bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regulation of Experimental Autoimmune Encephalomyelitis by TPL-2 Kinase
Authors: Sriskantharajah Srividya , Gückel Eva , Tsakiri Niki , Kierdorf Katrin , Brender Christine , Ben-Addi Abduelhakem , Veldhoen Marc , Tsichlis Philip N. , Stockinger Brigitta , O’Garra Anne , Prinz Marco , Kollias George , Ley Steven C. 
Published: March 2014

Abstract
Tumor progression locus 2 (TPL-2) expression is required for efficient polarization of naive T cells to Th1 effector cells in vitro, as well as for Th1-mediated immune responses. In the present study, we investigated the potential role of TPL-2 in Th17 cells. TPL-2 was found to be dispensable for Th17 cell differentiation in vitro, and for the initial priming of Th17 cells in experimental autoimmune encephalomyelitis (EAE), a Th17 cell–mediated disease model for multiple sclerosis. Nevertheless, TPL-2–deficient mice were protected from EAE, which correlated with reduced immune cell infiltration, demyelination, and axonal damage in the CNS. Adoptive transfer experiments demonstrated that there was no T cell–intrinsic function for TPL-2 in EAE, and that TPL-2 signaling was not required in radiation-sensitive hematopoietic cells. Rather, TPL-2 signaling in radiation-resistant stromal cells promoted the effector phase of the disease. Importantly, using a newly generated mouse strain expressing a kinase-inactive form of TPL-2, we demonstrated that stimulation of EAE was dependent on the catalytic activity of TPL-2 and not its adaptor function to stabilize the associated ubiquitin-binding protein ABIN-2. Our data therefore raise the possibility that small molecule inhibitors of TPL-2 may be beneficial in multiple sclerosis therapy.
CCL3 Production by Microglial Cells Modulates Disease Severity in Murine Models of Retinal Degeneration
Authors: Kohno Hideo , Maeda Tadao , Perusek Lindsay , Pearlman Eric , Maeda Akiko 
Published: March 2014

Abstract
Many degenerative retinal diseases illustrate retinal inflammatory changes that include infiltration of microglia and macrophages into the subretinal space. In this study, we examined the role of chemokines in the Abca4−/−Rdh8−/− mouse model of Stargardt disease and the Mertk−/− mouse model of retinitis pigmentosa. PCR array analysis of 84 chemokines and related molecules revealed 84.6-fold elevated expression of Ccl3 (MIP-1a) 24 h after light exposure in Abca4−/−Rdh8−/− mice. Only MIP-1 chemokines, including Ccl3 and Ccl4, displayed peak expression 24 h after light exposure, and peaked earlier than the other chemokines. Secretion of Ccl3 was documented only in microglia, whereas both microglia and retinal pigment epithelium cells produced Ccl2. Exposure of Cx3Cr1gfp/ΔAbca4−/−Rdh8−/− mice to intense light resulted in the appearance of Cx3Cr1GFP+ monocytes in the subretinal space. To address the in vivo role of CCL3 in retinal degeneration, Ccl3−/−Abca4−/−Rdh8−/− mice and Ccl3−/−Mertk−/− mice were generated. Following intense light exposure, Ccl3−/−Abca4−/−Rdh8−/− mice displayed persistent retinal inflammation with appearance of Iba-1+ cells in the subretinal space, severe photoreceptor cell death, and increased Ccl4 expression compared with Abca4−/−Rdh8−/− mice. In contrast, Ccl3−/−Abca4−/−Rdh8−/− mice exhibited a milder retinal inflammation and degeneration than Abca4−/−Rdh8−/− mice did in age-related chronic retinal degeneration under room light conditions. The deficiency of Ccl3 also attenuated the severity of retinal degeneration in Mertk−/− mice. Taken together, our results indicate that Ccl3 has an essential role in regulating the severity of retinal inflammation and degeneration in these mouse models.
Chemokine Cooperativity Is Caused by Competitive Glycosaminoglycan Binding
Authors: Verkaar Folkert , van Offenbeek Jody , van der Lee Miranda M. C. , van Lith Lambertus H. C. J. , Watts Anne O. , Rops Angelique L. W. M. M. , Aguilar David C. , Ziarek Joshua J. , van der Vlag Johan , Handel Tracy M. , Volkman Brian F. , Proudfoot Amanda E. I. , Vischer Henry F. , Zaman Guido J. R. , Smit Martine J. 
Published: March 2014

Abstract
Chemokines comprise a family of secreted proteins that activate G protein–coupled chemokine receptors and thereby control the migration of leukocytes during inflammation or immune surveillance. The positional information required for such migratory behavior is governed by the binding of chemokines to membrane-tethered glycosaminoglycans (GAGs), which establishes a chemokine concentration gradient. An often observed but incompletely understood behavior of chemokines is the ability of unrelated chemokines to enhance the potency with which another chemokine subtype can activate its cognate receptor. This phenomenon has been demonstrated to occur between many chemokine combinations and across several model systems and has been dubbed chemokine cooperativity. In this study, we have used GAG binding-deficient chemokine mutants and cell-based functional (migration) assays to demonstrate that chemokine cooperativity is caused by competitive binding of chemokines to GAGs. This mechanistic explanation of chemokine cooperativity provides insight into chemokine gradient formation in the context of inflammation, in which multiple chemokines are secreted simultaneously.
Critical Roles for PU.1, GATA1, and GATA2 in the Expression of Human FcεRI on Mast Cells: PU.1 and GATA1 Transactivate FCER1A, and GATA2 Transactivates FCER1A and MS4A2
Authors: Inage Eisuke , Kasakura Kazumi , Yashiro Takuya , Suzuki Ryuyo , Baba Yosuke , Nakano Nobuhiro , Hara Mutsuko , Tanabe Atsushi , Oboki Keisuke , Matsumoto Kenji , Saito Hirohisa , Niyonsaba François , Ohtsuka Yoshikazu , Ogawa Hideoki , Okumura Ko , Shimizu Toshiaki , Nishiyama Chiharu 
Published: March 2014

Abstract
The high-affinity IgE receptor, FcεRI, which is composed of α-, β-, and γ-chains, plays an important role in IgE-mediated allergic responses. In the current study, involvement of the transcription factors, PU.1, GATA1, and GATA2, in the expression of FcεRI on human mast cells was investigated. Transfection of small interfering RNAs (siRNAs) against PU.1, GATA1, and GATA2 into the human mast cell line, LAD2, caused significant downregulation of cell surface expression of FcεRI. Quantification of the mRNA levels revealed that PU.1, GATA1, and GATA2 siRNAs suppressed the α transcript, whereas the amount of β mRNA was reduced in only GATA2 siRNA transfectants. In contrast, γ mRNA levels were not affected by any of the knockdowns. Chromatin immunoprecipitation assay showed that significant amounts of PU.1, GATA1, and GATA2 bind to the promoter region of FCER1A (encoding FcεRIα) and that GATA2 binds to the promoter of MS4A2 (encoding FcεRIβ). Luciferase assay and EMSA showed that GATA2 transactivates the MS4A2 promoter via direct binding. These knockdowns of transcription factors also suppressed the IgE-mediated degranulation activity of LAD2. Similarly, all three knockdowns suppressed FcεRI expression in primary mast cells, especially PU.1 siRNA and GATA2 siRNA, which target FcεRIα and FcεRIβ, respectively. From these results, we conclude that PU.1 and GATA1 are involved in FcεRIα transcription through recruitment to its promoter, whereas GATA2 positively regulates FcεRIβ transcription. Suppression of these transcription factors leads to downregulation of FcεRI expression and IgE-mediated degranulation activity. Our findings will contribute to the development of new therapeutic approaches for FcεRI-mediated allergic diseases.
Involvement of the 4-1BB/4-1BBL Pathway in Control of Monocyte Numbers by Invariant NKT Cells
Authors: Cole Suzanne L. , Benam Kambez H. , McMichael Andrew J. , Ho Ling-Pei 
Published: March 2014

Abstract4-1BB is expressed on invariant (i)NKT cells, but its role is unclear. We showed previously that iNKT cells are involved in control of monocyte numbers during influenza A virus (IAV) infection and now question the role of the 4-1BB costimulatory pathway in the cross-talk between these cells. We found that iNKT cells and monocytes interact to promote expression of 4-1BB and 4-1BBL, respectively. Blockade of 4-1BB/L pathway under resting coculture conditions increased apoptosis of iNKT cells and monocytes. However, activation of iNKT cells overrides this survival signal, causing marked apoptosis of monocytes independent of 4-1BB/L. Blocking 4-1BBL in alpha-galactosylceramide-activated iNKT–monocyte cocultures reduced iNKT proliferation and abrogated monocytic IL-12 production. In vivo, expression of 4-1BB and 4-1BBL is increased on iNKT cells and Ly6Chi monocytes, respectively, during IAV infection, and there were lower frequencies of apoptosing Ly6Chi monocytes in the blood of iNKT knockout mice and higher numbers of monocytes in lungs compared with infected wild-type mice. Adoptive transfer of iNKT cells into the lungs of these mice reduced lung Ly6Chi monocytes levels, even when iNKT cells were preincubated with 4-1BB blocking Abs. These findings suggest that under resting conditions, 4-1BB/L engagement during iNKT–monocyte interaction promotes survival of these cells. When iNKT cells are activated, whether by alpha-galactosylceramide or during IAV infection, iNKT cells induced apoptosis of monocytes via a 4-1BB/L–independent mechanism, reducing monocyte numbers. 4-1BB/L costimulation amplified monocyte-mediated proliferation of iNKT cells, indirectly providing a method for monocytes to control their own numbers during infection.
Histone Deacetylase Inhibitor Sensitizes Apoptosis-Resistant Melanomas to Cytotoxic Human T Lymphocytes through Regulation of TRAIL/DR5 Pathway
Authors: Jazirehi Ali R. , Kurdistani Siavash K. , Economou James S. 
Published: March 2014

Abstract
Modern immune therapies (PD-1/PD-L1 and CTLA-4 checkpoints blockade and adoptive cell transfer) have remarkably improved the response rates of metastatic melanoma. These modalities rely on the killing potential of CTL as proximal mediator of antimelanoma responses. Mechanisms of tumor resistance to and the predominant cytotoxic pathway(s) used by melanoma-reactive CTL are important outcome determinants. We hypothesized that downmodulation of death receptors (DRs) in addition to aberrant apoptotic signaling might confer resistance to death signals delivered by CTL. To test these two hypotheses, we used an in vitro model of MART CTL–resistant melanoma sublines. TCR-transgenic and patient-derived CTLs used the TRAIL cytotoxic pathway through DR5. Furthermore, recombinant human TRAIL and drozitumab (anti-DR5 agonistic mAb) were used to explicitly verify the contribution of the DR5/TRAIL pathway in killing melanomas. CTL resistance was due to DR5 downregulation and an inverted ratio of pro- to antiapoptotic molecules, both of which were reversed by the histone deacetylase inhibitor suberoylanilide hydroxanic acid. Apoptosis negative (c-IAP-2 and Bcl-xL) and positive (DR5) regulators were potential incriminators partly regulating CTL sensitivity. These preclinical findings suggest that exposure to this chromatin remodeling drug of immune-resistant melanomas can skew toward an intracellular proapoptotic milieu, increase DR expression, and overcome acquired immune resistance.
CCL2 Shapes Macrophage Polarization by GM-CSF and M-CSF: Identification of CCL2/CCR2-Dependent Gene Expression Profile
Authors: Sierra-Filardi Elena , Nieto Concha , Domínguez-Soto Ángeles , Barroso Rubén , Sánchez-Mateos Paloma , Puig-Kroger Amaya , López-Bravo María , Joven Jorge , Ardavín Carlos , Rodríguez-Fernández José L. , Sánchez-Torres Carmen , Mellado Mario , Corbí Ángel L. 
Published: March 2014

Abstract
The CCL2 chemokine mediates monocyte egress from bone marrow and recruitment into inflamed tissues through interaction with the CCR2 chemokine receptor, and its expression is upregulated by proinflammatory cytokines. Analysis of the gene expression profile in GM-CSF– and M-CSF–polarized macrophages revealed that a high CCL2 expression characterizes macrophages generated under the influence of M-CSF, whereas CCR2 is expressed only by GM-CSF–polarized macrophages. Analysis of the factors responsible for this differential expression identified activin A as a critical factor controlling the expression of the CCL2/CCR2 pair in macrophages, as activin A increased CCR2 expression but inhibited the acquisition of CCL2 expression by M-CSF–polarized macrophages. CCL2 and CCR2 were found to determine the extent of macrophage polarization because CCL2 enhances the LPS-induced production of IL-10, whereas CCL2 blockade leads to enhanced expression of M1 polarization-associated genes and cytokines, and diminished expression of M2-associated markers in human macrophages. Along the same line, Ccr2-deficient bone marrow–derived murine macrophages displayed an M1-skewed polarization profile at the transcriptomic level and exhibited a significantly higher expression of proinflammatory cytokines (TNF-α, IL-6) in response to LPS. Therefore, the CCL2-CCR2 axis regulates macrophage polarization by influencing the expression of functionally relevant and polarization-associated genes and downmodulating proinflammatory cytokine production.
Hepatic Stellate Cells Orchestrate Clearance of Necrotic Cells in a Hypoxia-Inducible Factor-1α–Dependent Manner by Modulating Macrophage Phenotype in Mice
Authors: Mochizuki Akie , Pace Aaron , Rockwell Cheryl E. , Roth Katherine J. , Chow Aaron , O’Brien Kate M. , Albee Ryan , Kelly Kara , Towery Keara , Luyendyk James P. , Copple Bryan L. 
Published: March 2014

Abstract
Hypoxia-inducible factor-1α (HIF-1α) is activated in hepatic stellate cells (HSCs) by hypoxia and regulates genes important for tissue repair. Whether HIF-1α is activated in HSCs after acute injury and contributes to liver regeneration, however, is not known. To investigate this, mice were generated with reduced levels of HIF-1α in HSCs by crossing HIF-1α floxed mice with mice that express Cre recombinase under control of the glial fibrillary acidic protein (GFAP) promoter (i.e., HIF-1α-GFAP Cre+ mice). These mice and control mice (i.e., HIF-1α-GFAP Cre− mice) were treated with a single dose of carbon tetrachloride, and liver injury and repair were assessed. After carbon tetrachloride, HIF-1α was activated in HSCs. Although liver injury was not different between the two strains of mice, during resolution of injury, clearance of necrotic cells was decreased in HIF-1α-GFAP Cre+ mice. In these mice, the persistence of necrotic cells stimulated a fibrotic response characterized by extensive collagen deposition. Hepatic accumulation of macrophages, which clear necrotic cells from the liver after carbon tetrachloride, was not affected by HIF-1α deletion in HSCs. Conversion of macrophages to M1-like, proinflammatory macrophages, which have increased phagocytic activity, however, was reduced in HIF-1α-GFAP Cre+ mice as indicated by a decrease in proinflammatory cytokines and a decrease in the percentage of Gr1hi macrophages. Collectively, these studies have identified a novel function for HSCs and HIF-1α in orchestrating the clearance of necrotic cells from the liver and demonstrated a key role for HSCs in modulating macrophage phenotype during acute liver injury.
Interpretation of the full blood count in systemic disease – a guide for the physician
Authors: Leach M 
Published: March 2014

The full blood count (FBC) is perhaps the single most common investigation performed in medical patients. It has the potential, when interpreted carefully and in relation to the clinical history, to provide very useful information to assist in diagnosis and management. Clinicians are often alerted to the presence of a primary haematological disorder by abnormalities in the FBC. For the purpose of this review these diseases will not be discussed in detail but the reader will be alerted to pointers which might indicate primary blood disorders throughout the text. The haematology laboratory in large teaching hospitals will often provide up to 1,500 automated FBC analyses each day. These are individually checked for ‘flags’ provided by the analyser which indicate values outside the normal range. It is clearly essential that clinical information is provided with the request as this will influence how the result is handled by scientific and medical staff. Furthermore, significant abnormalities will generate a blood film request and the report will be most useful when interpreted in light of the patient’s working diagnosis. In cases where a diagnosis is not yet known, even brief information on presentation, for example ‘collapse with hypotension’, ‘fever on return to UK’, ‘weight loss and anorexia’, can all be important and help the lab provide clinicians with guidance. This short review aims to provide physicians with a workable guide to the interpretation of some of the commoner findings in the full blood count. Some of these will be very familiar to you but some will not. This review is not meant to be exhaustive as the rare minutiae will obscure the essential core material. Your haematology colleagues are always happy to help and available for assistance in difficult or problematic cases. I have not specified normal ranges in relation to each entity as these will be defined by your local laboratory.
Things that go bump in the night: diagnosing sleep-related movement disorders without a sleep laboratory
Authors: Reading P 
Published: March 2014

It is common for general physicians to experience diagnostic doubt and trepidation whenever faced with patients who exhibit abnormal nocturnal behaviours or excessive movements at night. There is also a perception that expensive and often poorly available overnight tests are usually required for diagnostic precision. In fact, the majority of conditions, whether they be parasomnias or, more rarely, nocturnal seizures, can be reliably diagnosed from a directed history, if available. Although the evidence base for treating parasomnias and sleep-related movement disorders remains minimal, accurate recognition is important for a variety of reasons. This review covers the diagnostic features of the full range of parasomnias and movement disorders that might present to a multidisciplinary adult sleep clinic. Throughout, it will be argued that the recognition of key or salient features obtained from a good history is the most important diagnostic tool. Indeed, when diagnostic doubt remains after a thorough sleep history, it is relatively rare for detailed tests to add much in the way of useful information.
Você é o que você veste? A associação da autoidentidade do gay masculino ao vestuário de luxo
Authors: Altaf Joyce Gonçalves , Troccoli Irene Raguenet , Moreira Mara Bastos 
Published: March 2014

The emergence of the identity of the homosexual modern consumer, favored by the social, economic and psychological conditions produced by capitalism, allowed homosexuals to feel free to express their identity, among other ways through the use of products and services. Thus, understanding what stimulates the consumption of a specific product category by this market niche is no doubt of great importance for the companies that intend to serve this public, considering their attractive consumption profile. This stimulated this exploratory qualitative study, that seeked to identify the relationship between luxury clothing consumption by homosexual men and the development of their extended self, and well as their self image construction. The four steps of the research, done with 12 men, were literature review, in-depth interviews, the filling of two forms (one with Likert scale and the other with a semantic scale), and the analysis of the results. The conclusion is that self concept directly influences the buying behavior of male homosexuals, and that most of the interviewees actually use luxury brands clothes to compose their extended selves.
EDUCAÇÃO INTEGRAL E A PERSPECTIVA HISTÓRICO-CRÍTICA: APROXIMAÇÕES POSSÍVEIS
Authors: Pattaro Rita De Cássia Ventura , Machado Vera Lúcia De Carvalho 
Published: March 2014

http://dx.doi.org/10.5902/198464444796 Considerando a importância da concepção e da prática de educação integral na história da educação brasileira, torna-se essencial entendê-la em sua plenitude para compreender suas proposições e de que maneira elas contribuem para a mudança social, brm como para uma formação completa das novas gerações. Por isso, este texto objetiva compreender as aproximações possíveis entre a concepção de educação integral e a perspectiva histórico-crítica, desenvolvida peloeducador Dermeval Saviani, correlacionando ambas com a jornada escolar ampliada. Foi utilizada a metodologia de pesquisa bibliográfica para a análise de uma teoria que é produto de reflexões e discussões com autores que se aproximam por terem o mesmo ideal de educação integral. Espera-se contribuir para as discussões sobre a implementação da política educacional de educação integral em tempo integral, balizadas pela perspectiva histórico-crítica.
GOLDEN5: UMA PROPOSTA DE CONSTRUÇÃO DE UM BOM AMBIENTE DE APRENDIZAGEM
Authors: Souza Rita De Cássia de , Rodriguez Maria Jose Lera 
Published: March 2014

http://dx.doi.org/10.5902/198464446954O Programa de intervenção educativa Golden5 foi criado em 2004 por uma equipe internacional visando melhorar o clima escolar no ensino secundário que passava por dificuldades semelhantes em vários países. Atualmente, seu uso tem se estendido para escolas infantis, primárias e atividades extraescolares para alunos com dificuldades escolares. Seu objetivo é melhorar o ambiente escolar a partir da intervenção docente. Para tanto, oferece aos professores um conjunto de ferramentas e habilidades que auxiliam a compreender o funcionamento do grupo e geri-lo de forma mais adequada. Vários estudos realizados acerca da aplicação do Golden5 em vários países, incluindo avaliações internas e externas ao Programa, mostraram resultados muito positivos. Apesar disso, é preciso considerar que sua aplicação depende da motivação e eficiência dos professores e isso certamente interfere nos resultados.
PERFIL DO ALUNO DE PSICOPEDAGOGIA
Authors: Peres Maria Regina 
Published: March 2014

http://dx.doi.org/10.5902/198464448480Os cursos de pós-graduação lato sensu, dentre eles o de psicopedagogia, têm apresentado uma crescente demanda nos últimos anos. Pouco se sabe sobre quem são os profissionais que procuram esses cursos. Realizamos um estudo com 251 alunos ingressantes no curso de psicopedagogia durante os anos de 2005 a 2012, pretendendo-se conhecer o perfil destes alunos e também os seus objetivos. Utilizamos um questionário de sondagem sobre a formação inicial do aluno, a sua atuação, experiência e futuras intenções. Os resultados indicaram que a maioria dos alunos são pedagogos que atuam como professores e objetivam alcançar melhorias na prática profissional. Concluiu-se que estes profissionais estão em busca de metodologias alternativas de trabalho que possam se reverter em melhorias educacionais. Palavras-chave: educação, prática profissional, metodologias.
Condições de trabalho docente: novas tessituras das políticas de avaliação para a qualidade
Authors: Nardi Elton Luiz , Schneider Marilda Pasqual 
Published: March 2014

http://dx.doi.org/10.5902/198464449123O artigo tem por objetivo analisar ações que implicam o trabalho docente, nomeadamente as que se referem às condições objetivas de trabalho e de emprego, tendo em conta novas tessituras das políticas de avaliação para a qualidade da educação básica implicadas no Ideb. Examina dados de questionários e entrevistas com gestores escolares e docentes do ensino fundamental, destinados a levantar ações delineadas entre 2010 e 2012, com vistas à melhoria da qualidade educacional. Assinala que, embora muitas ações informadas impliquem as condições de trabalho, a maioria delas focaliza condições objetivas e foi traçada tendo o Ideb como fator mobilizador. Conclui que o protagonismo a que a escola é chamada a exercer concentra-se na produção de resultados visando metas nacionais que têm asseverado as já difíceis condições de trabalho dos docentes. Palavras-chave: políticas de avaliação, Ideb, condições de trabalho docente.