bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acetylcholine from Visual Circuits Modulates the Activity of Arousal Neurons inDrosophila
Authors: Muraro Nara I. , Ceriani M. Fernanda 
Published: December 2015

Drosophila melanogaster's large lateral ventral neurons (lLNvs) are part of both the circadian and sleep-arousal neuronal circuits. In the past, electrophysiological analysis revealed that lLNvs fire action potentials (APs) in bursting or tonic modes and that the proportion of neurons firing in those specific patterns varies circadianly. Here, we provide evidence that lLNvs fire in bursts both during the day and at night and that the frequency of bursting is what is modulated in a circadian fashion. Moreover, we show that lLNvs AP firing is not only under cell autonomous control, but is also modulated by the network, and in the process we develop a novel preparation to assess this. We demonstrate that lLNv bursting mode relies on a cholinergic input because application of nicotinic acetylcholine receptor antagonists impairs this firing pattern. Finally, we found that bursting of lLNvs depends on an input from visual circuits that includes the cholinergic L2 monopolar neurons from the lamina. Our work sheds light on the physiological properties of lLNvs and on a neuronal circuit that may provide visual information to these important arousal neurons.SIGNIFICANCE STATEMENTCircadian rhythms are important for organisms to be able to anticipate daily changes in environmental conditions to adjust physiology and behavior accordingly. These rhythms depend on an endogenous mechanism that operates in dedicated neurons. In the fruit fly, the large lateral ventral neurons (lLNvs) are part of both the circadian and sleep-arousal neuronal circuits. Here, we provide new details about the firing properties of these neurons and demonstrate that they depend, not only on cell-autonomous mechanisms, but also on a specific neurotransmitter derived from visual circuits. Our work sheds light on the physiological properties of lLNvs and on a neuronal circuit that may provide visual information to these important arousal neurons.
Role of IL-10 in Resolution of Inflammation and Functional Recovery after Peripheral Nerve Injury
Authors: Siqueira Mietto Bruno , Kroner Antje , Girolami Elizabeth I. , Santos-Nogueira Eva , Zhang Ji , David Samuel 
Published: December 2015

A rapid proinflammatory response after peripheral nerve injury is required for clearance of tissue debris (Wallerian degeneration) and effective regeneration. Unlike the CNS, this response is rapidly terminated in peripheral nerves starting between 2 and 3 weeks after crush injury. We examined the expression and role of the anti-inflammatory cytokine IL-10 in the resolution of inflammation and regeneration after sciatic nerve crush injury in mice. IL-10 mRNA increased over the first 7 d after injury, whereas at the protein level, immunofluorescence labeling showed IL-10+cells increased almost 3-fold in the first 3 weeks, with macrophages being the major cell type expressing IL-10. The role of IL-10 in nerve injury was assessed using IL-10-null mice. Increased numbers of macrophages were found in the distal segment of IL-10-null mice at early (3 d) and late (14 and 21 d) time points, suggesting that IL-10 may play a role in controlling the early influx and the later efflux of macrophages out of the nerve. A chemokine/cytokine PCR array of the nerve 24 h after crush showed a 2- to 4-fold increase in the expression of 10 proinflammatory mediators inIL-10−/−mice. In addition, myelin phagocytosisin vitroby LPS stimulated bone-marrow-derived macrophages from IL-10-null mice failed to downregulate expression of proinflammatory chemokines/cytokines, suggesting that IL-10 is required for the myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory/pro-repair phenotype. The failure to switch off inflammation in IL-10-null mice was accompanied by impaired axon regeneration and poor recovery of motor and sensory function.SIGNIFICANCE STATEMENTAn appropriately regulated inflammatory response after peripheral nerve injury is essential for axon regeneration and recovery. The aim of this study was to investigate the expression and role of the anti-inflammatory cytokine IL-10 in terminating inflammation after sciatic nerve crush injury and promoting regeneration. IL-10 is rapidly expressed by macrophages after crush injury. Its role was assessed using IL-10-null mice, which showed that IL-10 plays a role in controlling the early influx and the later efflux of macrophages out of the injured nerve, reduces the expression of proinflammatory chemokines and cytokines, and is required for myelin-phagocytosis-induced shift of macrophages from proinflammatory to anti-inflammatory. Furthermore, lack of IL-10 leads to impaired axon regeneration and poor recovery of motor and sensory function.
Fbxo3-Dependent Fbxl2 Ubiquitination Mediates Neuropathic Allodynia through the TRAF2/TNIK/GluR1 Cascade
Authors: Lin Tzer-Bin , Hsieh Ming-Chun , Lai Cheng-Yuan , Cheng Jen-Kun , Chau Yat-Pang , Ruan Ting , Chen Gin-Den , Peng Hsien-Yu 
Published: December 2015

Emerging evidence has indicated that the pathogenesis of neuropathic pain is mediated by spinal neural plasticity in the dorsal horn, which provides insight for analgesic therapy. Here, we report that the abundance of tumor necrosis factor receptor-associated factor 2 and NcK-interacting kinase (TNIK), a kinase that is presumed to regulate neural plasticity, was specifically enhanced in ipsilateral dorsal horn neurons after spinal nerve ligation (SNL; left L5 and L6). Spinal TNIK-associated allodynia is mediated by downstream TNIK–GluR1 coupling and the subsequent phosphorylation-dependent trafficking of GluR1 toward the plasma membrane in dorsal horn neurons. Tumor necrosis factor receptor-associated factor 2 (TRAF2), which is regulated by spinal F-box protein 3 (Fbxo3)-dependent F-box and leucine-rich repeat protein 2 (Fbxl2) ubiquitination, contributes to SNL-induced allodynia by modifying TNIK/GluR1 phosphorylation-associated GluR1 trafficking. Although exhibiting no effect on Fbxo3/Fbxl2/TRAF2 signaling, focal knockdown of spinal TNIK expression prevented SNL-induced allodynia by attenuating TNIK/GluR1 phosphorylation-dependent subcellular GluR1 redistribution. In contrast, intrathecal administration of BC-1215 (N1,N2-Bis[[4-(2-pyridinyl)phenyl]methyl]-1,2-ethanediamine) (a novel Fbxo3 inhibitor) prevented SNL-induced Fbxl2 ubiquitination and subsequent TFAF2 de-ubiquitination to ameliorate behavioral allodynia via antagonizing TRAF2/TNIK/GluR1 signaling. By targeting spinal Fbxo3-dependent Fbxl2 ubiquitination and the subsequent TRAF2/TNIK/GluR1 cascade, spinal application of a TNF-α-neutralizing antibody ameliorated SNL-induced allodynia, and, conversely, intrathecal TNF-α injection into naive rats induced allodynia via a spinal Fbxo3/Fbxl2-dependent modification of the TRAF2/TNIK/GluR1 cascade. Together, our results suggest that spinal TNF-α contributes to the development of neuropathic pain by upregulating TRAF2/TNIK/GluR1 signaling via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic pain by targeting the F-box protein or TNIK.SIGNIFICANCE STATEMENTTNF-α participates in neuropathic pain development by facilitating the spinal TRAF2-dependent TNIK–GluR1 association, which drives GluR1-containing AMPA receptor trafficking toward the plasma membrane. In addition, F-box protein 3 modifies this pathway by inhibiting F-box and leucine-rich repeat protein 2-mediated TRAF2 ubiquitination, suggesting that protein ubiquitination contributes crucially to the development of neuropathic pain. These results provide a novel therapeutic strategy for pain relief.
Longitudinal plasma metanephrines preceding pheochromocytoma diagnosis: a retrospective case–control serum repository study
Authors: Olson S W , Yoon S , Baker T , Prince L K , Oliver D , Abbott K C 
Published: December 2015

ObjectivePlasma metanephrines (PMN) are highly sensitive for diagnosis of pheochromocytoma, but the natural history of PMN before pheochromocytoma diagnosis has not been previously described. The aim of the study was to compare the progression of PMN before pheochromocytoma diagnosis to matched healthy and essential hypertension disease controls.DesignA retrospective case–control Department of Defense Serum Repository (DoDSR) study.MethodsWe performed a DoDSR study that compared three longitudinal pre-diagnostic PMN for 30 biopsy-proven pheochromocytoma cases to three longitudinal PMN for age, sex, race, and age of serum sample matched healthy and essential hypertension disease controls. Predominant metanephrine (MN) or normetanephrine (NMN) production was identified for each case and converted to a percentage of the upper limit of normal to allow analysis of all cases together. PMN were measured by Quest Diagnostics.ResultsThe predominant plasma metanephrine (PPM) was >100 and 300% of the upper limit of normal a median of 6.6 and 4.1 years before diagnosis respectively. A greater percentage of pheochromocytoma patients had a PPM >100 and >300% of the upper limit of normal compared with combined healthy and essential hypertension disease controls <2, 2–8, and >8 years prior to diagnosis. For patients with a baseline PPM 90–300% of the upper limit of normal, a 25% rate of rise per year was 100% specific for pheochromocytoma.ConclusionsPPMs elevate years before diagnosis which suggests that delayed diagnoses are common. For mild PMN elevations, follow-up longitudinal PMN trends may provide a highly specific and economical diagnostic tool.
Neuroendocrine tumors producing calcitonin: characteristics, prognosis and potential interest of calcitonin monitoring during follow-up
Authors: Nozières Cécile , Chardon Laurence , Goichot Bernard , Borson-Chazot Françoise , Hervieu Valérie , Chikh Karim , Lombard-Bohas Catherine , Walter Thomas 
Published: December 2015

ObjectivesInappropriate calcitonin (CT) release, a major feature of medullary thyroid cancer (MTC), may occur in neuroendocrine tumors (NETs). The aims of this retrospective study were to assess i) the characteristics and prognosis of CT-producing NETs, and ii) the value of CT monitoring during follow-up.MethodsAll patients with NETs in whom serum CT was assayed between 2010 and 2012 were included. MTCs were excluded. Clinical, biological, and histological characteristics were studied.ResultsTwenty-one (12%) of 176 patients in whom serum CT was systematically assayed had concentrations >100 ng/l, with tumours predominantly of bronchial or pancreatic origin (P<0.0001), and of high grade (P=0.0006). Poor prognosis was linked to high CT levels, poor differentiation, and grade 3. In a total group of 24 patients with serum CT >100 ng/l, symptoms potentially attributable to CT were recorded in eight, with occasional overlap with the carcinoid syndrome among other secretory syndromes. Immunohistochemistry could be performed in six tumor specimens, CT being detected in five. In 11 patients with five or more successive CT assays, hormone levels were fairly well correlated with clinical courses.ConclusionSerum CT levels may be raised in some patients with NETs, especially from foregut origin, and of high grade. The suggested value of CT monitoring during follow-up must be confirmed in further studies.
Association of mitotane with chylomicrons and serum lipoproteins: practical implications for treatment of adrenocortical carcinoma
Authors: Kroiss Matthias , Plonné Dietmar , Kendl Sabine , Schirmer Diana , Ronchi Cristina L , Schirbel Andreas , Zink Martina , Lapa Constantin , Klinker Hartwig , Fassnacht Martin , Heinz Werner , Sbiera Silviu 
Published: December 2015

ObjectiveOral mitotane (o,p′-DDD) is a cornerstone of medical treatment for adrenocortical carcinoma (ACC). AimSerum mitotane concentrations >14 mg/l are targeted for improved efficacy but not achieved in about half of patients. Here we aimed at a better understanding of intestinal absorption and lipoprotein association of mitotane and metabolites o,p′-dichlorodiphenylacetic acid (o,p′-DDA) and o,p′-dichlorodiphenyldichloroethane (o,p′-DDE).DesignLipoproteins were isolated by ultracentrifugation from the chyle of a 29-year-old patient and serum from additional 14 ACC patients treated with mitotane. HPLC was applied for quantification of mitotane and metabolites. We assessed NCI–H295 cell viability, cortisol production, and expression of endoplasmic reticulum (ER) stress marker genes to study the functional consequences of mitotane binding to lipoproteins.ResultsChyle of the index patient contained 197 mg/ml mitotane, 53 mg/ml o,p′-DDA, and 51 mg/l o,p′-DDE. Of the total mitotane in serum, lipoprotein fractions contained 21.7±21.4% (VLDL), 1.9±0.8% (IDL), 8.9±5.5% (LDL1), 18.9±9.6% (LDL2), 10.1±4.0% (LDL3), and 26.3±13.0% (HDL2). Only 12.3±5.5% were in the lipoprotein-depleted fraction.DiscussionMitotane content of lipoproteins directly correlated with their triglyceride and cholesterol content. O,p′-DDE was similarly distributed, but 87.9±4.2% of o,p′-DDA found in the HDL2 and lipoprotein-depleted fractions. Binding of mitotane to human lipoproteins blunted its anti-proliferative and anti-hormonal effects on NCI–H295 cells and reduced ER stress marker gene expression.ConclusionMitotane absorption involves chylomicron binding. High concentrations of o,p′-DDA and o,p′-DDE in chyle suggest intestinal mitotane metabolism. In serum, the majority of mitotane is bound to lipoproteins. In vitro, lipoprotein binding inhibits activity of mitotane suggesting that lipoprotein-free mitotane is the therapeutically active fraction.
Comprehensive Genomic Profiling of Advanced Penile Carcinoma Suggests a High Frequency of Clinically Relevant Genomic Alterations
Authors: Ali Siraj M. , Pal Sumanta K. , Wang Kai , Palma Norma A. , Sanford Eric , Bailey Mark , He Jie , Elvin Julia A. , Chmielecki Juliann , Squillace Rachel , Dow Edward , Morosini Deborah , Buell Jamie , Yelensky Roman , Lipson Doron , Frampton Garrett M. , Howley Peter , Ross Jeffrey S. , Stephens Philip J. , Miller Vincent A. 
Published: December 2015

Abstract

Background.
Advanced penile squamous cell carcinoma (PSCC) is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. Comprehensive genomic profiling (CGP) was performed to identify clinically relevant genomic alterations (CRGAs).

Materials and Methods.
DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded sections in patients with advanced PSCC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 692× for 3,769 exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. CRGAs were defined as genomic alterations (GAs) linked to targeted therapies on the market or under evaluation in mechanism-driven clinical trials.

Results.
Twenty male patients with a median age of 60 years (range, 46–87 years) were assessed. Seventeen (85%) cases were stage IV and three cases (15%) were stage III. CGP revealed 109 GAs (5.45 per tumor), 44 of which were CRGAs (2.2 per tumor). At least one CRGA was detected in 19 (95%) cases, and the most common CRGAs were CDKN2A point mutations and homozygous deletion (40%), NOTCH1 point mutations and rearrangements (25%), PIK3CA point mutations and amplification (25%), EGFR amplification (20%), CCND1 amplification (20%), BRCA2 insertions/deletions (10%), RICTOR amplifications (10%), and FBXW7 point mutations (10%).

Conclusion.
CGP identified CRGAs in patients with advanced PSCC, including EGFR amplification and PIK3CA alterations, which can lead to the rational administration of targeted therapy and subsequent benefit for these patients.
Dominando a imagem: funções da pintura na narrativa
Authors: Bertho Sophie 
Published: December 2015

Este artigo tem por objetivo examinar as referências ao pictural na literatura e, especialmente, definir as funções da presença do quadro de pintura na narrativa. Com base na obra de Marcel Proust, À la Recherche du temps perdu, são analisadas as referências à pintura para se definir quatro tipos de função: psicológica, retórica, estrutural e ontológica, que são exemplificadas com excertos de Proust e comparadas a outras obras da literatura francesa. Conclui-se que as diferentes funções que a referência ao pictural exerce em um romance se distinguem por operarem no nível da recepção ou da produção, sendo que a função ontológica, a mais complexa, ultrapassa essa distinção e atinge o metadiscurso, revelando em uma outra arte, a pintura, a essência da arte primeira, a literatura. This essay investigates the pictorial references in literature and especially defines the role of the presence of paintings in the narrative. These pictorial references are analyzed in order to define four types of functions: psychological, rhetorical, structural and ontological, which are exemplified with Proust excerpts and compared to other works of French literature. The different functions of the pictorial references are operating in the novel at reception or production level, and by Proust the ontological function, more complex, beyond this distinction reaches metadiscourse, revealing in another art, painting, the essence of the first art, literature.
O arquivo da literatura em Borges e Calvino
Authors: Moreira Maria Elisa Rodrigues 
Published: December 2015

O presente artigo propõe uma reflexão crítico-analítica sobre a temática do arquivo a partir das obras de Jorge Luis Borges e Italo Calvino. Tomando por referencial teórico o livro Mal de arquivo, de Jacques Derrida, aborda-se, num primeiro momento, duas ficções dos escritores que têm o arquivo e a memória como tema: “A memória do mundo”, de Calvino, e “A memória de Shakespeare”, de Borges. Em seguida, busca-se compreender como o escritor argentino e o escritor italiano valem-se de sua memória literária e de seu papel de autoridade arcôntica para estabelecer um certo arquivo da literatura, identificando outros autores e obras que julgam dignos de uma sobrevida. Essas “máquinas-arquivísticas” literárias são analisadas nos livros póstumos Esse ofício do verso e Seis propostas para o próximo milênio, resultados das conferências de Borges e Calvino, respectivamente, destinadas às Norton Lectures. This article purposes an analytic-critic reflection about the thematic of the archive from Jorge Luis Borges and Italo Calvino’s works. Having the book Mal de arquivo, by Jacques Derrida, as a theoretical reference, in the first moment, two fictional works from writers that have the archive and the memory as subject: “A memória de Shakespeare”, by Borges, and “A memória do mundo”, by Calvino are approached. After that, it is seeking comprehending how the Argentinean writer and the Italian writer have their literary memory and their archontic authority to establish some kind of literature archive, identifying other authors and works that judge themselves worthy of a afterlife (Fortleben). These literary “archival-machines” are analyzed in posthumous books Esse ofício do verso e Seis propostas para o próximo milênio, results of Borges and Calvino’s conferences, respectively, to Norton Lectures.
Free Radical Scavenging and Alpha/Beta-glucosidases Inhibitory Activities of Rambutan (Nephelium lappaceum L.) Peel Extract
Authors: Widowati Wahyu , Maesaroh Maesaroh , Fauziah Nurul , Erawijantari Pande Putu , Sandra Ferry 
Published: December 2015

BACKGROUND: Diabetes mellitus (DM) is associated with oxidative reaction and hyperglycemic condition. Human body has an antioxidant defense system toward free radical, but overproduction of free radical causing imbalance condition between the free radical and the antioxidant defense in the body that lead to several diseases, including DM. Glucosidase is an enzyme that hydrolize carbohydrates causing increase of blood glucose level, so by inhibiting this enzyme blood glucose level in plasma could be effectively decreased. Rambutan (Nephelium lappaceum L.) peel has been reported to have many potential roles, such as antioxidant and anti-glycemia. Therefore our current study was conducted to evaluate possible effectivity of Rambutan peel to scavenge free radical and to inhibit α- and β-glucosidases. METHODS:Rambutan peel extraction (RPE) was performed based on maceration method. Geraniin was used as control. For antioxidant study, 2,2-diphenyl-1- picrylhydrazyl (DPPH) free radical scavenging test was performed. For glucosidase inhibitory activity study, α- and β-glucosidases inhibitory activity tests were performed. Results were analyzed for median of Inhibitory Concentration (IC50).RESULTS: The scavenging activity of RPE was comparable with Geraniin. Meanwhile, the α-glucosidase inhibitory activity of RPE was higher than the one of Geraniin. The α-glucosidase-inhibitory-activity IC50 of RPE and Geraniin were 0.106±0.080 μg/ml and 16.12±0.29 μg/ml, respectively. The β-glucosidase inhibitory activity of RPE was also higher than the one of Geraniin. The β-glucosidase-inhibitory-activity IC50 of RPE and Geraniin were 7.02±0.99 μg/ml and 19.81±0.66 μg/ml, respectively.CONCLUSION: Since RPE showed comparable free radical scavenging activity with Geraniin and higher α- and β-glucosidases inhibitory activities than Geraniin, RPE could be suggested as a promising antioxidant and antiglycemic agent. KEYWORDS: Nephelium lappaceum L., rambutan, hypoglycemic, antioxidant, free radical, diabetes mellitus, glucosidase, DPPH
Chronodisruption and Obesity
Authors: Meiliana Anna , Dewi Nurrani Mustika , Wijaya Andi 
Published: December 2015

BACKGROUND: Attempts to understand the causes of obesity and develop new therapeutic strategies have mostly focused on caloric intake and energy expenditure. Recent studies have shown that the circadian clock controls energy homeostasis by regulating circadian expression and/or activity of enzymes, hormones, and transport systems involved in metabolism. Moreover, disruption of circadian rhythms leads to obesity and metabolic disorders.CONTENT:Regularly alternating periods of light and darkness, such as normally occur with the rising and the setting of the sun, are essential for the maintenance of undisturbed circadian rhythms in all organisms including humans. The light-dark environment, as detected by specialized photoreceptors in the retinas, impacts the endogenous circadian clock in the anterior hypothalamus, the suprachiasmatic nuclei. These nuclei, via both neural and humoral signals, communicate with cells throughout the organism to establish regular circadian rhythms. The introduction of artificial sources of light roughly 150 years ago has significantly undermined the naturally occurring light-dark environment and, likewise, has disturbed circadian rhythms since light is now available at unusual times, i.e., at night. Light at night is known to cause circadian disruption and melatonin suppression. Many potentially pathophysiological consequences of these artificial light-mediated changes, include cancer, cardiovascular diseases, insomnia, metabolic syndrome, diabetes, and cognitive disorders may be aggravated by the increased exposure to light at night, which is inevitable in well-developed societies that have undergone extensive electrification.SUMMARY: Therefore, it is plausible that resetting of the circadian clock can be used as a new approach to attenuate obesity. Feeding regimens, such as restricted feeding, calorie restriction and intermittent fasting, provide a time cue and reset the circadian clock and lead to better health. In contrast, high-fat diet leads to disrupted circadian expression of metabolic factors and obesity.KEYWORDS: obesity, circadian clock, metabolism, chronodisruption