bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL CAMBIAMENTO DEICLEAVAGESPOLITICI IN EUROPA
Authors: Kriesi Hanspeter 
Published: September 2018

IntroduzioneIn questo lavoro discuterò un aspetto dell'opera di Stein Rokkan che ha prodotto un'ondata di recenti pubblicazioni e di cui io stesso mi sono occupato. Mi riferisco al ruolo deicleavagesnella politica dell'Europa occidentale contemporanea. Le principali argomentazioni del grande scienziato politico norvegese sulle strutture di conflitto nelle società dell'Europa occidentale e sulla loro trasposizione in sistemi partitici sono state proposte nel famoso saggioCleavage Structures, Party Systems, and Voting Alignmentsche Rokkan scrisse con Seymour M. Lipset (Lipset e Rokkan 1967). La sua idea consisteva nel collegare le configurazioni dei sistemi partitici europei contemporanei alle divisioni sociali e culturali che caratterizzavano le società europee all'epoca della formazione dei sistemi partitici, nella seconda metà del diciannovesimo secolo. Quando emerse la politica democratica, queste divisioni tradizionali opponevano principalmente gruppi sociali definiti in termini di religione, classe, unità territoriale ed etnia. Come è noto, Lipset e Rokkan sostennero che queste divisioni tradizionali erano state politicamente «congelate» e che, all'epoca in cui scrivevano (1967), i sistemi partitici europei riflettevano ancora la struttura delle divisioni della società che era esistita nei primi anni '20, quando le masse popolari avevano fatto il loro ingresso nella politica democratica.
IL MODELLO SVIZZERO: UN FUTURO PER L'EUROPA?
Authors: Blondel Jean 
Published: September 2018

IntroduzioneParlar bene della Svizzera non è mai andato di moda. Se all'indomani della seconda guerra mondiale André Siegfried ne scriveva come di una democrazia modello («une démocratie témoin») (Siegfried 1947), molti altri – politici e giornalisti in particolare – l'hanno osteggiata per la sua ricchezza o per il suo neutralismo e, come sostengono alcuni, per il fatto che quella ricchezza poggiava su attività sordide legate allo stesso neutralismo. Senza arrivare a tanto, Harold Wilson, primo ministro britannico negli anni sessanta e settanta, non fu certo l'unico a stigmatizzare gli «gnomi di Zurigo»!
I SISTEMI ELETTORALI MISTI. UNA CLASSIFICAZIONE
Authors: Chiaramonte Alessandro 
Published: September 2018

IntroduzioneA partire dagli anni '20-30, epoca dell'introduzione della proporzionale in molti paesi e dell'avvio del processo di strutturazione della politica di massa (Rokkan 1970), e fino all'inizio di questo decennio, i sistemi elettorali dei regimi democratici hanno mostrato una straordinaria continuità.
SINDACATO E CONSOLIDAMENTO DEMOCRATICO
Authors: Grassi Davide 
Published: September 2018

IntroduzioneLe recenti transizioni democratiche in America latina e nell'Europa del Sud hanno messo in evidenza la speciale posizione dei sindacati tra le forze della società civile che reagiscono con un'accresciuta mobilitazione all'avvio della liberalizzazione in seno a regimi autoritari (Berins Collier e Mahoney 1997). Le organizzazioni sindacali, infatti, hanno generalmente la capacità di promuovere, in momenti critici, una mobilitazione più ampia ed efficace rispetto ad altri gruppi sociali. Esse non solo possiedono reti organizzative che, attraverso strutture più o meno permanenti, facilitano lo svolgimento di proteste e dimostrazioni, ma possono anche contare su schiere di militanti con specifici interessi in comune e su identità collettive politicamente definite. A differenza di gruppi come le organizzazioni degli studenti e le associazioni religiose o di quartiere, inoltre, i sindacati possono colpire e danneggiare direttamente l'economia attraverso rivendicazioni salariali e scioperi (Valenzuela 1988, 3; Cella 1990, 17). La concomitanza delle transizioni politiche più recenti con una perdurante e diffusa crisi economica e con ripetuti tentativi di stabilizzazione e riforma hanno reso ancora più temibile questa capacità. Utilizzando poteri coercitivi garantiti dallo stato, o la semplice forza della persuasione, il sindacato, d'altra parte, può convincere la propria base ad aspettare sino a che le riforme producano dei risultati, contribuendo così a ridurre i livelli del conflitto sociale (Przeworski 1991, 181).
HS-1371, a novel kinase inhibitor of RIP3-mediated necroptosis
Authors: Park Han-Hee , Park Se-Yeon , Mah Shinmee , Park Jung-Hee , Hong Soon-Sun , Hong Sungwoo , Kim You-Sun 
Published: September 2018

AbstractNecroptosis is a type of programmed cell death that usually occurs under apoptosis-deficient conditions. Receptor-interacting protein kinase-3 (RIP3, or RIPK3) is a central player in necroptosis, and its kinase activity is essential for downstream necroptotic signaling events. Since RIP3 kinase activity has been associated with various diseases, the development of specific RIP3 inhibitors is an attractive strategy for therapeutic application. In this study, we identified a potent RIP3 inhibitor, HS-1371, by the extensive screening of chemical libraries focused on kinases. HS-1371 directly binds to RIP3 in an ATP-competitive and time-independent manner, providing a mechanism of action. Moreover, the compound inhibited TNF-induced necroptosis but did not inhibit TNF-induced apoptosis, indicating that this novel inhibitor has a specific inhibitory effect on RIP3-mediated necroptosis via the suppression of RIP3 kinase activity. Our results suggest that HS-1371 could serve as a potential preventive or therapeutic agent for diseases involving RIP3 hyperactivation.
Oncogenic PI3K/AKT promotes the step-wise evolution of combination BRAF/MEK inhibitor resistance in melanoma
Authors: Irvine Mal , Stewart Ashleigh , Pedersen Bernadette , Boyd Suzanah , Kefford Richard , Rizos Helen 
Published: September 2018

AbstractNearly all patients with BRAF-mutant melanoma will progress on BRAF inhibitor monotherapy and combination BRAF/MEK inhibitor therapy within the first year of therapy. In the vast majority of progressing melanomas, resistance occurs via the re-activation of MAPK signalling, commonly via alterations in BRAF, NRAS and MEK1/2. A small proportion of resistant melanomas rely on the activation of the compensatory PI3K/AKT signalling cascade, although activation of this pathway does not preclude patient responses to BRAF/MEK inhibition. We now show, that PI3K/AKT signalling via potent oncogenic PIK3CA and AKT3 mutants, is not sufficient to overcome proliferative arrest induced by BRAF/MEK inhibition, but rather enables the survival of a dormant population of MAPK-inhibited melanoma cells. The evolution of resistance in these surviving tumour cells was associated with MAPK re-activation and no longer depended on the initial PI3K/AKT-activating oncogene. This dynamic form of resistance alters signalling dependence and may lead to the evolution of tumour subclones highly resistant to multiple targeted therapies.
The FAK inhibitor BI 853520 exerts anti-tumor effects in breast cancer
Authors: Tiede Stefanie , Meyer-Schaller Nathalie , Kalathur Ravi Kiran Reddy , Ivanek Robert , Fagiani Ernesta , Schmassmann Philip , Stillhard Patrick , Häfliger Simon , Kraut Norbert , Schweifer Norbert , Waizenegger Irene C. , Bill Ruben , Christofori Gerhard 
Published: September 2018

AbstractFocal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that regulates a plethora of downstream signaling pathways essential for cell migration, proliferation and death, processes that are exploited by cancer cells during malignant progression. These well-established tumorigenic activities, together with its high expression and activity in different cancer types, highlight FAK as an attractive target for cancer therapy. We have assessed and characterized the therapeutic potential and the biological effects of BI 853520, a novel small chemical inhibitor of FAK, in several preclinical mouse models of breast cancer. Treatment with BI 853520 elicits a significant reduction in primary tumor growth caused by an anti-proliferative activity by BI 853520. In contrast, BI 853520 exerts effects with varying degrees of robustness on the different stages of the metastatic cascade. Together, the data demonstrate that the repression of FAK activity by the specific FAK inhibitor BI 853520 offers a promising anti-proliferative approach for cancer therapy.
Transgenerational transmission of hedonic behaviors and metabolic phenotypes induced by maternal overnutrition
Authors: Sarker Gitalee , Berrens Rebecca , von Arx Judith , Pelczar Pawel , Reik Wolf , Wolfrum Christian , Peleg-Raibstein Daria 
Published: September 2018

AbstractMaternal overnutrition has been associated with increased susceptibility to develop obesity and neurological disorders later in life. Most epidemiological as well as experimental studies have focused on the metabolic consequences across generations following an early developmental nutritional insult. Recently, it has been shown that maternal high-fat diet (HFD) affects third-generation female body mass via the paternal lineage. We showed here that the offspring born to HFD ancestors displayed addictive-like behaviors as well as obesity and insulin resistance up to the third generation in the absence of any further exposure to HFD. These findings, implicate that the male germ line is a major player in transferring phenotypic traits. These behavioral and physiological alterations were paralleled by reduced striatal dopamine levels and increased dopamine 2 receptor density. Interestingly, by the third generation a clear gender segregation emerged, where females showed addictive-like behaviors while male HFD offspring showed an obesogenic phenotype. However, methylome profiling of F1 and F2 sperm revealed no significant difference between the offspring groups, suggesting that the sperm methylome might not be the major carrier for the transmission of the phenotypes observed in our mouse model. Together, our study for the first time demonstrates that maternal HFD insult causes sustained alterations of the mesolimbic dopaminergic system suggestive of a predisposition to develop obesity and addictive-like behaviors across multiple generations.
Exposure to childhood abuse is associated with human sperm DNA methylation
Authors: Roberts Andrea L. , Gladish Nicole , Gatev Evan , Jones Meaghan J. , Chen Ying , MacIsaac Julia L. , Tworoger Shelley S. , Austin S. Bryn , Tanrikut Cigdem , Chavarro Jorge E. , Baccarelli Andrea A. , Kobor Michael S. 
Published: September 2018

AbstractOffspring of persons exposed to childhood abuse are at higher risk of neurodevelopmental and physical health disparities across the life course. Animal experiments have indicated that paternal environmental stressors can affect sperm DNA methylation and gene expression in an offspring. Childhood abuse has been associated with epigenetic marks in human blood, saliva, and brain tissue, with statistically significant methylation differences ranging widely. However, no studies have examined the association of childhood abuse with DNA methylation in gametes. We examined the association of childhood abuse with DNA methylation in human sperm. Combined physical, emotional, and sexual abuse in childhood was characterized as none, medium, or high. DNA methylation was assayed in 46 sperm samples from 34 men in a longitudinal non-clinical cohort using HumanMethylation450 BeadChips. We performed principal component analysis and examined the correlation of principal components with abuse exposure. Childhood abuse was associated with a component that captured 6.2% of total variance in DNA methylation (p < 0.05). Next, we investigated the regions differentially methylated by abuse exposure. We identified 12 DNA regions differentially methylated by childhood abuse, containing 64 probes and including sites on genes associated with neuronal function (MAPT,CLU), fat cell regulation (PRDM16), and immune function (SDK1). We examined adulthood health behaviors, mental health, and trauma exposure as potential mediators of an association between abuse and DNAm, and found that mental health and trauma exposure partly mediated the association. Finally, we constructed a parsimonious epigenetic marker for childhood abuse using a machine learning approach, which identified three probes that predicted high vs. no childhood abuse in 71% of participants. Our results suggested that childhood abuse is associated with sperm DNA methylation, which may have implications for offspring development. Larger samples are needed to identify with greater confidence specific genomic regions differentially methylated by childhood abuse.
Bi-directional genetic modulation of GSK-3β exacerbates hippocampal neuropathology in experimental status epilepticus
Authors: Engel Tobias , Gómez-Sintes Raquel , Alves Mariana , Jimenez-Mateos Eva M. , Fernández-Nogales Marta , Sanz-Rodriguez Amaya , Morgan James , Beamer Edward , Rodríguez-Matellán Alberto , Dunleavy Mark , Sano Takanori , Avila Jesus , Medina Miguel , Hernandez Felix , Lucas José J. , Henshall David C. 
Published: September 2018

AbstractGlycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimer’s and Huntington’s, and in psychiatric diseases. Recent studies have also linked GSK-3 dysregulation to neuropathological outcomes in epilepsy. To date, however, there has been no genetic evidence for the involvement of GSK-3 in seizure-induced pathology. Status epilepticus (prolonged, damaging seizure) was induced via a microinjection of kainic acid into the amygdala of mice. Studies were conducted using two transgenic mouse lines: a neuron-specific GSK-3β overexpression and a neuron-specific dominant-negative GSK-3β (GSK-3β-DN) expression in order to determine the effects of increased or decreased GSK-3β activity, respectively, on seizures and attendant pathological changes in the hippocampus. GSK-3 inhibitors were also employed to support the genetic approach. Status epilepticus resulted in a spatiotemporal regulation of GSK-3 expression and activity in the hippocampus, with decreased GSK-3 activity evident in non-damaged hippocampal areas. Consistent with this, overexpression of GSK-3β exacerbated status epilepticus-induced neurodegeneration in mice. Surprisingly, decreasing GSK-3 activity, either via overexpression of GSK-3β-DN or through the use of specific GSK-3 inhibitors, also exacerbated hippocampal damage and increased seizure severity during status epilepticus. In conclusion, our results demonstrate that the brain has limited tolerance for modulation of GSK-3 activity in the setting of epileptic brain injury. These findings caution against targeting GSK-3 as a treatment strategy for epilepsy or other neurologic disorders where neuronal hyperexcitability is an underlying pathomechanism.
LncRNA SNHG15 acts as a ceRNA to regulate YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma
Authors: Wu Dong-Mei , Wang Shan , Wen Xin , Han Xin-Rui , Wang Yong-Jian , Shen Min , Fan Shao-Hua , Zhang Zi-Feng , Shan Qun , Li Meng-Qiu , Hu Bin , Lu Jun , Chen Gui-Quan , Zheng Yuan-Lin 
Published: September 2018

AbstractOver the past decade, lncRNAs have been widely reported in human malignant tumors, including papillary thyroid carcinoma. LncRNA SNHG15 has been validated to be a tumor facilitator in several types of malignancies. The present study focused on the biological role of SNHG15 in papillary thyroid carcinoma. Based on the result of qPCR analysis, we identified the strong expression of SNHG15 in human papillary thyroid carcinoma tissues and cell lines. Moreover, Kaplan–Meier method was utilized to analyze the internal relevance between SNHG15 expression and overall survival rate of patients with papillary thyroid carcinoma. Loss-of-function assays were designed and conducted to determine the inhibitory effects of silenced SNHG15 on the cell growth and migration in papillary thyroid carcinoma. The mechanical investigation indicated that SNHG15 upregulated YAP1 by sponging miR-200a-3p. Moreover, results of gain-of-function assays validated the anti-oncogenic function of miR-200a-3p in papillary thyroid carcinoma. Finally, results of rescue assays validated the function of SNHG15-miR-200a-3p-YAP1 axis in papillary thyroid carcinoma. YAP1 is known as an oncogene and a core factor of Hippo pathway. Here, we demonstrated that SNHG15 inactivated Hippo signaling pathway in papillary thyroid carcinoma. In summary, our findings demonstrated that SNHG15 serves as a competitively endogenous RNA (ceRNA) to regulate YAP1-Hippo signaling pathway by sponging miR-200a-3p in papillary thyroid carcinoma.
CCN6-mediated MMP-9 activation enhances metastatic potential of human chondrosarcoma
Authors: Tzeng Huey-En , Tang Chih-Hsin , Wu Sz-Hua , Chen Hsien-Te , Fong Yi-Chin , Lu Yung-Chang , Chen Wei-Cheng , Huang Hsien-Da , Lin Chih-Yang , Wang Shih-Wei 
Published: September 2018

AbstractChondrosarcomas are primary malignant bone tumors that have a poor prognosis. WNT1-inducible signaling pathway protein-3 (WISP-3, also termed CCN6) belongs to the CCN family of proteins and is implicated in the regulation of various cellular functions, such as cell proliferation, differentiation, and migration. It is unknown as to whether CCN6 affects human chondrosarcoma metastasis. We show how CCN6 promotes chondrosarcoma cell migration and invasion via matrix metallopeptidase-9 (MMP)-9 expression. These effects were abolished by pretreatment of chondrosarcoma cells with PI3K, Akt, mTOR, and NF-κB inhibitors or short interfering (si)RNAs. Our investigations indicate that CCN6 facilitates metastasis through the PI3K/Akt/mTOR/NF-κB signaling pathway. CCN6 and MMP-9 expression was markedly increased in the highly migratory JJ012(S10) cell line compared with the primordial cell line (JJ012) in both in vitro and in vivo experiments. CCN6 knockdown suppressed MMP-9 production in JJ012(S10) cells and attenuated cell migration and invasion ability. Importantly, CCN6 knockdown profoundly inhibited chondrosarcoma cell metastasis to lung. Our findings reveal an important mechanism underlying CCN6-induced metastasis and they highlight the clinical significance between CCN6 and MMP-9 in regard to human chondrosarcoma. CCN6 appears to be a promising therapeutic target in chondrosarcoma metastasis.
Polybrene induces neural degeneration by bidirectional Ca2+ influx-dependent mitochondrial and ER–mitochondrial dynamics
Authors: Bao Feixiang , Shi Hongyan , Gao Mi , Yang Liang , Zhou Lingyan , Zhao Qiuge , Wu Yi , Chen Keshi , Xiang Ge , Long Qi , Guo Jingyi , Zhang Jian , Liu Xingguo 
Published: September 2018

AbstractHexadimethrine bromide (Polybrene) was once used clinically as a heparin neutralizer and has recently found use as a promoter in virus-mediated gene therapy trials and gene transfer in research. However, the potential for tissue-specific toxicity of polybrene at low doses has been ignored so far. Here, we found that after intracerebroventricular (ICV) polybrene injection, mice showed disability of movement accompanied neural death and gliosis in brain, and in human neurons, polybrene induces concentration-dependent neuritic beading and fragmentation. Mechanistically, polybrene induces a rapid voltage-dependent calcium channel (VDCC)-mediated influx of extracellular Ca2+. The elevated cytoplasmic Ca2+ activates DRP1, which leads to mitochondrial fragmentation and metabolic dysfunction. At the same time, Ca2+ influx induces endoplasmic reticulum (ER) fragmentation and tightened associations between ER and mitochondria, which makes mitochondria prone to Ca2+ overloading and ensuing permeability transition. These results reveal an unexpected neuronal toxicity of polybrene, wherein Ca2+ influx serves as a regulator for both mitochondrial dynamics and ER–mitochondrial remodeling.
MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis
Authors: Fernández-Ramos David , Fernández-Tussy Pablo , Lopitz-Otsoa Fernando , Gutiérrez-de-Juan Virginia , Navasa Nicolás , Barbier-Torres Lucía , Zubiete-Franco Imanol , Simón Jorge , Fernández Agustín F. , Arbelaiz Ander , Aransay Ana M. , Lavín José Luis , Beraza Naiara , Perugorria María J. , Banales Jesus M. , Villa Erica , Fraga Mario F. , Anguita Juan , Avila Matias A. , Berasain Carmen , Iruzibieta Paula , Crespo Javier , Lu Shelly C. , Varela-Rey Marta , Mato José M. , Delgado Teresa C. , Martínez-Chantar María L. 
Published: September 2018

AbstractGlycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
Distinct multilevel misregulations of Parkin and PINK1 revealed in cell and animal models of TDP-43 proteinopathy
Authors: Sun Xing , Duan Yongjia , Qin Caixia , Li Jian-Chiuan , Duan Gang , Deng Xue , Ni Jiangxia , Cao Xu , Xiang Ke , Tian Kuili , Chen Chun-Hong , Li Ang , Fang Yanshan 
Published: September 2018

AbstractParkin and PINK1 play an important role in mitochondrial quality control, whose malfunction may also be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). Excessive TDP-43 accumulation is a pathological hallmark of ALS and is associated with Parkin protein reduction in spinal cord neurons from sporadic ALS patients. In this study, we reveal that Parkin and PINK1 are differentially misregulated in TDP-43 proteinopathy at RNA and protein levels. Using knock-in flies, mouse primary neurons, and TDP-43Q331K transgenic mice, we further unveil that TDP-43 downregulates Parkin mRNA, which involves an unidentified, intron-independent mechanism and requires the RNA-binding and the protein–protein interaction functions of TDP-43. Unlike Parkin, TDP-43 does not regulate PINK1 at an RNA level. Instead, excess of TDP-43 causes cytosolic accumulation of cleaved PINK1 due to impaired proteasomal activity, leading to compromised mitochondrial functions. Consistent with the alterations at the molecular and cellular levels, we show that transgenic upregulation of Parkin but downregulation of PINK1 suppresses TDP-43-induced degenerative phenotypes in a Drosophila model of ALS. Together, these findings highlight the challenge associated with the heterogeneity and complexity of ALS pathogenesis, while pointing to Parkin–PINK1 as a common pathway that may be differentially misregulated in TDP-43 proteinopathy.