bluuebunny/crossref_metadata_2025 huggingface dataset:
Augmented pressor and sympathetic responses to skeletal muscle metaboreflex activation in type 2 diabetes patients
Authors: Holwerda Seth W. , Restaino Robert M. , Manrique Camila , Lastra Guido , Fisher James P. , Fadel Paul J.
Published: November 2015

Previous studies have reported exaggerated increases in arterial blood pressure during exercise in type 2 diabetes (T2D) patients. However, little is known regarding the underlying neural mechanism(s) involved. We hypothesized that T2D patients would exhibit an augmented muscle metaboreflex activation and this contributes to greater pressor and sympathetic responses during exercise. Mean arterial pressure (MAP), heart rate (HR), and muscle sympathetic nerve activity (MSNA) were measured in 16 patients with T2D (8 normotensive and 8 hypertensive) and 10 healthy controls. Graded isolation of the muscle metaboreflex was achieved by postexercise ischemia (PEI) following static handgrip performed at 30% and 40% maximal voluntary contraction (MVC). A cold pressor test (CPT) was also performed as a generalized sympathoexcitatory stimulus. Increases in MAP and MSNA during 30 and 40% MVC handgrip were augmented in T2D patients compared with controls ( P < 0.05), and these differences were maintained during PEI (MAP: 30% MVC PEI: T2D, Δ16 ± 2 mmHg vs. controls, Δ8 ± 1 mmHg; 40% MVC PEI: T2D, Δ26 ± 3 mmHg vs. controls, Δ16 ± 2 mmHg, both P < 0.05). MAP and MSNA responses to handgrip and PEI were not different between normotensive and hypertensive T2D patients ( P > 0.05). Interestingly, MSNA responses were also greater in T2D patients compared with controls during the CPT ( P < 0.05). Collectively, these findings indicate that muscle metaboreflex activation is augmented in T2D patients and this contributes, in part, to augmented pressor and sympathetic responses to exercise in this patient group. Greater CPT responses suggest that a heightened central sympathetic reactivity may be involved.
Brief serotonin exposure initiates arteriolar inward remodeling processes in vivo that involve transglutaminase activation and actin cytoskeleton reorganization
Authors: Foote Christopher A. , Castorena-Gonzalez Jorge A. , Staiculescu Marius C. , Clifford Philip S. , Hill Michael A. , Meininger Gerald A. , Martinez-Lemus Luis A.
Published: November 2015

Inward remodeling of the resistance vasculature is strongly associated with life-threatening cardiovascular events. Previous studies have demonstrated that both actin polymerization and the activation of transglutaminases mediate early stages of the transition from a structurally normal vessel to an inwardly remodeled one. Ex vivo studies further suggest that a few hours of exposure to vasoconstrictor agonists induces inward remodeling in the absence of changes in intraluminal pressure. Here we report that a short, 10-min, topical exposure to serotonin (5-HT) + Nω-nitro-l-arginine methyl ester hydrochloride (l-NAME) was sufficient to initiate inward remodeling processes in rat cremasteric feed arterioles (100–200 μm lumen diameter), in vivo. Addition of the transglutaminase inhibitor, cystamine, blocked the in vivo remodeling. We further demonstrate that, in isolated arterioles, 5-HT + l-NAME activates transglutaminases and modulates the phosphorylation state of cofilin, a regulator of actin depolymerization. The 5-HT + l-NAME-induced remodeling process in isolated arterioles was also inhibited by an inhibitor of Lim Kinase, the kinase that phosphorylates and inactivates cofilin. Therefore, our results indicate that a brief vasoconstriction induced by 5-HT + l-NAME is able to reduce the passive structural diameter of arterioles through processes that are dependent on the activation of transglutaminases and Lim kinase, and the subsequent phosphorylation of cofilin.
VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development
Authors: Yun Eun Jun , Lorizio Walter , Seedorf Gregory , Abman Steven H. , Vu Thiennu H.
Published: November 2015

Prevention or treatment of lung diseases caused by the failure to form, or destruction of, existing alveoli, as observed in infants with bronchopulmonary dysplasia and adults with emphysema, requires understanding of the molecular mechanisms of alveolar development. In addition to its critical role in gas exchange, the pulmonary circulation also contributes to alveolar morphogenesis and maintenance by the production of paracrine factors, termed “angiocrines,” that impact the development of surrounding tissue. To identify lung angiocrines that contribute to alveolar formation, we disrupted pulmonary vascular development by conditional inactivation of the Vegf-A gene during alveologenesis. This resulted in decreased pulmonary capillary and alveolar development and altered lung elastin and retinoic acid (RA) expression. We determined that RA is produced by pulmonary endothelial cells and regulates pulmonary angiogenesis and elastin synthesis by induction of VEGF-A and fibroblast growth factor (FGF)-18, respectively. Inhibition of RA synthesis in newborn mice decreased FGF-18 and elastin expression and impaired alveolarization. Treatment with RA and vitamin A partially reversed the impaired vascular and alveolar development induced by VEGF inhibition. Thus we identified RA as a lung angiocrine that regulates alveolarization through autocrine regulation of endothelial development and paracrine regulation of elastin synthesis via induction of FGF-18 in mesenchymal cells.
Carvedilol binding to β2-adrenergic receptors inhibits CFTR-dependent anion secretion in airway epithelial cells
Authors: Peitzman Elizabeth R. , Zaidman Nathan A. , Maniak Peter J. , O'Grady Scott M.
Published: November 2015

Carvedilol functions as a nonselective β-adrenergic receptor (AR)/α1-AR antagonist that is used for treatment of hypertension and heart failure. Carvedilol has been shown to function as an inverse agonist, inhibiting G protein activation while stimulating β-arrestin-dependent signaling and inducing receptor desensitization. In the present study, short-circuit current ( Isc) measurements using human airway epithelial cells revealed that, unlike β-AR agonists, which increase Isc, carvedilol decreases basal and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate-stimulated current. The decrease in Iscresulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR). The carvedilol effect was abolished by pretreatment with the β2-AR antagonist ICI-118551, but not the β1-AR antagonist atenolol or the α1-AR antagonist prazosin, indicating that its inhibitory effect on Iscwas mediated through interactions with apical β2-ARs. However, the carvedilol effect was blocked by pretreatment with the microtubule-disrupting compound nocodazole. Furthermore, immunocytochemistry experiments and measurements of apical CFTR expression by Western blot analysis of biotinylated membranes revealed a decrease in the level of CFTR protein in monolayers treated with carvedilol but no significant change in monolayers treated with epinephrine. These results demonstrate that carvedilol binding to apical β2-ARs inhibited CFTR current and transepithelial anion secretion by a mechanism involving a decrease in channel expression in the apical membrane.
Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria
Authors: Agrawal Anurag , Mabalirajan Ulaganathan
Published: November 2015

Altered bioenergetics with increased mitochondrial reactive oxygen species production and degradation of epithelial function are key aspects of pathogenesis in asthma and chronic obstructive pulmonary disease (COPD). This motif is not unique to obstructive airway disease, reported in related airway diseases such as bronchopulmonary dysplasia and parenchymal diseases such as pulmonary fibrosis. Similarly, mitochondrial dysfunction in vascular endothelium or skeletal muscles contributes to the development of pulmonary hypertension and systemic manifestations of lung disease. In experimental models of COPD or asthma, the use of mitochondria-targeted antioxidants, such as MitoQ, has substantially improved mitochondrial health and restored respiratory function. Modulation of noncoding RNA or protein regulators of mitochondrial biogenesis, dynamics, or degradation has been found to be effective in models of fibrosis, emphysema, asthma, and pulmonary hypertension. Transfer of healthy mitochondria to epithelial cells has been associated with remarkable therapeutic efficacy in models of acute lung injury and asthma. Together, these form a 3R model—repair, reprogramming, and replacement—for mitochondria-targeted therapies in lung disease. This review highlights the key role of mitochondrial function in lung health and disease, with a focus on asthma and COPD, and provides an overview of mitochondria-targeted strategies for rejuvenating cellular respiration and optimizing respiratory function in lung diseases.
Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results in Regression of Established Tumors
Authors: Baird Jason R. , Friedman David , Cottam Benjamin , Dubensky Thomas W. , Kanne David B. , Bambina Shelly , Bahjat Keith , Crittenden Marka R. , Gough Michael J.
Published: November 2015

Cytotoxic therapies prime adaptive immune responses to cancer by stimulating the release of tumor-associated antigens. However, the tumor microenvironment into which these antigens are released is typically immunosuppressed, blunting the ability to initiate immune responses. Recently, activation of the DNA sensor molecule STING by cyclic dinucleotides was shown to stimulate infection-related inflammatory pathways in tumors. In this study, we report that the inflammatory pathways activated by STING ligands generate a powerful adjuvant activity for enhancing adaptive immune responses to tumor antigens released by radiotherapy. In a murine model of pancreatic cancer, we showed that combining CT-guided radiotherapy with a novel ligand of murine and human STING could synergize to control local and distant tumors. Mechanistic investigations revealed T-cell–independent and TNFα-dependent hemorrhagic necrosis at early times, followed by later CD8 T-cell–dependent control of residual disease. Clinically, STING was found to be expressed extensively in human pancreatic tumor and stromal cells. Our findings suggest that this novel STING ligand could offer a potent adjuvant for leveraging radiotherapeutic management of pancreatic cancer. Cancer Res; 76(1); 50–61. ©2015 AACR.
PD-1 Blunts the Function of Ovarian Tumor–Infiltrating Dendritic Cells by Inactivating NF-κB
Authors: Karyampudi Lavakumar , Lamichhane Purushottam , Krempski James , Kalli Kimberly R. , Behrens Marshall D. , Vargas Doris M. , Hartmann Lynn C. , Janco Jo Marie T. , Dong Haidong , Hedin Karen E. , Dietz Allan B. , Goode Ellen L. , Knutson Keith L.
Published: November 2015

The PD-1:PD-L1 immune signaling axis mediates suppression of T-cell–dependent tumor immunity. PD-1 expression was recently found to be upregulated on tumor-infiltrating murine (CD11c+CD11b+CD8−CD209a+) and human (CD1c+CD19−) myeloid dendritic cells (TIDC), an innate immune cell type also implicated in immune escape. However, there is little knowledge concerning how PD-1 regulates innate immune cells. In this study, we examined the role of PD-1 in TIDCs derived from mice bearing ovarian tumors. Similar to lymphocytes, TIDC expression of PD-1 was associated with expression of the adapter protein SHP-2, which signals to NF-κB; however, in contrast to its role in lymphocytes, we found that expression of PD-1 in TIDC tonically paralyzed NF-κB activation. Further mechanistic investigations showed that PD-1 blocked NF-κB–dependent cytokine release in a SHP-2–dependent manner. Conversely, inhibition of NF-κB–mediated antigen presentation by PD-1 occurred independently of SHP-2. Collectively, our findings revealed that PD-1 acts in a distinct manner in innate immune cells compared with adaptive immune cells, prompting further investigations of the signaling pathways controlled by this central mediator of immune escape in cancer. Cancer Res; 76(2); 239–50. ©2015 AACR.
PRC2 Epigenetically Silences Th1-Type Chemokines to Suppress Effector T-Cell Trafficking in Colon Cancer
Authors: Nagarsheth Nisha , Peng Dongjun , Kryczek Ilona , Wu Ke , Li Wei , Zhao Ende , Zhao Lili , Wei Shuang , Frankel Timothy , Vatan Linda , Szeliga Wojciech , Dou Yali , Owens Scott , Marquez Victor , Tao Kaixiong , Huang Emina , Wang Guobin , Zou Weiping
Published: November 2015

Infiltration of tumors with effector T cells is positively associated with therapeutic efficacy and patient survival. However, the mechanisms underlying effector T-cell trafficking to the tumor microenvironment remain poorly understood in patients with colon cancer. The polycomb repressive complex 2 (PRC2) is involved in cancer progression, but the regulation of tumor immunity by epigenetic mechanisms has yet to be investigated. In this study, we examined the relationship between the repressive PRC2 machinery and effector T-cell trafficking. We found that PRC2 components and demethylase JMJD3-mediated histone H3 lysine 27 trimethylation (H3K27me3) repress the expression and subsequent production of Th1-type chemokines CXCL9 and CXCL10, mediators of effector T-cell trafficking. Moreover, the expression levels of PRC2 components, including EZH2, SUZ12, and EED, were inversely associated with those of CD4, CD8, and Th1-type chemokines in human colon cancer tissue, and this expression pattern was significantly associated with patient survival. Collectively, our findings reveal that PRC2-mediated epigenetic silencing is not only a crucial oncogenic mechanism, but also a key circuit controlling tumor immunosuppression. Therefore, targeting epigenetic programs may have significant implications for improving the efficacy of current cancer immunotherapies relying on effective T-cell–mediated immunity at the tumor site. Cancer Res; 76(2); 275–82. ©2015 AACR.
Promises and Challenges of Smac Mimetics as Cancer Therapeutics
Authors: Fulda Simone
Published: November 2015

Inhibitor of Apoptosis (IAP) proteins block programmed cell death and are expressed at high levels in various human cancers, thus making them attractive targets for cancer drug development. Second mitochondrial activator of caspases (Smac) mimetics are small-molecule inhibitors that mimic Smac, an endogenous antagonist of IAP proteins. Preclinical studies have shown that Smac mimetics can directly trigger cancer cell death or, even more importantly, sensitize tumor cells for various cytotoxic therapies, including conventional chemotherapy, radiotherapy, or novel agents. Currently, several Smac mimetics are under evaluation in early clinical trials as monotherapy or in rational combinations (i.e., GDC-0917/CUDC-427, LCL161, AT-406/Debio1143, HGS1029, and TL32711/birinapant). This review discusses the promise as well as some challenges at the translational interface of exploiting Smac mimetics as cancer therapeutics. Clin Cancer Res; 21(22); 5030–6. ©2015 AACR.

See all articles in this CCR Focus section, “Cell Death and Cancer Therapy.”
Autophagy, Metabolism, and Cancer
Authors: White Eileen , Mehnert Janice M. , Chan Chang S.
Published: November 2015

Macroautophagy (autophagy hereafter) captures intracellular proteins and organelles and degrades them in lysosomes. The degradation breakdown products are released from lysosomes and recycled into metabolic and biosynthetic pathways. Basal autophagy provides protein and organelle quality control by eliminating damaged cellular components. Starvation-induced autophagy recycles intracellular components into metabolic pathways to sustain mitochondrial metabolic function and energy homeostasis. Recycling by autophagy is essential for yeast and mammals to survive starvation through intracellular nutrient scavenging. Autophagy suppresses degenerative diseases and has a context-dependent role in cancer. In some models, cancer initiation is suppressed by autophagy. By preventing the toxic accumulation of damaged protein and organelles, particularly mitochondria, autophagy limits oxidative stress, chronic tissue damage, and oncogenic signaling, which suppresses cancer initiation. This suggests a role for autophagy stimulation in cancer prevention, although the role of autophagy in the suppression of human cancer is unclear. In contrast, some cancers induce autophagy and are dependent on autophagy for survival. Much in the way that autophagy promotes survival in starvation, cancers can use autophagy-mediated recycling to maintain mitochondrial function and energy homeostasis to meet the elevated metabolic demand of growth and proliferation. Thus, autophagy inhibition may be beneficial for cancer therapy. Moreover, tumors are more autophagy-dependent than normal tissues, suggesting that there is a therapeutic window. Despite these insights, many important unanswered questions remain about the exact mechanisms of autophagy-mediated cancer suppression and promotion, how relevant these observations are to humans, and whether the autophagy pathway can be modulated therapeutically in cancer. Clin Cancer Res; 21(22); 5037–46. ©2015 AACR.

See all articles in this CCR Focus section, “Cell Death and Cancer Therapy.”
Cell Death and Cancer Therapy: Don't Forget to Kill the Cancer Cell!
Authors: Letai Anthony
Published: November 2015

In our current age of targeted therapies, there is understandably considerable attention paid to the specific molecular targets of pharmaceutical intervention. For a targeted drug to work, it must bind to a target selectively and impair its function. Monitoring biomarkers of the impaired target function can provide vital in vivo pharmacodynamic information. Moreover, genetic changes to the target are often the source of resistance to targeted agents. However, for the treatment of cancer, it is necessary that the therapy not only provide efficient binding and inhibition of the target, but also that this intervention reliably kills the cancer cell. In this CCR Focus section, four articles make the connection between therapies that target T-cell activation, autophagy, IAP proteins, and BCL-2 and the commitment of cancer cells to cell death. Before addressing those exciting classes of targeted therapies, however, an overview is provided to discuss cell death induced by what is arguably still the most successful set of drugs in the history of medical oncology, conventional chemotherapy. Clin Cancer Res; 21(22); 5015–20. ©2015 AACR.

See all articles in this CCR Focus section, "Cell Death and Cancer Therapy."
Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms
Authors: Diamond Eli L. , Durham Benjamin H. , Haroche Julien , Yao Zhan , Ma Jing , Parikh Sameer A. , Wang Zhaoming , Choi John , Kim Eunhee , Cohen-Aubart Fleur , Lee Stanley Chun-Wei , Gao Yijun , Micol Jean-Baptiste , Campbell Patrick , Walsh Michael P. , Sylvester Brooke , Dolgalev Igor , Aminova Olga , Heguy Adriana , Zappile Paul , Nakitandwe Joy , Ganzel Chezi , Dalton James D. , Ellison David W. , Estrada-Veras Juvianee , Lacouture Mario , Gahl William A. , Stephens Philip J. , Miller Vincent A. , Ross Jeffrey S. , Ali Siraj M. , Briggs Samuel R. , Fasan Omotayo , Block Jared , Héritier Sebastien , Donadieu Jean , Solit David B. , Hyman David M. , Baselga José , Janku Filip , Taylor Barry S. , Park Christopher Y. , Amoura Zahir , Dogan Ahmet , Emile Jean-Francois , Rosen Neal , Gruber Tanja A. , Abdel-Wahab Omar
Published: November 2015

Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders.

Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR.

This article is highlighted in the In This Issue feature, p. 109
Enhanced Eryptosis Following Exposure to Carnosic Acid
Authors: Stockinger Katja , Bissinger Rosi , Bouguerra Ghada , Abbès Salem , Lang Florian
Published: November 2015

Background/Aims: The phenolic abietane diterpene component of rosemary and sage, carnosic acid, may either induce or inhibit apoptosis of nucleated cells. The mechanisms involved in the effects of carnosic acid include altered mitochondrial function and gene expression. Human erythrocytes lack mitochondria and nuclei but are nevertheless able to enter suicidal death or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Cellular mechanisms involved in the stimulation of eryptosis include oxidative stress, increase of cytosolic Ca2+ activity ([Ca2+]i), and ceramide formation. The present study explored, whether and how carnosic acid induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin V binding, cell volume from forward scatter, [Ca2+]i from Fluo3-fluorescence, ROS formation from DCFDA dependent fluorescence and ceramide abundance utilizing specific antibodies. Results: A 48 hours exposure of human erythrocytes to carnosic acid significantly increased the percentage of annexin-V-binding cells (2.5 µg/ml), significantly decreased forward scatter (10 µg/ml), significantly increased Fluo3 fluorescence (10 µg/ml), significantly increased ceramide abundance (10 µg/ml), significantly increased hemolysis (10 µg/ml), but significantly decreased DCFDA fluorescence (10 µg/ml). The effect of carnosic acid on annexin-V-binding was significantly blunted, but not abolished by removal of extracellular Ca2+. Conclusion: Carnosic acid triggers cell shrinkage and phospholipid scrambling of the human erythrocyte cell membrane, an effect paralleled by and/or in part due to Ca2+ entry and increased ceramide abundance.
22q11.2 Deletion Syndrome due to a Translocation t(6;22) in a Patient Conceived via in vitro Fertilization
Authors: Gollo Dantas Anelisa , Bortolai Adriana , Moysés-Oliveira Mariana , Takeno Herrero Sylvia , Azoubel Antunes Adriana , Tavares Costa-Carvalho Beatriz , Ayres Meloni Vera , Melaragno Maria Isabel
Published: November 2015

We report on a patient conceived via in vitro fertilization (IVF) with a 22q11.2 deletion due to an unusual unbalanced translocation involving chromosomes 6 and 22 in a karyotype with 45 chromosomes. Cytogenomic studies showed that the patient has a 3.3-Mb deletion of chromosome 22q and a 0.4-Mb deletion of chromosome 6p, which resulted in haploinsufficiency of the genes responsible for the 22q11.2 deletion syndrome and also of the IRF4 gene, a member of the interferon regulatory factor family of transcription factors, which is expressed in the immune system cells. The rearrangement could be due to the manipulation of the embryo or as a sporadic event unrelated to IVF. Translocation involving chromosome 22 in a karyotype with 45 chromosomes is a rare event, with no previous reports involving chromosomes 6p and 22q.
Human Papillomavirus Genotyping to Predict the Risk of Cervical Precancerous Lesions or Cancer in Women with Minor Abnormal Cytology in China
Authors: Lin Chun-Qing , Cui Jian-Feng , Zhang Xun , Pan Qin-Jing , Chen Wen , Qiao You-Lin
Published: November 2015

Objective: To evaluate the role of human papillomavirus (HPV) genotyping in predicting the risk of cervical precancerous lesions or cancer in women with minor abnormal cytology. Methods and Materials: This study was conducted on 329 women with atypical squamous cells of undetermined significance (ASC-US) and 77 women with low-grade squamous intraepithelial lesions (LSIL) out of a total of 4,215 participants in a multicenter, cross-sectional study. Liquid-based cytology and the Hybrid Capture 2 test (HC2) were used to screen eligible women, and a Linear Array HPV genotyping test was performed on women with positive HC2 results. Results: The sensitivity and specificity for detecting cervical intraepithelial neoplasia grade 2 or worse (CIN2+) based on HPV 16/18 were 82% [95% confidence interval (CI): 52-95%] and 91% (95% CI: 87-94%) in women with ASC-US and 67% (95% CI: 35-88%) and 84% (95% CI: 73-91%) in women with LSIL. The women infected with HPV 16/18 had a significantly higher risk of developing CIN2+ than those infected with other high-risk HPV types in both the ASC-US (OR 9.93, 95% CI: 2.02-48.88) and LSIL (OR 7.45, 95% CI: 1.60-34.68) arms. Conclusions: Genotyping for HPV 16/18 greatly improves specificity, but at the expense of potential sensitivity in the triage of minor cytology abnormalities. The role of genotyping for HPV 16/18 in order to triage women with minor abnormal cytology should be further evaluated in future studies.
Turismo e Confronto com a Identidade Cultural: impactos psicossociais da atividade turística em Diamantina- MG
Authors: Silva Diego Rodrigues da , Sant' Anna Paulo Afranio
Published: November 2015

Esta pesquisa tem por objetivo discutir os impactos psicossociais da atividade turística em Diamantina, a partir da concepção de identidade cultural, mais especificamente, a partir das questões identitárias que se apresentam no contato da população local com o turista. Procurou-se centrar sobre os elementos e situações que confrontam ou contrastam significativamente com o modo de vida local. Para tal, realizou-se um grupo focal com os principais representantes dos setores ligados a atividade turística na cidade. Os discursos indicaram que os residentes percebem os impactos de uma forma negativa, sinalizando situações de ameaça e agressão ao modo de vida, além do turismo não ser o único vetor de alteração da identidade tradicional.Palavras-chave: identidade, turismo, impacto do turismo, confronto/negação da identidade, Diamantina.
Cuando el Cielo Tiembla: crónicas del pánico en Villa Gesell
Authors: Korstanje Maximiliano E
Published: November 2015

ResumenLas vacaciones son parte esencial de la vida de los ciudadanos. Todas nuestras expectativas están puestas en este momento mágico. No obstante, en ciertas ocasiones lo que empieza por ser un sueño pasa a ser una pesadilla. Este es el caso de los cuatro jóvenes muertos luego de que un rayo impactara en una carpa en la playa de la ciudad de Villa Gesell. Nada puede prepararnos para lo peor, siquiera en los momentos únicos. En este contexto, exploramos no solo las raíces antropológicas del riesgo y las vacaciones, sino el discurso periodístico que cubre la noticia. Nuestra tesis es que lejos de todo lo que se piensa, la tragedia no afecta al turismo sino que le da su razón de existir, duplicando su atractividad. Palabras claves: Vacaciones, ritos de pasaje, turismo, riesgo, desastre.
Análisis Interactivo de Valoraciones y Prácticas de los Turistas en el Museo Egidio Feruglio (Patagonia, Argentina)
Authors: Valenzuela Cristian Matias Gonzalez
Published: November 2015

El binomio patrimonio y turismo involucra diversas valoraciones y prácticas sociales, dependiendo su multiplicidad y variabilidad en función de los actores sociales participantes. Entre los diversos actores, el turista atribuye diferentes tipos de valores, y consecuentemente, desenvuelve acciones múltiples en los espacios patrimoniales que merecen un abordaje complejo. En este sentido, el presente artículo describirá las valoraciones y prácticas de los turistas tanto en el viaje como en la visita del museo, y sus interpelaciones interactivas entre las mismas. En la investigación se desarrolla un estudio exploratorio y descriptivo con triangulación metodológica, donde se toma como caso de estudio el Museo Egidio Feruglio (Trelew, Argentina).Los datos se recolectaron mediante encuestas y observaciones realizadas a los turistas, complementado con datos obtenidos de las entrevistas aplicadas al personal del museo. Los principales resultados obtenidos se concentraron en el conocimiento de las motivaciones, percepciones y satisfacciones de los turistas como formas de expresión de sus valoraciones; y en el comportamiento de viaje, conducta atencional y desplazamiento espacial en el museo como modos de manifestación de sus prácticas. Las conclusiones residieron en los procesos de interacción entre diferentes tipos de valores sobre el patrimonio, como el de uso, simbólico y forma-estético. A su vez, las interpelaciones manifiestas en las prácticas de consumo, recreación y aprendizaje del turista dentro del museo analizado.
As Pesquisas de Demanda Turística em Minas Gerais: evolução histórica, principais desafios e perspectivas de futuro
Authors: Morais Raul Suhett de , Oliveira Rafael Almeida de , Paim Alessandra Hayssa Caetano de Azevedo
Published: November 2015

As pesquisas de demanda turística (PDT) têm sido uma ferramenta útil de trabalho das instituições relacionadas ao desenvolvimento do turismo desde meados do século passado, apesar de, no Brasil, os primeiros estudos sobre o perfil dos visitantes só terem começado a aparecer depois da década de 1980. O Governo do Estado de Minas Gerais tem realizado PDTs desde 2006 com a intenção de conhecer o perfil dos visitantes do estado e, a partir desses dados, enfocar as políticas públicas relacionadas ao fenômeno turístico. Este artigo começa com um referencial teórico que cobre, principalmente, dois aspectos muito importantes das PDTs mineiras: a regionalização do turismo, na forma dos Circuitos Turísticos; e como os modelos de pesquisas feitas em Minas Gerais se enquadram nos estudos feitos em outros destinos. O desenvolvimento mostra a evolução das pesquisas levadas a cabo no estado, os principais desafios já enfrentados e por enfrentar, como a PDT tem ajudado a orientar as políticas públicas e, por fim, quais as perspectivas de futuro no tema.
Perfil, Expectativas de Consumo e Satisfação dos Visitantes de Fim de Semana da Vila Histórica de Paranapiacaba - Santo André, SP
Authors: Flaminio Giovana Carla , Lobo Heros Augusto Santos
Published: November 2015

Este artigo apresenta uma descrição e análise do perfil, expectativas e níveis de satisfação da demanda de visitantes de final de semana da Vila Paranapiacaba, um consolidado destino de turismo histórico-ferroviário. Para tanto, foram realizadas pesquisa de campo, com a aplicação de 321 questionários. Os resultados demonstraram que Paranapiacaba atrai visitantes de classe média e alta, oriundos principalmente de municípios em um raio de até 119 km de distância, sendo que metade destes está no local pela primeira vez. A maioria dos visitantes passa somente algumas horas na vila histórica, utilizando principalmente os atrativos históricos, culturais e naturais e os serviços de alimentação, com pouco uso dos meios de hospedagem e outros serviços e infraestruturas para o turismo. As expectativas dos visitantes são em sua maioria atendidas pela oferta atual, conferindo um grau predominantemente positivo na avaliação de satisfação. Desta forma, conclui-se que a Vila de Paranapiacaba necessita de algumas melhorias apenas na infraestrutura e nos serviços básicos, bem como deve aproveitar melhor os canais virtuais de divulgação, que ainda ocupam pequena parcela como meio de divulgação do destino. Quanto aos empreendimentos, sugere-se que caminhem para a diferenciação em sua forma de atendimento e nos produtos oferecidos, aspectos pontuados pelos visitantes. Por fim, ressalta-se a necessidade de pesquisas complementares no destino, em eventos e nos dias úteis com escolas, para o conhecimento amplo de toda a demanda, bem como sua curva sazonal de visitação.
Why teach the history of Africa and of the negro intodays Brazil?
Authors: Munanga Kabengele
Published: November 2015

O Brasil oferece o melhor exemplo de um país que nasceu do encontro das diversidades étnicas e culturais. Povos indígenas, primeiros habitantes da terra que se tornou Brasil; aventureiros e colonizadores portugueses; africanos deportados e aqui escravizados; imigrantes europeus de diversas origens étnicas e culturais e imigrantes asiáticos, todos formam as raízes culturais do Brasil de hoje. Sem dúvida, os sangues se misturaram como continuam a se misturar. Os deuses se tocaram e as cercas das identidades se aproximaram. No entanto, as resistências identitárias dessas matrizes culturais formadoras do Brasil continuam a se manifestar, influenciando a vida cotidiana de todos os brasileiros indistintamente. Por outro lado, os preconceitos culturais, apesar da mestiçagem, não deixaram de existir como ilustrado hoje pela chamada intolerância religiosa e pelos preconceitos raciais que estão correndo soltos até nos campos de futebol. A questão fundamental que se coloca é como ensinar a história desses povos que na historiografia oficial foi preterida e substituída pela história de um único continente, silenciando a rica diversidade cultural em nome de um monoculturalismo justificado pelo chamado sincretismo cultural ou mestiçagem, quando na realidade o que se ensina mesmo é a Europa com sua história e sua cultura. Aqui se coloca a importância de uma educação multicultural que enfoque nossa rica diversidade ao incluir na formação da cidadania a história e a cultura de outras raízes formadoras do Brasil. As leis 10 639/03 e 11645/08 que tornam obrigatório o ensino da história do continente africano, dos negros e povos indígenas brasileiros têm essa função reparatória e corretora.
Atherosclerosis Susceptibility in Mice Is Independent of the
V1
Immunoglobulin Heavy Chain Gene
Authors: Centa Monica , Gruber Sabrina , Nilsson Daniel , Polyzos Konstantinos A. , Johansson Daniel K. , Hansson Göran K. , Ketelhuth Daniel F.J. , Binder Christoph J. , Malin Stephen
Published: November 2015

Objective—

The
V1
(
V

H

S107.1.42
) immunoglobulin heavy chain gene is thought to be critical in producing IgM natural antibodies of the T15-idiotype that protect against both atherosclerosis and infection from
Streptococcus pneumoniae
. Our aim was to determine whether genetic loss of the
V1
gene increased atherosclerotic plaque burden in vivo because of a reduction in the T15-idiotype or other atheroprotective antibodies.

Approach and Results—

We crossed
V

H

S107.1.42
-deficient mice with the atherosclerosis-prone
Apoe
−/−
and
Ldlr
−/−
strains. Although these double knockout strains manifested no defects in B-cell development, we did observe a substantial reduction in early immune responses against phosphocholine after immunization. However, the titers of plasma antibodies reacting against defined atherosclerotic antigens such as oxidized low-density lipoprotein, as well as the T15-idiotype, were unaffected by loss of the
V

H

S107.1.42
gene in hypercholesterolemic mice. Furthermore, we observed no increase in atherosclerotic lesion formation, either within the aortic arch or aortic root. Robust deposition of IgM within atherosclerotic plaques could also be readily observed in both control and experimental mice.

Conclusions—

Our data indicate that IgM-dependent protection against atherosclerosis is unlikely to be dependent on antibodies that use the
V

H

S107.1.42
gene, in contrast to the acute immune response conferred by this heavy chain in the response to phosphocholine and in providing resistance against lethal
S pneumoniae
infection.
Novel Genetic Loci Associated With Retinal Microvascular Diameter
Authors: Jensen Richard A. , Sim Xueling , Smith Albert Vernon , Li Xiaohui , Jakobsdóttir Jóhanna , Cheng Ching-Yu , Brody Jennifer A. , Cotch Mary Frances , Mcknight Barbara , Klein Ronald , Wang Jie Jin , Kifley Annette , Harris Tamara B. , Launer Lenore J. , Taylor Kent D. , Klein Barbara E.K. , Raffel Leslie J. , Li Xiang , Ikram M. Arfan , Klaver Caroline C. , van der Lee Sven J. , Mutlu Unal , Hofman Albert , Uitterlinden André G. , Liu Chunyu , Kraja Aldi T. ,   The CHARGE Exome Chip Blood Pressure Consortium, Mitchell Paul , Gudnason Vilmundur , Rotter Jerome I. , Boerwinkle Eric , van Duijn Cornelia M. , Psaty Bruce M. , Wong Tien Y.
Published: November 2015

Background—

There is increasing evidence that retinal microvascular diameters are associated with cardiovascular and cerebrovascular conditions. The shared genetic effects of these associations are currently unknown. The aim of this study was to increase our understanding of the genetic factors that mediate retinal vessel size.

Methods and Results—

This study extends previous genome-wide association study results using 24 000+ multiethnic participants from 7 discovery cohorts and 5000+ subjects of European ancestry from 2 replication cohorts. Using the Illumina HumanExome BeadChip, we investigate the association of single-nucleotide polymorphisms and variants collectively across genes with summary measures of retinal vessel diameters, referred to as the central retinal venule equivalent and the central retinal arteriole equivalent. We report 4 new loci associated with central retinal venule equivalent, one of which is also associated with central retinal arteriole equivalent. The 4 single-nucleotide polymorphisms are rs7926971 in
TEAD1
(
P
=3.1×10
−
11
; minor allele frequency=0.43), rs201259422 in
TSPAN10
(
P
=4.4×10
−9
; minor allele frequency=0.27), rs5442 in
GNB3
(
P
=7.0×10
−10
; minor allele frequency=0.05), and rs1800407 in
OCA2
(
P
=3.4×10
−8
; minor allele frequency=0.05). The latter single-nucleotide polymorphism, rs1800407, was also associated with central retinal arteriole equivalent (
P
=6.5×10
−12
). Results from the gene-based burden tests were null. In phenotype look-ups, single-nucleotide polymorphism rs201255422 was associated with both systolic (
P
=0.001) and diastolic blood pressures (
P
=8.3×10
−04
).

Conclusions—

Our study expands the understanding of genetic factors influencing the size of the retinal microvasculature. These findings may also provide insight into the relationship between retinal and systemic microvascular disease.
Heidegger’s (Dramatic?) Dialogues
Authors: Hyland Drew A.
Published: November 2015

Taking my cue from the richly dramatic character of the Platonic dialogues and how that dramatic character informs the thought therein, I attempt a reading of Heidegger’s dialogue on a country path that takes similar account of the dramatic themes of that dialogue. Accordingly, I address such themes as the fact that the characters of the dialogue are not given personal names, the fact that it is and must be a dialogue that occurs on a country path, and the strange interactions of the three characters. The paper culminates in a discussion of the role of “night,” which, I argue, functions as our guiding image of Ereignis.
Validation of serum free light chain reference ranges in primary care
Authors: Galvani Luca , Flanagan Jane , Sargazi Mansour , Neithercut William D
Published: November 2015

Background

The demand for measurement of serum immunoglobulin free kappa (κ) and lambda (λ) light chains has increased. The κ:λ ratio is used to assist in diagnosis/monitoring of plasma cell disorders. The binding site reference range for serum-free light chain κ:λ ratios of 0.26–1.65 was derived from healthy volunteers. Subsequently, a reference range of 0.37–3.1 for patients with chronic kidney disease has been proposed. Elevated free light chain concentrations and borderline raised free light chain ratios also may be found in polyclonal gammopathies and with other non-renal illnesses. This assessment was conducted to validate the established free light chain reference ranges in individuals from primary care.

Method

A total of 130 samples were identified from routine blood samples collected in primary care for routine biochemistry testing and estimated glomerular filtration rate calculation.

Results

The median and range of κ:λ ratios found in each estimated glomerular filtration rate group used for chronic kidney disease classification were higher than previously described. This was the case for individuals with normal or essentially normal renal function with estimated glomerular filtration rates>90, (0.58–1.76) and estimated glomerular filtration rate of 60–90 mL/min/1.73 m2, (0.71–1.93). Individuals with estimated glomerular filtration rate 15–30, (0.72–4.50) and estimated glomerular filtration rate <15 ml/min/1.73 m2 (0.71–4.95) also had higher values when compared to the current renal reference range of 0.37–3.10.

Conclusions

Elevation of free light chain-κ:λ ratios may occur in the absence of a reduced renal function shown by a normal estimated glomerular filtration rate and in the presence of reduced renal function by estimated glomerular filtration rate when comparing results with the established reference ranges. Explanations include choice of analytical systems or the presence of other concurrent non-plasma cell illness.
Thermal and mechanical properties of two kinds of hydroxyl-terminated polyether prepolymers and the corresponding polyurethane elastomers
Authors: Mao Kezhu , Xia Min , Luo Yunjun
Published: November 2015

In order to analyze the differences in performance between two kinds of hydroxyl-terminated polyether (HTPE) binders, the curing reaction kinetics of the prepolymers and polyfunctional isocyanate (N-100) molecules and the thermal properties of the prepolymers and the corresponding polyurethane (PU) elastomers were studied by non-isothermal differential scanning calorimetry. The mechanical properties of PU elastomers were also studied by uniaxial tensile tests. With these data, the binder type could be chosen more appropriately for its application in rocket propellant formulations. The results showed that the reactivity of hydroxyl-terminated block copolyether (TPEG) with an isocyanate group is higher than that of hydroxyl-terminated random copolyether (PET). The chain flexibility of TPEG was less than that of PET, but the stereoregularity and crystallization ability of the former were superior. Compared to the prepolymers, the chain flexibility of the corresponding PU elastomers was reduced, and the crystallization ability became weaker such that their onset of crystallization was delayed. After the prepolymers were reacted with N-100, the thermal properties of PU elastomers remained consistent with their respective prepolymers. In summary, it was concluded that the mechanical properties of TPEG/N-100 PU elastomer films were found to be superior to the PET/N-100 films.
Approach–Avoidance Training Effects Are Moderated by Awareness of Stimulus–Action Contingencies
Authors: Van Dessel Pieter , De Houwer Jan , Gast Anne
Published: November 2015

Prior research suggests that repeatedly approaching or avoiding a stimulus changes the liking of that stimulus. In two experiments, we investigated the relationship between, on one hand, effects of approach–avoidance (AA) training on implicit and explicit evaluations of novel faces and, on the other hand, contingency awareness as indexed by participants’ memory for the relation between stimulus and action. We observed stronger effects for faces that were classified as contingency aware and found no evidence that AA training caused changes in stimulus evaluations in the absence of contingency awareness. These findings challenge the standard view that AA training effects are (exclusively) the product of implicit learning processes, such as the automatic formation of associations in memory.
Continuity and Change in Labor Process Analysis Forty Years After Labor and Monopoly Capital
Authors: Smith Chris
Published: November 2015

Braverman’s Labor and Monopoly Capital tapped into a late twentieth century sense that work while appearing ever safer, cleaner and more automated, was actually, less skilled, more controlled, and more intensive. For Braverman the general movement in work in the twentieth century had been towards degradation of skill and worker control, devoid of creative technical content and thought. Braverman’s monumental book drew on Marx’s writings on technology and the labour process, for the conditions of American capitalism in the 1970s. He provoked such heated debate that the term ‘Bravermania’ has entered the sociological lexicon. His analysis on the labour process in late modernity has seen scholars of organization, work and society at loggerheads over an array of issues. While some writers have attacked Braverman for underplaying the potential for worker resistance, others have defended his analysis as more nuanced and ultimately true to its Marxist inheritance. These debates, which continue to this day on both sides of the Atlantic, but as the paper demonstrates, there has been a movement away from some of the grander themes of Labor and Monopoly Capital (the state, the class structure, the universal market) towards a narrow focus on skill. But there has also been a widening of debates, with new themes (embodiment of labour, globalization, heightened mobility of labour, fragmentation of employment contracts, and spatial division of labour) which has moved labour process theory on and continued to rejuvenate discussion around the control and direction of work that Braverman helped to initiate.
Virtual reality as an ecologically valid tool for assessing multifaceted episodic memory in children and adolescents
Authors: Picard Laurence , Abram Maria , Orriols Eric , Piolino Pascale
Published: November 2015

The majority of episodic memory (EM) tests are far removed from what we experience in daily life and from the definition of this type of memory. This study examines the developmental trajectory of the main aspects of episodic memory—what, where, and when—and of feature binding in a naturalistic virtual environment. A population of 125 participants aged from 6 to 24 years was asked to navigate, by using a joystick, in a virtual urban environment composed of specific areas, and to memorize as many elements as possible (e.g., scenes, details, spatial and temporal contexts). The ability to recall factual content associated to details or spatiotemporal context increased steadily from the age of 8 to young adulthood. These results indicate main developmental differences in feature binding abilities in naturalistic events which are very sensitive to age in comparison with a standard EM assessment. Virtual reality therefore appears to be an appropriate technique to assess crucial aspects of EM development in children and adolescents and it should provide helpful tools for the detection of subtle memory deficits.