bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermocapillary instabilities in a horizontal liquid layer under partial basal slip
Authors: Kowal Katarzyna N. , Davis Stephen H. , Voorhees Peter W.
Published: September 2018

We investigate the onset of three-dimensional hydrothermal waves in a low-capillary-number liquid layer of arbitrary depth, bounded by a free liquid–gas interface from above and a partial slip, rigid surface from below. A selection of two- and three-dimensional hydrothermal waves, longitudinal rolls and longitudinal travelling waves, form the preferred mode of instability, which depends intricately on the magnitude of the basal slip. Partial slip is destabilizing for all modes of instability. Specifically, the minimal Marangoni number required for the onset of instability follows

$M_{m}\sim a(\unicode[STIX]{x1D6FD}^{-1}+b)^{-c}$

for each mode, where

$a,b,c>0$

and

$\unicode[STIX]{x1D6FD}^{-1}$

is the slip parameter. In the limit of free slip, longitudinal travelling waves disappear in favour of longitudinal rolls. With increasing slip, it is common for two-dimensional hydrothermal waves to exchange stability in favour of longitudinal rolls and oblique hydrothermal waves. Two types of oblique hydrothermal waves appear under partial slip, which exchange stability with increasing slip. The oblique mode that is preferred under no slip persists and remains near longitudinal for small slip parameters.
Cross-Country Evidence on the Relationship between Societal Trust and Risk-Taking by Banks
Authors: Kanagaretnam Kiridaran , Lobo Gerald J. , Wang Chong , Whalen Dennis J.
Published: September 2018

We study the relationship between societal trust and risk-taking in the banking industry. Prior literature has found that societal trust is positively related to both financial reporting conservatism and financial reporting transparency, which reduce bank managers’ ability to take excessive risk. Additionally, bank managers in high-trust countries are more likely to exhibit higher pro-social behavior and, therefore, less likely to take excessive risk for personal benefit. Consistent with these arguments, we document that banks in countries with higher societal trust exhibit lower risk-taking and that these banks also experienced less financial trouble and fewer failures during the 2007–2009 financial crisis.
Polar answers
Authors: ENFIELD N. J. , STIVERS TANYA , BROWN PENELOPE , ENGLERT CHRISTINA , HARJUNPÄÄ KATARIINA , HAYASHI MAKOTO , HEINEMANN TRINE , HOYMANN GERTIE , KEISANEN TIINA , RAUNIOMAA MIRKA , RAYMOND CHASE WESLEY , ROSSANO FEDERICO , YOON KYUNG-EUN , ZWITSERLOOD INGE , LEVINSON STEPHEN C.
Published: September 2018

How do people answer polar questions? In this fourteen-language study of answers to questions in conversation, we compare the two main strategies; first, interjection-type answers such asuh-huh(or equivalentsyes,mm, head nods, etc.), and second, repetition-type answers that repeat some or all of the question. We find that all languages offer both options, but that there is a strong asymmetry in their frequency of use, with a global preference for interjection-type answers. We propose that this preference is motivated by the fact that the two options are not equivalent in meaning. We argue that interjection-type answers are intrinsically suited to be the pragmatically unmarked, and thus more frequent, strategy for confirming polar questions, regardless of the language spoken. Our analysis is based on the semantic-pragmatic profile of the interjection-type and repetition-type answer strategies, in the context of certain asymmetries inherent to the dialogic speech act structure of question–answer sequences, including sequential agency and thematic agency. This allows us to see possible explanations for the outlier distributions found in ǂĀkhoe Haiǁom and Tzeltal.
PLURINAZIONALISMO E DEMOCRAZIA
Authors: Linz Juan J.
Published: September 2018

Introduzione

Pochi Stati sono Stati nazionali, e gran parte delle nazioni non sono destinate a raggiungere la condizione di Stato sovrano. Una trasformazione delle società plurinazionali in Stati nazionali «monocromatici» come quelli esistenti in passato è impossibile nel contesto di istituzioni liberaldemocratiche. La maggioranza delle cosiddette «nuove nazioni» sono in realtà Stati multinazionali o quantomeno multiculturali. Non solo i cittadini risiedono geograficamente in ambiti frammisti; le loro famiglie hanno unbackgroundeterogeneo e, dato non meno e forse più importante, hanno identità duali. Le istituzioni e i processi democratici devono riconoscere queste situazioni di fatto, questo tipo di pluralismo. In che misura, in uno Stato democratico, il pluralismo deve essere basato sulla rappresentanza e sui diritti di gruppo oppure sui diritti individuali? In che misura particolari soluzioni istituzionali rischiano di condurre ad un conflitto tra questi due principii ed approcci nel contesto della politica democratica? In che modo sarà protetta la libertà degli individui di scegliere la propria identità senza vedersi imporre identità inclusive? Questi sono problemi teorici e pratici sia per le democrazie contemporanee, sia per i paesi avviati verso la democrazia. Come potranno, gli Stati democratici multinazionali, guadagnarsi una legittimità sufficiente a rendere i processi decisionali democratici possibili e compatibili con il pluralismo nazionale e culturale? In particolare, come si potrà, in società di questo genere, rendere compatibile il federalismo con i diritti delle minoranze all'interno di unità territoriali, se in queste unità esistono maggioranze «nazionali»? Se non diamo soluzione a questi interrogativi, rischiamo di riprodurre in scala ridotta i problemi creati dai fondatori degli Stati nazionali in società multinazionali. Quali forme può assumere il pluralismo nazionale e culturale nelle società democratiche, e qual è il ruolo che le istituzioni e i processi democratici possono svolgere per rendere compatibili il pluralismo e la libertà individuale? Questi sono alcuni dei quesiti che dobbiamo sollevare e a cui dobbiamo dare risposta.
INTEGRAZIONE EUROPEA E WELFARE STATES NAZIONALI
Authors: Scharpf Fritz W. , Verzichelli Luca
Published: September 2018

Introduzione

Il processo di integrazione europea è caratterizzato da una asimmetria fondamentale descritta accuratamente da Joseph Weiler (1981) come un dualismo tra le norme sopranazionali europee ed il policy-making europeo di tipo intergovernativo. Weiler ha ancora ragione nella sua critica agli scienziati politici, colpevoli di aver troppo a lungo concentrato la propria attenzione soltanto sugli aspetti della negoziazione intergovernativa e di aver ignorato (o comunque non aver preso sufficientemente in considerazione) l'emergere, essenzialmente per via giurisdizionale, di un ordinamento legale europeo che prevale sulle leggi nazionali (Weiler 1994). Questa omissione è tanto più grave poiché ha impedito di individuare il parallelismo, politicamente assai significativo, tra il dualismo indicato da Weiler e la più comune contrapposizione tra una integrazione «positiva» ed una «negativa» (Tinbergen 1965; Rehbinder e Stewart 1984), cioè tra le misure che allargano l'integrazione del mercato eliminando i vincoli nazionali sugli scambi e le distorsioni competitive, da un lato, e le politiche europee comuni che modellano le condizioni sotto le quali i mercati operano, dall'altro.
DAL PLURALISMO POLARIZZATO AL PLURALISMO MODERATO. IL MODELLO DI SARTORI E LA TRANSIZIONE ITALIANA
Authors: Pappalardo Adriano
Published: September 2018

Introduzione

Negli anni novanta, l'Italia è entrata in un processo di transizione che è ormai divenuto oggetto di un'abbondante letteratura nazionale e straniera. Piuttosto ovviamente, la natura di tale transizione è ben diversa da quelle dei paesi postcomunisti e, come ha opportunamente sottolineato Pasquino (1994; 1995), poco comparabile con altri precedenti storici. Anche la Francia, che questo autore considera il miglior termine di confronto, lo è in realtà assai relativamente sotto una varietà di punti di vista. Mentre infatti la Quarta e, per lungo tempo, anche la Quinta Repubblica sono rimasti classici casi di pluralismo polarizzato (Sartori 1982, 256–262), l'Italia degli anni novanta non può più essere definita tale, e proprio per questo (o, almeno, anche per questo) si è avviata alla presente transizione. Come è noto, inoltre, le riforme golliste investirono essenzialmente le principali istituzioni politiche della repubblica, ma lasciarono inalterati il subsistema burocratico e la struttura (centralizzata) dello Stato, che sono, invece, componenti tutt'altro che secondarie per comprendere il decorso e gli eventuali sbocchi della crisi italiana. Ma, infine, tale crisi si intreccia anche al declino dello Stato sociale e interventista, coinvolgendo la ridefinizione dei confini fra politica ed economia e il ruolo delle grandi organizzazioni degli interessi, sindacati in testa. Come dire che, oltre al sistema politico-istituzionale ed alla pubblica amministrazione, le relazioni industriali e i loro attori pubblici e privati rappresentano una terza dimensione di cambiamento, che altrove è stata poco importante (Francia), ovvero incomparabilmente diversa (regimi postcomunisti).
ALLA RICERCA DELLA COLLEGIALITÀ Dl GOVERNO: I VERTICI Dl MAGGIORANZA DAL 1970 AL 1994
Authors: Criscitiello Annarita
Published: September 2018

Premessa

Le radici della debolezza del governo collegiale nell'Italia repubblicana sono state individuate nel modello costituzionale formale così come fu ideato dai padri fondatori. Ma anche nel fatto che i governi italiani, tranne qualche eccezione, sono sempre stati governi di coalizione, una condizione che necessariamente rende il processo decisionale collegiale molto più complicato e controverso (Pappalardo 1978; Bogdanor 1983; Pridham 1986; Budge e Keman 1990; Laver e Schofield 1990).
PERCHÉ È DIFFICILE COSTRUIRE LE ISTITUZIONI
Authors: Lanzara Giovan Francesco
Published: September 2018

Introduzione

La costruzione di un'istituzione, qualsiasi cosa possa significare, è comunque un processo che implica la formazione di una struttura, o codice, o pattern regolato di comportamenti che acquista legittimità e «funziona» in un contesto sociale specifico, fino a diventare un elemento costitutivo della vita sociale, stabile e persistente nel corso del tempo. Tale struttura può essere in parte il risultato di un progetto deliberato, in parte l'esito non intenzionale dell'azione umana e dell'interazione sociale. Il più delle volte è congiuntamente l'uno e l'altro, in combinazioni variabili a seconda delle contingenze. Se la struttura «funziona», essa potrà autosostenersi e riprodursi nel tempo. Ma in caso di «fallimento», provocato da un rendimento scadente o dall'erosione di legittimità morale e politica, non necessariamente verrà rimpiazzata in modo rapido e completo. Più verosimilmente le sue componenti fondamentali, anche se obsolete, continueranno a sopravvivere per lungo tempo «come frammenti di rotte catene, pendenti dalle volte di vecchi edifici» (Tocqueville 1969), senza alcuna funzione specifica, o forse subiranno un lento processo di mutamento, assumendo gradualmente nuove funzioni e significati col passare del tempo.
I CONFLITTI POLITICI IN EUROPA: PERSISTENZA E MUTAMENTO
Authors: Mair Peter
Published: September 2018

Introduzione

Malgrado un trentennio di attente analisi condotte da studiosi provenienti da diversi campi disciplinari e una voluminosa letteratura dedicata alla comprensione e spesso alla verifica della cosiddetta «ipotesi del congelamento» (freezing hypothesis), su ciò che Lipset e Rokkan pensassero si fosse consolidato negli anni '20 permane ancora oggi non poca confusione.
Disturbed interhemispheric functional connectivity in visual pathway in individuals with unilateral retinal detachment: A resting state fMRI study
Authors: YUAN QING , KANG HONG-HUA , SHI WEN-QING , GONG YING-XIN , SU TING , ZHU PEI-WEN , MIN YOU-LAN , YE LEI , JIANG NAN , SHAO YI
Published: September 2018

Previous neuroimaging studies demonstrated that retinal detachment (RD) subjects were associated with abnormal spontaneous brain activities; however, whether the altered interhemispheric functional connectivity (FC) occurred in RD patients remains unknown. The current study tried to explore the alternations of interhemispheric FC of the whole brain in unilateral RD patients using the voxel-mirrored homotopic connectivity (VMHC) method and their connections to clinical features. Methods: We recruited 30 patients with RD (16 males and 14 females) and 30 healthy controls (HCs) (16 males and 14 females) whose age and sex were closely matched. All subjects underwent the rs-fMRI scans. The VMHC method was applied to directly assess the hemispheres’ functional interaction. The VMHC in these brain areas, which could be used as biomarkers to differentiate RD from HC, was identified by the receiver operating characteristic (ROC) curve analyses. The relations between these patients’ clinical features and their mean VMHC signal values in multiple brain regions were calculated by Pearson correlation analysis. Results: RD patients had significantly lower VMHC values than HCs in the bilateral occipital lobe (Brodmann areas, BA 18), bilateral superior temporal gyrus (BA 39), and bilateral cuneus (BA 19). Moreover, the mean VMHC signal values of the bilateral cuneus were in positive correlation with the duration of the RD (r = 0.446, P = 0.013). Conclusion: Our results provided an evidence of disturbed interhemispheric FC in the visual area occurred in RD patients, which might provide some useful information to understand the neural mechanism of RD patients with acute vision loss. Furthermore, the VMHC values might indicate the progress of the RD.
Graduate Applicant Intentions and Behavioral Beliefs
Authors: Adams Samantha , Görgens-Ekermans Gina , De Kock François
Published: September 2018

Abstract. Laws promoting equal employment opportunity (EEO) in favor of applicants from “protected groups” are commonplace in many countries. The present study compared graduate applicants from protected vs. unprotected groups. Drawing on the theory of planned behavior and on social cognitive theory we explored how intentions to apply for jobs are shaped by behavioral beliefs (internal factors) and protection status (external factor). Results from structural invariance analysis showed that, overall, beliefs influenced applicant intentions similarly in both groups. However, relative weights analysis revealed notable differences in the relative influence of attitude and norm beliefs. The findings suggest that recruitment practitioners and scholars may better understand how applicant intentions are formed if the role of protection status is considered in conjunction with applicant beliefs.
Importance of Hydrothermal Vents in Scavenging Removal of 230Th in the Nansen Basin
Authors: Valk O. , Rutgers van der Loeff M. M. , Geibert W. , Gdaniec S. , Rijkenberg M. J. A. , Moran S. B. , Lepore K. , Edwards R. L. , Lu Y. , Puigcorbé V.
Published: September 2018

In this study we present dissolved and particulate 230Th and 232Th results, as well as particulate 234Th data, obtained as part of the GEOTRACES central Arctic Ocean sections GN04 (2015) and IPY11 (2007). Samples were analyzed following GEOTRACES methods and compared to previous results from 1991. We observe significant decreases in 230Th concentrations in the deep waters of the Nansen Basin. We ascribe this nonsteady state removal process to a variable release and scavenging of trace metals near an ultraslow spreading ridge. This finding demonstrates that hydrothermal scavenging in the deep‐sea may vary on annual time scales and highlights the importance of repeated GEOTRACES sections.
O-GlcNAcylation on Rab3A attenuates its effects on mitochondrial oxidative phosphorylation and metastasis in hepatocellular carcinoma
Authors: Wu Weicheng , Zheng Xixi , Wang Jing , Yang Tianxiao , Dai Wenjuan , Song Shushu , Fang Lan , Wang Yilin , Gu Jianxin
Published: September 2018

Rab3A is a small Ras-like GTPase critical for membrane traffic. Although the functions of Rab3A have been reported in several cancers, the roles of Rab3A in hepatocellular carcinoma (HCC) have never been determined. To investigate the potential roles of Rab3A in HCC progression, we first determined Rab3A levels in HCC tissues and observed upregulated mRNA and protein levels of Rab3A in most tumor tissues. However, in vitro data showed that decreasing Rab3A in most HCC cell lines conferred no significant effects and overexpressing Rab3A in PLC/PRF/5 cells even inhibited migration and invasion. Meanwhile, the upregulation of Rab3A in HCC patients did not correlate with metastasis or overall survival of HCC patients. These contradict data suggested that Rab3A might act as metastatic suppressor and its effects might be attenuated in most HCC cells. Further experiments revealed that O-GlcNAcylation on Rab3A was key for attenuating Rab3A-mediated effects by regulating its GTP-binding activity, and verified the effects of Rab3A and its aberrant O-GlcNAcylation on HCC metastasis in vitro and in vivo. We also found that Rab3A and its O-GlcNAcylation had opposite roles in mitochondria oxidative phosphorylation (mtOXPHOS), and their functions on HCC metastasis were partially depended on their effects on metabolic reprogramming.
CPEB1 mediates hepatocellular carcinoma cancer stemness and chemoresistance
Authors: Xu Min , Fang Shiji , Song Jingjing , Chen Minjiang , Zhang Qianqian , Weng Qiaoyou , Fan Xiaoxi , Chen Weiqian , Wu Xulu , Wu Fazong , Tu Jianfei , Zhao Zhongwei , Ji Jiansong
Published: September 2018

Cancer stem cells (CSCs) are a subpopulation of cells within tumors that are believed to possess pluripotent properties and thought to be responsible for tumor initiation, progression, relapse and metastasis. Cytoplasmic polyadenylation element-binding protein 1 (CPEB1), a sequence-specific RNA-binding protein that regulates mRNA polyadenylation and translation, has been linked to cancer progression and metastasis. However, the involvement of CPEB1 in hepatocellular carcinoma (HCC) remains unclear. In this study, we have demonstrated that CPEB1 directly regulates sirtuin 1 (SIRT1) mRNA to mediate cancer stemness in HCC. Cancer stemness was analyzed by self-renewal ability, chemoresistance, metastasis, expression of stemness-related genes and CSC marker-positive cell populations. The results indicate that CPEB1 is downregulated in HCC. Overexpression of CPEB1 dramatically reduced HCC cell stemness, whereas silencing CPEB1 enhances it. Using site-directed mutagenesis, a luciferase reporter assay, and immunoprecipitation, we found that CPEB1 could directly target the 3′-UTR of SIRT1, control poly(A) tail length and suppress its translation to mediate cancer stemness in vitro and in vivo. Overall, our findings suggest that the negative regulation between CPEB1 and SIRT1 contributes to the suppression of cancer stemness in HCC. CPEB1 may have potential as a therapeutic target in HCC.
RETRACTED ARTICLE: miR-665 promotes hepatocellular carcinoma cell migration, invasion, and proliferation by decreasing Hippo signaling through targeting PTPRB
Authors: Hu Yuanchang , Yang Chao , Yang Shikun , Cheng Feng , Rao Jianhua , Wang Xuehao
Published: September 2018

Growing evidence suggests that aberrant microRNA (miRNA) expression contributes to hepatocellular carcinoma (HCC) development and progression. However, the potential role and mechanism of miR-665 in the progression of liver cancer remains largely unknown. Our current study showed that miR-665 expression was upregulated in HCC cells and tissues. High expression of miR-665 exhibited more severe tumor size, vascular invasion and Edmondson grading in HCC patients. Gain- or loss-of-function assays demonstrated that miR-665 promoted cell proliferation, migration, invasion, and the epithelial–mesenchymal transition (EMT) of HCC cells in vitro and in vivo. Tyrosine phosphatase receptor type B (PTPRB) was downregulated in HCC tissues, and was negatively correlated with miR-665 expression. Through western blotting and luciferase reporter assay, PTPRB was identified as a direct downstream target of miR-665. Restoration of PTPRB reverses the effects of miR-665 on HCC migration, invasion, and cell proliferation. A mechanistic study showed that PTPTRB mediated the functional role of miR-665 through regulation of the Hippo signaling pathway. In conclusion, our results suggested that miR-665 was a negative regulator of the PTPRB and could promote tumor proliferation and metastasis in HCC through decreasing Hippo signaling pathway activity, which can be a potential target for HCC treatment.
RB1CC1-enhanced autophagy facilitates PSCs activation and pancreatic fibrogenesis in chronic pancreatitis
Authors: Li Le , Wang Gang , Hu Ji-Sheng , Zhang Guang-Quan , Chen Hong-Ze , Yuan Yue , Li Yi-Long , Lv Xin-Jian , Tian Feng-Yu , Pan Shang-Ha , Bai Xue-Wei , Sun Bei
Published: September 2018

Chronic pancreatitis (CP) is described as a progressive fibro-inflammatory disorder of the exocrine disease, which eventually leads to damage of the gland. Excessive activation of pancreatic stellate cells (PSCs) is a critical participant in the initiation of CP. Autophagy is involved in multiple degeneration and inflammation in acute pancreatitis and CP. In our study, we report that retinoblastoma coiled coil protein 1 (RB1CC1) expression and the autophagic level are elevated in activated PSCs. RB1CC1 is positively correlated with pancreatic fibrogenesis in tissues and plasma of CP patients. Knockdown of RB1CC1 restrains alpha smooth muscle actin (α-SMA) and collagen expressions, and autophagy in activated PSCs in vitro. Furthermore, we show that RB1CC1 induces PSC activation via binding to ULK1 promoter and the direct interaction with ULK1 protein. These suppress ULK1 expression and its kinase activity. In mice, knockdown of RB1CC1 blocks autophagy and then inhibits the pancreatic duct ligation-induced pancreatic fibrosis. Consequently, our study highlights that RB1CC1-mediated autophagy is a key event for the activation of PSCs. Inhibition of RB1CC1 alleviates autophagy, which plays a critical role in anti-fibrotic activation in PSCs and CP progression. RB1CC1 could be a novel strategy for the treatment of pancreatic fibrosis.
MTP18 overexpression contributes to tumor growth and metastasis and associates with poor survival in hepatocellular carcinoma
Authors: Zhang Yu , Li Hui , Chang Hulin , Du Lixue , Hai Jun , Geng Xilin , Yan Xiang
Published: September 2018

Background

Human MTP18 (mitochondrial protein 18 kDa) is a novel nuclear-encoded mitochondrial membrane protein that is involved in controlling mitochondrial fission. Our bioinformatic analysis of TCGA data revealed an aberrant overexpression of MTP18 in hepatocellular carcinoma (HCC). We analyzed its biological effects and prognostic significance in this malignancy.

Methods

MTP18 expression was evaluated by qRT-PCR and western blot analysis in 20 paired tumor and peritumor tissues. Clinical impact of MTP18 overexpression was assessed in 156 patients with HCC. The effects of MTP18 knockdown or overexpression on cell growth and metastasis were determined by cell proliferation, colony formation, cell cycle, apoptosis, migration, and invasion assays. Furthermore, the underlying molecular mechanisms by which MTP18 overexpression promoted HCC cell growth and metastasis were explored.

Results

MTP18 was commonly overexpressed in HCC tissues mainly due to the downregulation of miR-125b, which significantly contributed to poor prognosis of HCC patients. Functional experiments revealed that MTP18 promoted both the growth and metastasis of HCC cells by inducing the progression of cell cycle, epithelial to mesenchymal transition (EMT) and production of MMP–9, and suppressing cell apoptosis. Mechanistically, increased mitochondrial fission and subsequent ROS production was found to be involved in the promotion of growth and metastasis by MTP18 in HCC cells.

Conclusions

MTP18 plays a pivotal oncogenic role in hepatocellular carcinogenesis; its overexpression may serve as a novel prognostic factor and a therapeutic target in HCC.
A structural investigation of NRZ mediated apoptosis regulation in zebrafish
Authors: Suraweera Chathura D. , Caria Sofia , Järvå Michael , Hinds Mark G. , Kvansakul Marc
Published: September 2018

Bcl-2 family proteins play a crucial role in regulating apoptosis, a process critical for development, eliminating damaged or infected cells, host-pathogen interactions and in disease. Dysregulation of Bcl-2 proteins elicits an expansive cell survival mechanism promoting cell migration, invasion and metastasis. Through a network of intra-family protein–protein interactions Bcl-2 family members regulate the release of cell death factors from mitochondria. NRZ is a novel zebrafish pro-survival Bcl-2 orthologue resident on mitochondria and the endoplasmic reticulum (ER). However, the mechanism of NRZ apoptosis inhibition has not yet been clarified. Here we examined the interactions of NRZ with pro-apoptotic members of the Bcl-2 family using a combination of isothermal calorimetry and mutational analysis of NRZ. We show that NRZ binds almost all zebrafish pro-apoptotic proteins and displays a broad range of affinities. Furthermore, we define the structural basis for apoptosis inhibition of NRZ by solving the crystal structure of both apo-NRZ and a holo form bound to a peptide spanning the binding motif of the pro-apoptotic zBad, a BH3-only protein orthologous to mammalian Bad. The crystal structure of NRZ revealed that it adopts the conserved Bcl-2 like fold observed for other cellular pro-survival Bcl-2 proteins and employs the canonical ligand binding groove to bind Bad BH3 peptide. NRZ engagement of Bad BH3 involves the canonical ionic interaction between NRZ R86 and Bad D104 and an additional ionic interaction between NRZ D79 and Bad R100, and substitution of either NRZ R86 or D79 to Ala reduces the binding to Bad BH3 tenfold or more. Our findings provide a detailed mechanistic understanding for NRZ mediated anti-apoptotic activity in zebrafish by revealing binding to both Bad and Noxa, suggesting that NRZ is likely to occupy a unique mechanistic role in zebrafish apoptosis regulation by acting as a highly promiscuous pro-apoptotic Bcl-2 binder.
Taurine attenuates arsenic-induced pyroptosis and nonalcoholic steatohepatitis by inhibiting the autophagic-inflammasomal pathway
Authors: Qiu Tianming , Pei Pei , Yao Xiaofeng , Jiang Liping , Wei Sen , Wang Zhidong , Bai Jie , Yang Guang , Gao Ni , Yang Lei , Qi Shuangyue , Yan Rushan , Liu Xiaofang , Sun Xiance
Published: September 2018

Arsenic exposure causes nonalcoholic steatohepatitis (NASH). Inflammation is a key contributor to the pathology of nonalcoholic fatty liver disease (NAFLD), including NASH. However, it is unclear how arsenic induces inflammation. In mouse livers, we show that arsenic trioxide (As2O3) induced NASH, increased autophagy and NLRP3 inflammasome activation, increased lipid accumulation, and resulted in dysregulation of lipid-related genes. Supplemented with taurine (Tau) attenuated the inflammation and autophagy caused by As2O3. In HepG2 cells, we found that As2O3-induced pyroptotic cell death was dependent upon the activation of NLRP3 inflammasome, which was CTSB-dependent. In addition, inhibiting autophagy alleviated the As2O3-induced increase of cytosolic CTSB expression and subsequent release of LDH, activation of the NLRP3 inflammasome, and pyroptosis. Moreover, we found that Tau alleviated As2O3-induced elevation of autophagy, CTSB expression, and activation of the NLRP3 inflammasome, and reduced the release of LDH, pyroptotic cell death, and inflammation. Interestingly, As2O3-induced lipid accumulation could not be alleviated by either inhibition of autophagy nor by inhibition of CTSB. Additionally, neither inhibition of the NLRP3 inflammasome or Tau treatment could alleviate lipid accumulation. These results demonstrated that As2O3-induced pyroptosis involves autophagy, CTSB, and the NLRP3 inflammasome cascade, and that Tau alleviates As2O3-induced liver inflammation by inhibiting the autophagic-CTSB-NLRP3 inflammasomal pathway rather than decreasing lipid accumulation. These findings give insight into the association of autophagy, inflammation, pyroptosis, and NASH induced by As2O3.
A miR-125b/CSF1-CX3CL1/tumor-associated macrophage recruitment axis controls testicular germ cell tumor growth
Authors: Batool Aalia , Wang Yu-Qian , Hao Xiao-Xia , Chen Su-Ren , Liu Yi-Xun
Published: September 2018

Tumor growth is modulated by crosstalk between cancer cells and the tumor microenvironment. Recent advances have shown that miRNA dysfunction in tumor cells can modulate the tumor microenvironment to indirectly determine their progression. However, this process is poorly understood in testicular germ cell tumors (TGCTs). We reported here that miR-125b was repressed in TGCT samples by epigenetic modifications rather than genetic alternations. Furthermore, miR-125b overexpression significantly alleviated the tumor growth in two NCCIT human embryonic carcinoma xenograft models in vivo, whereas miR-125b did not stimulate autonomous tumor cell growth in vitro. Notably, forced expression of miR-125b in NCCIT embryonic carcinoma cells decreased the abundance of host tumor-associated macrophages (TAMs) within tumor microenvironment. Selective deletion of host macrophages by clodronate abolished the anti-tumoral ability of miR-125b in xenograft models. By RNA profiling, Western blot and luciferase reporter assay, we further observed that miR-125b directly regulated tumor cell-derived chemokine CSF1 and CX3CL1, which are known to control the recruitment of TAMs to tumor sites. Lastly, we found that one set of miRNAs, which are under the regulation of miR-125b, might convergently target CSF1/CX3CL1 in NCCIT cells using miRNA profiling. These findings uncover the anticancer effect of miR-125b via mediating tumor-stroma crosstalk in xenograft models of TGCTs and raise the possibility of targeting miR-125b as miRNA therapeutics.
IGF1R upregulation confers resistance to isoform-specific inhibitors of PI3K in PIK3CA-driven ovarian cancer
Authors: Zorea Jonatan , Prasad Manu , Cohen Limor , Li Nan , Schefzik Roman , Ghosh Susmita , Rotblat Barak , Brors Benedikt , Elkabets Moshe
Published: September 2018

Genomic alterations (GA) in PIK3CA leads to the hyper-activation of the phosphatidylinositol-4, 5-bisphosphate 3-kinase (PI3K) pathway in more than 20% of ovarian cancer (OC) patients. Therefore, PI3K therapies are under clinical evaluation for this subset of patients. Evidently, in clinical trials testing the efficacy of isoform-specific inhibitors of PI3K (PI3Ki), patients having a stable disease eventually relapse, as tumors become resistant to treatment. Hence, there is an urgent clinical need to develop new therapeutic combinations to improve the efficacy of PI3Ki in PIK3CA-driven OC patients. Here we identified the molecular mechanism that limits the efficacy of the beta-sparing PI3Ki, Taselisib (GDC0032), in PIK3CA-mutated OC cell lines (IGROV1 and OAW42) that acquired resistance to GDC0032. By comparing the molecular profile of GDC0032-sensitve and -resistant OC cell lines, we found that AKT/mTOR inhibition is required for GDC0032 efficacy. In resistant cells, the sustained activation of AKT/mTOR was regulated by the upregulation of the insulin growth factor 1 receptor (IGF1R). Knockdown of IGF1R re-sensitized cells to GDC0032 in vitro, and the combination of AEW541, an IGF1R inhibitor, with GDC0032 exhibited potent anti-tumor activity in vitro and in vivo. We further demonstrated that IGF1R regulates tumor cell proliferation in IGROV1 cells, whereas in OAW42, it determines autophagy as well. Overall, our findings suggest that the dual inhibition of PI3K and IGF1R may be considered as a new therapeutic strategy in PIK3CA-driven OC.
Strobilurin biosynthesis in Basidiomycete fungi
Authors: Nofiani Risa , de Mattos-Shipley Kate , Lebe Karen E. , Han Li-Chen , Iqbal Zafar , Bailey Andrew M. , Willis Christine L. , Simpson Thomas J. , Cox Russell J.
Published: September 2018

Strobilurins from fungi are the inspiration for the creation of the β-methoxyacrylate class of agricultural fungicides. However, molecular details of the biosynthesis of strobilurins have remained cryptic. Here we report the sequence of genomes of two fungi that produce strobilurins and show that each contains a biosynthetic gene cluster, which encodes a highly reducing polyketide synthase with very unusual C-terminal hydrolase and methyltransferase domains. Expression of stpks1 in Aspergillus oryzae leads to the production of prestrobilurin A when the fermentation is supplemented with a benzoyl coenzyme A (CoA) analogue. This enables the discovery of a previously unobserved route to benzoyl CoA. Reconstruction of the gene cluster in A. oryzae leads to the formation of prestrobilurin A, and addition of the gene str9 encoding an FAD-dependent oxygenase leads to the key oxidative rearrangement responsible for the creation of the β-methoxyacrylate toxophore. Finally, two methyltransferases are required to complete the synthesis.
Asymmetric remote C-H borylation of internal alkenes via alkene isomerization
Authors: Chen Xu , Cheng Zhaoyang , Guo Jun , Lu Zhan
Published: September 2018

Recent years have witnessed the growing interest in the remote functionalization of alkenes for it offers a strategy to activate the challenging C–H bonds distant from the initiation point via alkene isomerization/functionalization. However, the catalytic enantioselective isomerization/functionalization with one single transition metal catalyst remains rare. Here we report a highly regio- and enantioselective cobalt-catalyzed remote C–H bond borylation of internal alkenes via sequential alkene isomerization/hydroboration. A chiral ligand featured twisted pincer, anionic, and non-rigid characters is designed and used for this transformation. This methodology, which is operationally simple using low catalyst loading without additional activator, shows excellent enantioselectivity and can be used to convert various internal alkenes with regio- and stereoisomers to valuable chiral secondary organoboronates with good functional group tolerance.
Mapping protein selectivity landscapes using multi-target selective screening and next-generation sequencing of combinatorial libraries
Authors: Naftaly Si , Cohen Itay , Shahar Anat , Hockla Alexandra , Radisky Evette S. , Papo Niv
Published: September 2018

Characterizing the binding selectivity landscape of interacting proteins is crucial both for elucidating the underlying mechanisms of their interaction and for developing selective inhibitors. However, current mapping methods are laborious and cannot provide a sufficiently comprehensive description of the landscape. Here, we introduce a novel and efficient strategy for comprehensively mapping the binding landscape of proteins using a combination of experimental multi-target selective library screening and in silico next-generation sequencing analysis. We map the binding landscape of a non-selective trypsin inhibitor, the amyloid protein precursor inhibitor (APPI), to each of the four human serine proteases (kallikrein-6, mesotrypsin, and anionic and cationic trypsins). We then use this map to dissect and improve the affinity and selectivity of APPI variants toward each of the four proteases. Our strategy can be used as a platform for the development of a new generation of target-selective probes and therapeutic agents based on selective protein–protein interactions.
Identification of small-molecule ion channel modulators in C. elegans channelopathy models
Authors: Jiang Qiang , Li Kai , Lu Wen-Jing , Li Shuang , Chen Xin , Liu Xi-Juan , Yuan Jie , Ding Qiurong , Lan Feng , Cai Shi-Qing
Published: September 2018

Ion channels are important therapeutic targets, but the discovery of ion channel drugs remains challenging due to a lack of assays that allow high-throughput screening in the physiological context. Here we report C. elegans phenotype-based methods for screening ion channel drugs. Expression of modified human ether-a-go-go-related gene (hERG) potassium channels in C. elegans results in egg-laying and locomotive defects, which offer indicators for screening small-molecule channel modulators. Screening in worms expressing hERGA561V, which carries a trafficking-defective mutation A561V known to associate with long-QT syndrome, identifies two functional correctors Prostratin and ingenol-3,20-dibenzoate. These compounds activate PKCε signaling and consequently phosphorylate S606 at the pore region of the channel to promote hERGA561V trafficking to the plasma membrane. Importantly, the compounds correct electrophysiological abnormalities in hiPSC-derived cardiomyocytes bearing a heterozygous CRISPR/Cas9-edited hERGA561V. Thus, we have developed an in vivo high-throughput method for screening compounds that have therapeutic potential in treating channelopathies.
Acoustic communities reflects lateral hydrological connectivity in riverine floodplain similarly to macroinvertebrate communities
Authors: Desjonquères Camille , Rybak Fanny , Castella Emmanuel , Llusia Diego , Sueur Jérôme
Published: September 2018

Recent studies revealed that information on ecological patterns and processes can be investigated using sounds emanating from animal communities. In freshwater environments, animal communities are strongly shaped by key ecological factors such as lateral connectivity and temperature. We predict that those ecological factors are linked to acoustic communities formed by the collection of sounds emitted underwater. To test this prediction, we deployed a passive acoustic monitoring during 15 days in six floodplain channels of the European river Rhône. The six channels differed in their temperature and level of lateral connectivity to the main river. In parallel, we assessed the macroinvertebrate communities of these six channels using classical net sampling methods. A total of 128 sound types and 142 animal taxa were inventoried revealing an important underwater diversity. This diversity, instead of being randomly distributed among the six floodplain channels, was site-specific. Generalized mixed-effects models demonstrated a strong effect of both temperature and lateral connectivity on acoustic community composition. These results, congruent with macroinvertebrate community composition, suggest that acoustic communities reflect the interactions between animal communities and their environment. Overall our study strongly supports the perspectives offered by acoustic monitoring to describe and understand ecological patterns in freshwater environments.
The allergic response mediated by fire ant venom proteins
Authors: Zamith-Miranda Daniel , Fox Eduardo G. P. , Monteiro Ana Paula , Gama Diogo , Poublan Luiz E. , de Araujo Almair Ferreira , Araujo Maria F. C. , Atella Georgia C. , Machado Ednildo A. , Diaz Bruno L.
Published: September 2018

Fire ants are widely studied, invasive and venomous arthropod pests. There is significant biomedical interest in immunotherapy against fire ant stings. However, mainly due to practical reasons, the physiological effects of envenomation has remained poorly characterized. The present study takes advantage of a recently-described venom protein extract to delineate the immunological pathways underlying the allergic reaction to fire ant venom toxins. Mice were injected with controlled doses of venom protein extract. Following sensitization and a second exposure, a marked footpad swelling was observed. Based on eosinophil recruitment and production of Th2 cytokines, we hereby establish that fire ant proteins per se can lead to an allergic response, which casts a new light into the mechanism of action of these toxins.
Longitudinal Patterns in Clinical and Imaging Measurements Predict Residual Survival in Glioblastoma Patients
Authors: Smedley Nova F. , Ellingson Benjamin M. , Cloughesy Timothy F. , Hsu William
Published: September 2018

The growing amount of longitudinal data for a large population of patients has necessitated the application of algorithms that can discover patterns to inform patient management. This study demonstrates how temporal patterns generated from a combination of clinical and imaging measurements improve residual survival prediction in glioblastoma patients. Temporal patterns were identified with sequential pattern mining using data from 304 patients. Along with patient covariates, the patterns were incorporated as features in logistic regression models to predict 2-, 6-, or 9-month residual survival at each visit. The modeling approach that included temporal patterns achieved test performances of 0.820, 0.785, and 0.783 area under the receiver operating characteristic curve for predicting 2-, 6-, and 9-month residual survival, respectively. This approach significantly outperformed models that used tumor volume alone (p < 0.001) or tumor volume combined with patient covariates (p < 0.001) in training. Temporal patterns involving an increase in tumor volume above 122 mm3/day, a decrease in KPS across multiple visits, moderate neurologic symptoms, and worsening overall neurologic function suggested lower residual survival. These patterns are readily interpretable and found to be consistent with known prognostic indicators, suggesting they can provide early indicators to clinicians of changes in patient state and inform management decisions.
Community Structure, Dynamics and Interactions of Bacteria, Archaea and Fungi in Subtropical Coastal Wetland Sediments
Authors: Cheung Man Kit , Wong Chong Kim , Chu Ka Hou , Kwan Hoi Shan
Published: September 2018

Bacteria, archaea and fungi play crucial roles in wetland biogeochemical processes. However, little is known about their community structure, dynamics and interactions in subtropical coastal wetlands. Here, we examined communities of the three kingdoms in mangrove and mudflat sediments of a subtropical coastal wetland using Ion Torrent amplicon sequencing and co-occurrence network analysis. Bacterial, archaeal and fungal communities comprised mainly of members from the phyla Proteobacteria and Bacteroidetes, Bathyarchaeota and Euryarchaeota, and Ascomycota, respectively. Species richness and Shannon diversity were highest in bacteria, followed by archaea and were lowest in fungi. Distinct spatiotemporal patterns were observed, with bacterial and fungal communities varying, to different extent, between wet and dry seasons and between mangrove and mudflat, and archaeal community remaining relatively stable between seasons and regions. Redundancy analysis revealed temperature as the major driver of the seasonal patterns of bacterial and fungal communities but also highlighted the importance of interkingdom biotic factors in shaping the community structure of all three kingdoms. Potential ecological interactions and putative keystone taxa were identified based on co-occurrence network analysis. These findings facilitate current understanding of the microbial ecology of subtropical coastal wetlands and provide a basis for better modelling of ecological processes in this important ecosystem.
Modelling realistic microgels in an explicit solvent
Authors: Camerin F. , Gnan N. , Rovigatti L. , Zaccarelli E.
Published: September 2018

Thermoresponsive microgels are polymeric colloidal networks that can change their size in response to a temperature variation. This peculiar feature is driven by the nature of the solvent-polymer interactions, which triggers the so-called volume phase transition from a swollen to a collapsed state above a characteristic temperature. Recently, an advanced modelling protocol to assemble realistic, disordered microgels has been shown to reproduce experimental swelling behavior and form factors. In the original framework, the solvent was taken into account in an implicit way, condensing solvent-polymer interactions in an effective attraction between monomers. To go one step further, in this work we perform simulations of realistic microgels in an explicit solvent. We identify a suitable model which fully captures the main features of the implicit model and further provides information on the solvent uptake by the interior of the microgel network and on its role in the collapse kinetics. These results pave the way for addressing problems where solvent effects are dominant, such as the case of microgels at liquid-liquid interfaces.
First insight into microbiome profile of fungivorous thrips Hoplothrips carpathicus (Insecta: Thysanoptera) at different developmental stages: molecular evidence of Wolbachia endosymbiosis
Authors: Kaczmarczyk Agnieszka , Kucharczyk Halina , Kucharczyk Marek , Kapusta Przemysław , Sell Jerzy , Zielińska Sylwia
Published: September 2018

Insects’ exoskeleton, gut, hemocoel, and cells are colonized by various microorganisms that often play important roles in their host life. Moreover, insects are frequently infected by vertically transmitted symbionts that can manipulate their reproduction. The aims of this study were the characterization of bacterial communities of four developmental stages of the fungivorous species Hoplothrips carpathicus (Thysanoptera: Phlaeothripidae), verification of the presence of Wolbachia, in silico prediction of metabolic potentials of the microorganisms, and sequencing its mitochondrial COI barcode. Taxonomy-based analysis indicated that the bacterial community of H. carpathicus contained 21 bacterial phyla. The most abundant phyla were Proteobacteria, Actinobacteria, Bacterioidetes and Firmicutes, and the most abundant classes were Alphaproteobacteria, Actinobacteria, Gammaproteobacteria and Betaproteobacteria, with different proportions in the total share. For pupa and imago (adult) the most abundant genus was Wolbachia, which comprised 69.95% and 56.11% of total bacterial population respectively. Moreover, similarity analysis of bacterial communities showed that changes in microbiome composition are congruent with the successive stages of H. carpathicus development. PICRUSt analysis predicted that each bacterial community should be rich in genes involved in membrane transport, amino acid metabolism, carbohydrate metabolism, replication and repair processes.
Heterocyclic sterol probes for live monitoring of sterol trafficking and lysosomal storage disorders
Authors: Králová Jarmila , Jurášek Michal , Krčová Lucie , Dolenský Bohumil , Novotný Ivan , Dušek Michal , Rottnerová Zdeňka , Kahle Michal , Drašar Pavel , Bartůněk Petr , Král Vladimír
Published: September 2018

The monitoring of intracellular cholesterol homeostasis and trafficking is of great importance because their imbalance leads to many pathologies. Reliable tools for cholesterol detection are in demand. This study presents the design and synthesis of fluorescent probes for cholesterol recognition and demonstrates their selectivity by a variety of methods. The construction of dedicated library of 14 probes was based on heterocyclic (pyridine)-sterol derivatives with various attached fluorophores. The most promising probe, a P1-BODIPY conjugate FP-5, was analysed in detail and showed an intensive labelling of cellular membranes followed by intracellular redistribution into various cholesterol rich organelles and vesicles. FP-5 displayed a stronger signal, with faster kinetics, than the commercial TF-Chol probe. In addition, cells with pharmacologically disrupted cholesterol transport, or with a genetic mutation of cholesterol transporting protein NPC1, exhibited strong and fast FP-5 signal in the endo/lysosomal compartment, co-localizing with filipin staining of cholesterol. Hence, FP-5 has high potential as a new probe for monitoring cholesterol trafficking and its disorders.