Ags and cytokine microenvironment they encounter. IL-9–secreting Th9 cells are the most recent Th subset to be described. PU.1, one of the transcription factors required for the development of Th9 cells, binds to the Il9 gene. In this study, we show that PU.1 increases histone acetylation at the Il9 locus through direct interactions with histone acetyltransferases. In the absence of PU.1, there is decreased association of Gcn5 and p300/CBP associated factor and increased association of histone deacetylases at the Il9 locus in Th9 cells. Inhibition of histone deacetylase activity augments PU.1-dependent IL-9 production. PU.1 forms a complex with Gcn5, and inhibition of the expression of Gcn5 results in reduced IL-9 production. Moreover, the effects of Gcn5 on IL-9 production are specific as the production of IL-10 and IL-21, two additional cytokines produced by Th9 cells, is not altered after decreased Gcn5 expression. Together, these data define a PU.1-dependent mechanism for altered histone acetylation and expression of the Il9 locus in Th9 cells.
The Akt1 Isoform Is Required for Optimal IFN-β Transcription through Direct Phosphorylation of β-Catenin
Authors: Gantner Benjamin N. , Jin Huali , Qian Feng , Hay Nissim , He Bin , Ye Richard D. 
Published: August 2012

Abstract
IFN-β is a critical antiviral cytokine that is capable of modulating the systemic immune response. The transcriptional induction of IFN-β is a highly regulated process, involving the activation of pattern recognition receptors and their downstream signaling pathways. The Akt family of serine/threonine kinases includes three isoforms. The specific role for the individual Akt isoforms in pattern recognition and signaling remains unclear. In this article, we report that the TLR3-mediated expression of IFN-β is blunted in cells that lack Akt1. The expression of IFN-β–inducible genes such as CCL5 and CXCL10 was also reduced in Akt1-deficient cells; the induction of TNF-α and CXCL2, whose expression does not rely on IFN-β, was not reduced in the absence of Akt1. Macrophages from Akt1−/− mice displayed deficient clearance of HSV-1 along with reduced IFN-β expression. Our results demonstrate that Akt1 signals through β-catenin by phosphorylation on Ser552, a site that differs from the glycogen synthase kinase 3 β phosphorylation site. Stimulation of a chemically activated version of Akt1, in the absence of other TLR3-dependent signaling, was sufficient for accumulation and phosphorylation of β-catenin at Ser552. Taken together, these results demonstrate that the Akt1 isoform is required for β-catenin–mediated promotion of IFN-β transcription downstream of TLR3 activation.
Cutting Edge: Intravascular Staining Redefines Lung CD8 T Cell Responses
Authors: Anderson Kristin G. , Sung Heungsup , Skon Cara N. , Lefrancois Leo , Deisinger Angela , Vezys Vaiva , Masopust David 
Published: August 2012

Abstract
Nonlymphoid T cell populations control local infections and contribute to inflammatory diseases, thus driving efforts to understand the regulation of their migration, differentiation, and maintenance. Numerous observations indicate that T cell trafficking and differentiation within the lung are starkly different from what has been described in most nonlymphoid tissues, including intestine and skin. After systemic infection, we found that &gt;95% of memory CD8 T cells isolated from mouse lung via standard methods were actually confined to the pulmonary vasculature, despite perfusion. A respiratory route of challenge increased virus-specific T cell localization within lung tissue, although only transiently. Removing blood-borne cells from analysis by the simple technique of intravascular staining revealed distinct phenotypic signatures and chemokine-dependent trafficking restricted to Ag-experienced T cells. These results precipitate a revised model for pulmonary T cell trafficking and differentiation and a re-evaluation of studies examining the contributions of pulmonary T cells to protection and disease.
A Century of Imagery Research: Reflections on Cheves Perky’s Contribution to Our Understanding of Mental Imagery
Authors: Waller David , Schweitzer Jeffrey R. , Brunton J. Ryan , Knudson Roger M. 
Published: August 2012

Abstract
We review contemporary scientific research on the relationship between visual perception and visual mental imagery in the context of Cheves Perky’s (1910) landmark article on imagery and imagination. This body of research has firmly established a strong connection between the psychology of imagery and perception and has contributed a strong voice to the imagery debate. We then use the concept of embodiment to discuss additional avenues of inquiry at which Perky’s work hinted. These include a more thorough examination of the relationship between imagery and emotion, the creative, active aspects of imagery and imagination, and the methods we can bring to bear on understanding imagery and imagination as a human experience.
Speech Perception and Reading: Two Parallel Modes of Understanding Language and Implications for Acquiring Literacy Naturally
Authors: Massaro Dominic W. 
Published: August 2012

Abstract
I review 2 seminal research reports published in this journal during its second decade more than a century ago. Given psychology’s subdisciplines, they would not normally be reviewed together because one involves reading and the other speech perception. The small amount of interaction between these domains might have limited research and theoretical progress. In fact, the 2 early research reports revealed common processes involved in these 2 forms of language processing. Their illustration of the role of Wundt’s apperceptive process in reading and speech perception anticipated descriptions of contemporary theories of pattern recognition, such as the fuzzy logical model of perception. Based on the commonalities between reading and listening, one can question why they have been viewed so differently. It is commonly believed that learning to read requires formal instruction and schooling, whereas spoken language is acquired from birth onward through natural interactions with people who talk. Most researchers and educators believe that spoken language is acquired naturally from birth onward and even prenatally. Learning to read, on the other hand, is not possible until the child has acquired spoken language, reaches school age, and receives formal instruction. If an appropriate form of written text is made available early in a child’s life, however, the current hypothesis is that reading will also be learned inductively and emerge naturally, with no significant negative consequences. If this proposal is true, it should soon be possible to create an interactive system, Technology Assisted Reading Acquisition, to allow children to acquire literacy naturally.
Effect of Prior Practice on the Stimulus-Response Compatibility Effect in a Mixed Mapping Environment
Authors: Creekmur Beth , Vu Kim-Phuong L. 
Published: August 2012

Abstract
A stimulus-response compatibility (SRC) effect is obtained when performance is better with compatible mappings than with incompatible mappings. When mappings are mixed within a task, the SRC effect is often eliminated or reversed. The present study examines how 1,600 trials with different practice tasks can affect the response selection process in these mixed mapping environments. Participants were assigned to one of three practice groups: mixed mapping, pure compatible mapping, and pure incompatible mapping. Subsequently, all participants performed an experimental session in which compatible and incompatible trials were mixed. The SRC effect was eliminated in the experimental mixed mapping session, regardless of practice condition. The results suggest that practice does not change the need to suppress the direct response selection route in a mixed mapping task. However, reaction time distributions and sequential analyses were modulated by practice condition, which indicates that the new associations acquired during practice may activate new routes that interact with preexisting ones.
Boèce, Porphyre et les variétés de l’abstractionnisme
Authors: Marenbon John 
Published: August 2012

Selon Alain de Libera, Boèce donne au célèbre questionnaire de Porphyre sur les universaux une réponse abstractionniste : ce n’est que dans la pensée que peuvent exister les universaux, quoiqu’ils dérivent, par le processus d’abstraction, de ce qui est commun dans les choses. Je mets en contraste cet « abstractionnisme neutre » et un « abstractionnisme réaliste » selon lequel ce n’est qu’en concevant les universaux que la pensée humaine saisit proprement la forme — ou similitude — par laquelle les particuliers appartiennent à telle espèce ou à tel genre. J’essaie de démontrer que, dans son second commentaire sur l’Isagoge, Boèce hésite entre les deux sortes d’abstractionnisme, tandis que, dans la Consolation, il opte pour l’abstractionnisme réaliste.
Managing HIV‐infected children in a low‐resource, public clinic: a comparison of nurse vs. clinical officer practices in ART refill, calculation of adherence and subsequent appointments
Authors: Weigel Ralf , Feldacker Caryl , Tweya Hannock , Gondwe Chimwemwe , Chiwoko Jane , Gumulira Joe , Kalulu Mike , Phiri Sam 
Published: August 2012

BackgroundIn Malawi, as in other sub‐Saharan African countries, nurses manage patients of all ages on antiretroviral treatment (ART). Nurse management of children is rarely studied. We compare ART prescribing between nurses and clinical officers during routine clinic visits at an urban, public clinic to inform policy in paediatric ART management.MethodsCaregivers of children on first‐line ART provided information about visit dates, pill counts, ART dosage and formulation to a nurse and, subsequently, to a clinical officer. Nurses and clinical officers independently calculated adherence, dosage based on body weight, and set next appointment date. Clinical officers, but not nurses, accessed an electronic data system that made the calculations for them based on information from prior visits, actual and expected pill consumption, and standard drug supplies. Nurses calculated with pen and paper. For numerical variables, Bland‐Altman graphs plot differences of each nurse–clinical officer pair against the mean, show the 95% limits of agreement (LoA), and also show the mean difference across all reviews. Kappa statistics assess agreement for categorical variables.ResultsA total of 704 matched nurse–clinical officer reviews of 367 children attending the ART clinics between March and July 2010 were analyzed. Eight nurses and 18 clinical officers were involved; two nurses and five clinical officers managed 100 visits or more. Overall, there was a good agreement between the two cadres. Differences between nurses and clinical officers were within narrow LoA and mean differences showed little deviation from zero, indicating little skewing towards one cadre. LoA of adherence and morning and evening ART dosages varied from −24% to 24%, −0.4 to 0.4 and −0.41 to 0.40 tablets, respectively, with mean differences (95% CI) of 0.003 (−0.9, 0.91), −0.005 (−0.02, 0.01) and −0.009 (−0.02, 0.01). Next appointment calculations differed more between cadres with LoA from −40 to 42 days [mean difference: 0.96 days (95% CI:−0.6 to 2.5)], but agreement in the ART formulation prescribed was very good (kappa 0.93).ConclusionsNurses’ ART prescribing practices and calculations of adherence and next appointments are similar to clinical officers, although clinical officers used an electronic system. Our findings support the decision of Malawi's health officials to utilize nurses to manage paediatric ART patients.
Distinct plasma metabolomic signatures differentiate autoimmune encephalitis from drug‐resistant epilepsy
Authors: Xiong Wenzheng , Yeo Tianrong , May Jeanne Tan May , Demmers Tor , Ceronie Bryan , Ramesh Archana , McGinty Ronan N. , Michael Sophia , Torzillo Emma , Sen Arjune , Anthony Daniel C. , Irani Sarosh R. , Probert Fay 
Published: June 2024

AbstractObjectiveDifferentiating forms of autoimmune encephalitis (AE) from other causes of seizures helps expedite immunotherapies in AE patients and informs studies regarding their contrasting pathophysiology. We aimed to investigate whether and how Nuclear Magnetic Resonance (NMR)‐based metabolomics could differentiate AE from drug‐resistant epilepsy (DRE), and stratify AE subtypes.MethodsThis study recruited 238 patients: 162 with DRE and 76 AE, including 27 with contactin‐associated protein‐like 2 (CASPR2), 29 with leucine‐rich glioma inactivated 1 (LGI1) and 20 with N‐methyl‐d‐aspartate receptor (NMDAR) antibodies. Plasma samples across the groups were analyzed using NMR spectroscopy and compared with multivariate statistical techniques, such as orthogonal partial least squares discriminant analysis (OPLS‐DA).ResultsThe OPLS‐DA model successfully distinguished AE from DRE patients with a high predictive accuracy of 87.0 ± 3.1% (87.9 ± 3.4% sensitivity and 86.3 ± 3.6% specificity). Further, pairwise OPLS‐DA models were able to stratify the three AE subtypes. Plasma metabolomic signatures of AE included decreased high‐density lipoprotein (HDL, −(CH2)n−, –CH3), phosphatidylcholine and albumin (lysyl moiety). AE subtype‐specific metabolomic signatures were also observed, with increased lactate in CASPR2, increased lactate, glucose, and decreased unsaturated fatty acids (UFA, –CH2CH=) in LGI1, and increased glycoprotein A (GlycA) in NMDAR‐antibody patients.InterpretationThis study presents the first non‐antibody‐based biomarker for differentiating DRE, AE and AE subtypes. These metabolomics signatures underscore the potential relevance of lipid metabolism and glucose regulation in these neurological disorders, offering a promising adjunct to facilitate the diagnosis and therapeutics.