bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients
Authors: de Miranda Noel F. C. C. , Georgiou Konstantinos , Chen Longyun , Wu Chenglin , Gao Zhibo , Zaravinos Apostolos , Lisboa Susana , Enblad Gunilla , Teixeira Manuel R. , Zeng Yixin , Peng Roujun , Pan-Hammarström Qiang 
Published: August 2014

Key PointsSequencing of Chinese DLBCL reveals novel mutation targets and highlights additional/alternative tumorigenic pathways in these tumors. DTX1 is frequently mutated in Chinese DLBCL and deleterious mutations in this gene contribute to the activation of the Notch pathway.
MicroRNA regulation of tumorigenesis, cancer progression and interpatient heterogeneity: towards clinical use
Authors: Nana-Sinkam S Patrick , Croce Carlo M 
Published: August 2014

AbstractIn the past two decades, microRNAs have emerged as crucial mediators of organ development and human disease. Here, we discuss their role as drivers or suppressors of the hallmarks of cancer during tumorigenesis and progression, in defining interpatient heterogeneity and the promise of therapeutic application.
Characterisation of a recombinant β-xylosidase (xylA) from Aspergillus oryzae expressed in Pichia pastoris
Authors: Kirikyali Narin , Wood Jonathan , Connerton Ian F 
Published: August 2014

Abstract
β-xylosidases catalyse the hydrolysis of short chain xylooligosaccharides from their non-reducing ends into xylose. In this study we report the heterologous expression of Aspergillus oryzae β-xylosidase (XylA) in Pichia pastoris under the control of the glyceraldehyde-3-phosphate dehydrogenase promoter. The recombinant enzyme was optimally active at 55°C and pH 4.5 with Km and Vmax values of 1.0 mM and 250 μmol min−1 mg−1 respectively against 4-nitrophenyl β-xylopyranoside. Xylose was a competitive inhibitor with a Ki of 2.72 mM, whereas fructose was an uncompetitive inhibitor reducing substrate binding affinity (Km) and conversion efficiency (Vmax). The enzyme was characterised to be an exo-cutting enzyme releasing xylose from the non-reducing ends of β-1,4 linked xylooligosaccharides (X2, X3 and X4). Catalytic conversion of X2, X3 and X4 decreased (Vmax and kcat) with increasing chain length.
Syncrip/hnRNP Q influences synaptic transmission and regulates BMP signaling at the Drosophila neuromuscular synapse
Authors: Halstead James M. , Lin Yong Qi , Durraine Lita , Hamilton Russell S. , Ball Graeme , Neely Greg G. , Bellen Hugo J. , Davis Ilan 
Published: August 2014

ABSTRACT
Synaptic plasticity involves the modulation of synaptic connections in response to neuronal activity via multiple pathways. One mechanism modulates synaptic transmission by retrograde signals from the post-synapse that influence the probability of vesicle release in the pre-synapse. Despite its importance, very few factors required for the expression of retrograde signals, and proper synaptic transmission, have been identified. Here, we identify the conserved RNA binding protein Syncrip as a new factor that modulates the efficiency of vesicle release from the motoneuron and is required for correct synapse structure. We show that syncrip is required genetically and its protein product is detected only in the muscle and not in the motoneuron itself. This unexpected non-autonomy is at least partly explained by the fact that Syncrip modulates retrograde BMP signals from the muscle back to the motoneuron. We show that Syncrip influences the levels of the Bone Morphogenic Protein ligand Glass Bottom Boat from the post-synapse and regulates the pre-synapse. Our results highlight the RNA-binding protein Syncrip as a novel regulator of synaptic output. Given its known role in regulating translation, we propose that Syncrip is important for maintaining a balance between the strength of presynaptic vesicle release and postsynaptic translation.
Spanish unspecified objects as null incorporated nouns
Authors: Armstrong Grant 
Published: August 2014

AbstractIn this paper it is argued that unspecified objects in sentences such as Maria leyo anoche (= Maria read (something) last night) should be represented as null incorporated nouns in l-syntax (Hale & Keyser 1993, 2002). Specifically, the material understood as ‘something’ is a null bare N that incorporates into the verb ‘read,’ forming an endocentric compound meaning ‘THING-read.’ While the general idea underlying such a hypothesis is not new (Mateu 2012; Marti 2011; Zubizarreta & Oh 2007), the analysis outlined here provides the first explicit formalization of it in such a way that can account for a wide range of properties (some not yet described in the literature) that are intimately related to what can be broadly defined as ‘noun incorporation constructions’ cross-linguistically. Like certain types of noun incorporation constructions in other languages, unspecified object constructions have the following properties: (i) they are restricted lexically (in this case to ‘activity’/‘manner’ verbs), (ii) the verb+unspecified object may have a conventionalized interpretation, (iii) unspecified objects are indefinite and take obligatory narrow scope with respect to all other operators, (iv) unspecified objects may be modified ‘externally’ by a limited set of adjectives (v) the verb+unspecified object gives rise to an atelic reading. All of these properties are shown to derive from the fact that unspecified objects are null incorporated nouns. This is desirable since the same set of properties are shared by different types of noun incorporation constructions in languages outside Romance and, to a large extent, by bare noun constructions in Spanish and other Romance languages (Espinal & McNally 2011).
Evolving targets for lipid‐modifying therapy
Authors: Do Rose Q , Nicholls Stephen J , Schwartz Gregory G 
Published: August 2014

AbstractThe pathogenesis and progression of atherosclerosis are integrally connected to the concentration and function of lipoproteins in various classes. This review examines existing and emerging approaches to modify low‐density lipoprotein and lipoprotein (a), triglyceride‐rich lipoproteins, and high‐density lipoproteins, emphasizing approaches that have progressed to clinical evaluation. Targeting of nuclear receptors and phospholipases is also discussed.
Changes in Second-Language Learners’ Oral Skills and Socio-Affective Profiles Following Study Abroad: A Mixed-Methods Approach
Authors: Hardison Debra M. 
Published: August 2014

Abstract: Research on the effectiveness of short-term study-abroad (SA) programs for improving oral skills has shown mixed results. In this study, 24 L2 German learners (L1 English) provided pre- and post-SA speech samples addressing a hypothetical situation and completed surveys on cross-cultural interest and adaptability; L2 communication affect, strategies, perceived competence; and L2 contact. Native speakers (NSs) provided ratings for pronunciation, fluency, grammar, vocabulary, and accentedness. Results revealed significant improvement in all oral skills and positive changes in the socio-affective factors. Participants who reported more positive affect in interactions with NSs pre-SA tended to spend more hours in extended interactions with them while abroad. These hours were related to increased positive communication affect post-SA. No significant relationships were found between L2 contact and gains in oral skills. Homestay experiences were positive, providing opportunities for extended interactions and cultural knowledge. For classroom learners, findings suggest a role for e-languaging tasks with NSs.
Les effets de l’enseignement des phénomènes d’enchaînement sur la production orale des élèves dans un cours d’espagnol langue étrangère au Québec
Authors: Uribe Cristina , Cedergren Henrietta , Payeras Jessica 
Published: August 2014

Résumé :Le présent article offre un aperçu d’une étude expérimentale réalisée dans le cadre d’un cours d’espagnol langue étrangère donné dans une école secondaire à Montréal. Cette étude avait deux objectifs : (a) vérifier l’impact d’une instruction explicite sur le fonctionnement de la synalèphe et de l’enchaînement sur la production orale des étudiants et (b) confirmer si la réalisation de ces phénomènes est associée aux évaluations de niveau d’aisance perçue par des locuteurs hispanophones natifs. Pour ce faire, une intervention pédagogique a été mise en place durant six semaines afin de montrer aux apprenants le fonctionnement desdits phénomènes. Cette étude a été menée selon un protocole expérimental pré-test/post-test auprès de deux classes ayant un niveau similaire de langue et la même charge horaire par semaine. L’une des deux classes formait le groupe témoin (n = 22) et l’autre, le groupe expérimental (n = 24). Trois locuteurs hispanophones natifs ont évalué, selon leur propre perception, la réalisation des phénomènes enseignés et le niveau d’aisance des énoncés produits par les apprenants. Notre analyse suggère que l’instruction explicite sur les deux phénomènes contribue à leur intégration dans la production orale des apprenants. Nous avons également trouvé une corrélation entre les variables « réalisation des phénomènes d’enchaînement » et « niveau d’aisance perçue » : les participants qui enchaînent les mots au cours de leurs productions ont été perçus comme ayant un niveau d’aisance plus élevé que ceux qui ne les enchaînent pas.
GATA-3 Dose-Dependent Checkpoints in Early T Cell Commitment
Authors: Scripture-Adams Deirdre D. , Damle Sagar S. , Li Long , Elihu Koorosh J. , Qin Shuyang , Arias Alexandra M. , Butler Robert R. , Champhekar Ameya , Zhang Jingli A. , Rothenberg Ellen V. 
Published: August 2014

Abstract
GATA-3 expression is crucial for T cell development and peaks during commitment to the T cell lineage, midway through the CD4−CD8− (double-negative [DN]) stages 1–3. We used RNA interference and conditional deletion to reduce GATA-3 protein acutely at specific points during T cell differentiation in vitro. Even moderate GATA-3 reduction killed DN1 cells, delayed progression to the DN2 stage, skewed DN2 gene regulation, and blocked appearance of the DN3 phenotype. Although a Bcl-2 transgene rescued DN1 survival and improved DN2 cell generation, it did not restore DN3 differentiation. Gene expression analyses (quantitative PCR, RNA sequencing) showed that GATA-3–deficient DN2 cells quickly upregulated genes, including Spi1 (PU.1) and Bcl11a, and downregulated genes, including Cpa3, Ets1, Zfpm1, Bcl11b, Il9r, and Il17rb with gene-specific kinetics and dose dependencies. These targets could mediate two distinct roles played by GATA-3 in lineage commitment, as revealed by removing wild-type or GATA-3–deficient early T lineage cells from environmental Notch signals. GATA-3 worked as a potent repressor of B cell potential even at low expression levels, so that only full deletion of GATA-3 enabled pro–T cells to reveal B cell potential. The ability of GATA-3 to block B cell development did not require T lineage commitment factor Bcl11b. In prethymic multipotent precursors, however, titration of GATA-3 activity using tamoxifen-inducible GATA-3 showed that GATA-3 inhibits B and myeloid developmental alternatives at different threshold doses. Furthermore, differential impacts of a GATA-3 obligate repressor construct imply that B and myeloid development are inhibited through distinct transcriptional mechanisms. Thus, the pattern of GATA-3 expression sequentially produces B lineage exclusion, T lineage progression, and myeloid-lineage exclusion for commitment.
Circulating CXCR5+PD-1+ Response Predicts Influenza Vaccine Antibody Responses in Young Adults but not Elderly Adults
Authors: Herati Ramin Sedaghat , Reuter Morgan A. , Dolfi Douglas V. , Mansfield Kathleen D. , Aung Htin , Badwan Osama Z. , Kurupati Raj K. , Kannan Senthil , Ertl Hildegund , Schmader Kenneth E. , Betts Michael R. , Canaday David H. , Wherry E. John 
Published: August 2014

Abstract
Although influenza vaccination is recommended for all adults annually, the incidence of vaccine failure, defined as weak or absent increase in neutralizing Ab titers, is increased in the elderly compared with young adults. The T follicular helper cell (Tfh) subset of CD4 T cells provides B cell help in germinal centers and is necessary for class-switched Ab responses. Previous studies suggested a role for circulating Tfh cells (cTfh) following influenza vaccination in adults, but cTfh have not been studied in elderly adults in whom weak vaccine responses are often observed. In this study, we studied cTfh expressing CXCR5 and programmed death-1 (PD-1). cTfh from elderly adults were present at reduced frequency, had decreased in vitro B cell help ability, and had greater expression of ICOS compared with young adults. At 7 d after inactivated influenza vaccination, cTfh correlated with influenza vaccine–specific IgM and IgG responses in young adults but not in elderly adults. In sum, we have identified aging-related changes in cTfh that correlated with reduced influenza vaccine responses. Future rational vaccine design efforts should incorporate Tfh measurement as an immune correlate of protection, particularly in the setting of aging.
Helicobacter pylori–Induced IL-1β Secretion in Innate Immune Cells Is Regulated by the NLRP3 Inflammasome and Requires the Cag Pathogenicity Island
Authors: Semper Raphaela P. , Mejías-Luque Raquel , Groß Christina , Anderl Florian , Müller Anne , Vieth Michael , Busch Dirk H. , Prazeres da Costa Clarissa , Ruland Jürgen , Groß Olaf , Gerhard Markus 
Published: August 2014

Abstract
Infection with the gram-negative bacterium Helicobacter pylori is the most prevalent chronic bacterial infection, affecting ∼50% of the world’s population, and is the main risk factor of gastric cancer. The proinflammatory cytokine IL-1β plays a crucial role in the development of gastric tumors and polymorphisms in the IL-1 gene cluster leading to increased IL-1β production have been associated with increased risk for gastric cancer. To be active, pro–IL-1β must be cleaved by the inflammasome, an intracellular multiprotein complex implicated in physiological and pathological inflammation. Recently, H. pylori was postulated to activate the inflammasome in murine bone marrow–derived dendritic cells; however, the molecular mechanisms as well as the bacterial virulence factor acting as signal 2 activating the inflammasome remain elusive. In this study, we analyzed the inflammasome complex regulating IL-1β upon H. pylori infection as well as the molecular mechanisms involved. Our results indicate that H. pylori–induced IL-1β secretion is mediated by activation of the nucleotide-binding oligomerization domain-like receptor family, pyrin domain–containing 3 inflammasome. We also show that reactive oxygen species, potassium efflux, and lysosomal destabilization are the main cellular mechanisms responsible of nucleotide-binding oligomerization domain family, pyrin domain–containing 3 inflammasome activation upon H. pylori infection, and identify vacuolating cytotoxin A and cag pathogenicity island as the bacterial virulence determinants involved. Moreover, in vivo experiments indicate an important role for the inflammasome in the onset and establishment of H. pylori infection and in the subsequent inflammatory response of the host.
Immunoregulation of Dendritic Cells by the Receptor T cell Ig and Mucin Protein-3 via Bruton’s Tyrosine Kinase and c-Src
Authors: Maurya Neeraj , Gujar Ravindra , Gupta Mamta , Yadav Vinod , Verma Saurabh , Sen Pradip 
Published: August 2014

Abstract
The receptor T cell Ig and mucin protein-3 (TIM-3) has emerged as an important regulator of innate immune responses. However, whether TIM-3–induced signaling promotes or inhibits the activation and maturation of dendritic cells (DCs) still remains uncertain. In addition, the TIM-3 signaling events involved in this immunoregulatory function are yet to be established. In this article, we report that TIM-3 crosslinking by anti–TIM-3 Ab inhibited DC activation and maturation by blocking the NF-κB pathway. After Ab-mediated crosslinking, TIM-3 became tyrosine phosphorylated, which then sequentially bound and activated the nonreceptor tyrosine kinases Bruton’s tyrosine kinase (Btk) and c-Src. Activation of Btk–c-Src signaling in turn triggered the secretion of some inhibitory factor (or factors) from DCs that inhibited the NF-κB pathway and subsequent activation and maturation of DCs. Silencing of Btk or c-Src abrogated the inhibitory effects of TIM-3 on DCs. These results demonstrate an essential role for Btk–c-Src signaling in TIM-3–induced DC suppression. Thus, in addition to demonstrating an inhibitory role for TIM-3 signaling in DC activation, we define the molecular mechanism by which TIM-3 mediates this effect.
Notch Signaling at Later Stages of NK Cell Development Enhances KIR Expression and Functional Maturation
Authors: Felices Martin , Ankarlo Dave E. M. , Lenvik Todd R. , Nelson Heather H. , Blazar Bruce R. , Verneris Michael R. , Miller Jeffrey S. 
Published: August 2014

AbstractThe Notch signaling pathway plays a substantial role in human NK cell development. However, the role of Notch on killer Ig–like receptor (KIR) upregulation and acquisition of effector function has not been explored. To evaluate how Notch influences terminal differentiation, cord blood–derived NK cells or sorted peripheral blood NK cells were cultured with IL-15 for 7 d with inhibitory or activating Notch signals. Inhibition of Notch signaling significantly decreased KIR expression, whereas activation enhanced it. Overexpression of activated Notch on cord blood–derived NK cells resulted in a 2-fold increase in KIR expression, indicating that Notch signaling plays a direct, cell-intrinsic role in KIR regulation. Moreover, Notch-mediated KIR expression on NK cells is regulated through cis inhibition by delta-like ligand 1. Notch signaling also enhances CD16 upregulation that precedes KIR expression. Concomitant with the upregulation of KIR and CD16, Notch signaling induces increased cytolytic effector capacity and cytokine secretion, even in posttransplant samples in which NK cell function is inherently defective. Given these attributes of Notch signaling, we propose that Notch agonists may enhance NK cell maturation and tumor killing in a posttransplant setting.
Macrophage Migration Inhibitory Factor Triggers Chemotaxis of CD74+CXCR2+ NKT Cells in Chemically Induced IFN-γ–Mediated Skin Inflammation
Authors: Hsieh Chia-Yuan , Chen Chia-Ling , Lin Yee-Shin , Yeh Trai-Ming , Tsai Tsung-Ting , Hong Ming-Yuan , Lin Chiou-Feng 
Published: August 2014

Abstract
IFN-γ mediates chemically induced skin inflammation; however, the mechanism by which IFN-γ–producing cells are recruited to the sites of inflammation remains undefined. Secretion of macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, from damaged cells may promote immune cell recruitment. We hypothesized that MIF triggers an initial step in the chemotaxis of IFN-γ–producing cells in chemically induced skin inflammation. Using acute and chronic models of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin inflammation in mouse ears, MIF expression was examined, and its role in this process was investigated pharmacologically. The cell populations targeted by MIF, their receptor expression patterns, and the effects of MIF on cell migration were examined. TPA directly caused cytotoxicity accompanied by MIF release in mouse ear epidermal keratinocytes, as well as in human keratinocytic HaCaT cells. Treatment with the MIF antagonist (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester considerably attenuated TPA-induced ear swelling, leukocyte infiltration, epidermal cell proliferation, and dermal angiogenesis. Inhibition of MIF greatly diminished the dermal infiltration of IFN-γ+ NKT cells, whereas the addition of exogenous TPA and MIF to NKT cells promoted their IFN-γ production and migration, respectively. MIF specifically triggered the chemotaxis of NKT cells via CD74 and CXCR2, and the resulting depletion of NKT cells abolished TPA-induced skin inflammation. In TPA-induced skin inflammation, MIF is released from damaged keratinocytes and then triggers the chemotaxis of CD74+CXCR2+ NKT cells for IFN-γ production.
Identification of Immunogenic Antigens from Aspergillus fumigatus by Direct Multiparameter Characterization of Specific Conventional and Regulatory CD4+ T Cells
Authors: Bacher Petra , Kniemeyer Olaf , Teutschbein Janka , Thön Marcel , Vödisch Martin , Wartenberg Dirk , Scharf Daniel H. , Koester-Eiserfunke Nora , Schütte Mark , Dübel Stefan , Assenmacher Mario , Brakhage Axel A. , Scheffold Alexander 
Published: August 2014

Abstract
CD4+ T cells orchestrate immune responses against fungi, such as Aspergillus fumigatus, a major fungal pathogen in humans. The complexity of the fungal genome and lifestyle questions the existence of one or a few immune-dominant Ags and complicates systematic screening for immunogenic Ags useful for immunotherapy or diagnostics. In this study, we used a recently developed flow cytometric assay for the direct ex vivo characterization of A. fumigatus–specific CD4+ T cells for rapid identification of physiological T cell targets in healthy donors. We show that the T cell response is primarily directed against metabolically active A. fumigatus morphotypes and is stronger against membrane protein fractions compared with cell wall or cytosolic proteins. Further analysis of 15 selected single A. fumigatus proteins revealed a highly diverse reactivity pattern that was donor and protein dependent. Importantly, the parallel assessment of T cell frequency, phenotype, and function allowed us to differentiate between proteins that elicit strong memory T cell responses in vivo versus Ags that induce T cell exhaustion or no reactivity in vivo. The regulatory T cell (Treg) response mirrors the conventional T cell response in terms of numbers and target specificity. Thus, our data reveal that the fungal T cell immunome is complex, but the ex vivo characterization of reactive T cells allows us to classify Ags and to predict potential immunogenic targets. A. fumigatus–specific conventional T cell responses are counterbalanced by a strong Treg response, suggesting that Treg-depletion strategies may be helpful in improving antifungal immunity.
CD4+ T Cells and CD40 Participate in Selection and Homeostasis of Peripheral B Cells
Authors: Schwartz Marc A. , Kolhatkar Nikita S. , Thouvenel Chris , Khim Socheath , Rawlings David J. 
Published: August 2014

AbstractControl of peripheral B cell development and homeostasis depends critically on coordinate signals received through the BAFFRs and BCRs. The extent to which other signals contribute to this process, however, remains undefined. We present data indicating that CD4+ T cells directly influence naive B cell development via CD40 signaling. Loss of CD4+ T cells or CD40–CD40L interaction leads to reduced B cell homeostatic proliferation and hindered B cell reconstitution posttransplantation. Furthermore, we demonstrate that in the absence of CD40 signals, these events are modulated by BCR self-reactivity. Strikingly, murine models lacking CD40 reveal a broadly altered BCR specificity and limited diversity by both single-cell cloning and high-throughput sequencing techniques. Collectively, our results imply that any setting of T cell lymphopenia or reduced CD40 function, including B cell recovery following transplantation, will impact the naive B cell repertoire.