bluuebunny/crossref_metadata_2025_split huggingface dataset:
An early actinopterygian ichthyofauna from the Scottish Lower Coal Measures Formation: Westphalian A (Bashkirian)
Authors: Elliott Francis M. 
Published: April 2018

ABSTRACTTen new early actinopterygian taxa are described from material collected from five North Lanarkshire coal shale tips in the Midland Valley of Scotland. The newly described taxa includeRhadinichthys?ornatocephalum, Rhadinichthys glabrolepis, Pseudogonatodus aurulentum, Pseudohaplolepis argentatum,Rhadinichthys?plumosumandLanarkichthys gardineri.Also included are the haplolepidsBlairolepis wallacei, Parahaplolepis poppaea, Braccohaplolepis fenestratumandAndrewsolepis lochlani.Additional information was also obtained for a further two named species,Rhadinichthys monensisEgerton andRhadinichthys grossartiTraquair. The material used for this study was obtained from finely laminated slabs of carbonaceous shale containing incomplete and disarticulated specimens, including isolated skull dermal elements and scales preserveden masse. Using this information, the dermal skull bones of a number of taxa were reconstructed and illustrated in dorsal and lateral views. Furthermore, morphological characteristics of the skull roof of each taxon was used to obtain an appropriate dataset, in order to undertake non-vigorous phylogenic analyses to demonstrate possible relationships between the various groups within the assemblage. In addition, ossified endocranial remains from specimens ofRhadinichthys monensiswere examined.
Nonlinear and Synergistic Effects of ULF Pc5, VLF Chorus, and EMIC Waves on Relativistic Electron Flux at Geosynchronous Orbit
Authors: Simms Laura E. , Engebretson Mark J. , Clilverd Mark A. , Rodger Craig J. , Reeves Geoffrey D. 
Published: April 2018

AbstractUsing data covering the years 2005–2009, we study the linear and nonlinear responses of log10 relativistic electron flux measured at geosynchronous orbit to ultralow frequency (ULF) Pc5, very low frequency (VLF) lower band chorus, and electromagnetic ion cyclotron (EMIC) waves. We use regression models incorporating a quadratic term and a synergistic interaction term. Relativistic electron fluxes respond to ULF Pc5 and VLF chorus waves both linearly and nonlinearly. ULF Pc5 waves contribute both to electron enhancement (at midrange wave activity) and loss (at high levels of wave activity). Nonlinear effects of VLF chorus are positive (i.e., cause acceleration), adding to the positive linear effects. Synergistic interaction effects between high levels of VLF chorus and midrange values of ULF Pc5 waves result in more electron acceleration than would be predicted by a simpler additive model. Similarly, the negative effect of EMIC waves (losses) is more influential than would be predicted by a linear model when combined with either VLF chorus or ULF Pc5 waves. During disturbed conditions (high Kp), geostationary electron flux responds more strongly to the same levels of ULF Pc5 and VLF chorus waves. This flux also responds more to ULF Pc5 and chorus waves during southward Bz conditions. Unstandardized regression coefficients for models incorporating nonlinear and synergistic effects of waves are presented for use in future modeling.
Multiscale Insights Into Borehole Instabilities in High‐Porosity Sandstones
Authors: Wu Huanran , Zhao Jidong , Guo Ning 
Published: April 2018

AbstractThis paper presents a multiscale analysis of the classical borehole instability problem in high‐porosity sandstones using a hierarchical multiscale approach. A rigorous, two‐way message‐passing coupling of finite element method and discrete element method is employed, where the finite element method is employed to solve a boundary value problem and the constitutive material responses required at each of its integration points are derived by the discrete element method solution to an embedded representative volume element instead of by using an assumed phenomenological model. We employ this multiscale approach to examine the successive failure of a borehole subjected to gradually decreased support stresses at the inner borehole wall or increased far‐field stresses. To reproduce the material behavior of high‐porosity sandstone, representative volume elements with a high‐porosity structure and interparticle bonds are generated. It is found that stress concentration triggers the initial failure at the borehole wall, and the subsequent failure in form of deformation bands is driven by further stress concentration ahead of the band tips. The failure pattern around the borehole varies with initial stress state and global loading path. The comparison of the local stress paths of the initial failure points in various cases reveals that the change of failure pattern from shear failure to mixed‐mode failure and to compaction failure is dominated by the increased mean stress. Cross‐scale parametric studies show that the failure mode changes from clear compaction bands to multiple arrays of shear bands by changing the high‐porosity specimen to a low‐porosity one. The increase in cohesion strength expands the yield locus and enlarges the critical mean stress between different failure patterns. Hence, the failure mode may change from compaction failure to mixed‐mode failure or from mixed‐mode failure to shear failure due purely to the increased cohesion strength. The qualitative comparisons indicate greater length, larger area, and more severe damage of the diametrically opposite failure with the increase in minor principal stress σ0 and principal stress ratio. The diametrically opposite failure mode is found a good indicator for σ0 direction, but it may also occur under hydrostatic far‐field stress due to material anisotropy.
Convective Hydration of the Upper Troposphere and Lower Stratosphere
Authors: Schoeberl Mark R. , Jensen Eric J. , Pfister Leonhard , Ueyama Rei , Avery Melody , Dessler Andrew E. 
Published: April 2018

AbstractWe use our forward domain filling trajectory model to explore the impact of tropical convection on stratospheric water vapor (H2O) and tropical tropopause layer cloud fraction (TTLCF). Our model results are compared to winter 2008/2009 TTLCF derived from Cloud‐Aerosol Lidar with Orthogonal Polarization and lower stratospheric H2O observations from the Microwave Limb Sounder. Convection alters the in situ water vapor by driving the air toward ice saturation relative humidity. If the air is subsaturated, then convection hydrates the air through the evaporation of ice, but if the air is supersaturated, then convective ice crystals grow and precipitate, dehydrating the air. On average, there are a large number of both hydrating and dehydrating convective events in the upper troposphere, but hydrating events exceed dehydrating events. Explicitly adding convection produces a less than 2% increase in global stratospheric water vapor during the period analyzed here. Tropical tropopause temperature is the primary control of stratospheric water vapor, and unless convection extends above the tropopause, it has little direct impact. Less than 1% of the model parcels encounter convection above the analyzed cold‐point tropopause. Convection, on the other hand, has a large impact on TTLCF. The model TTLCF doubles when convection is included, and this sensitivity has implications for the future climate‐related changes, given that tropical convective frequency and convective altitudes may change.
The ribosome, (slow) beating heart of cancer (stem) cell
Authors: Bastide Amandine , David Alexandre 
Published: April 2018

AbstractThe ribosome has long been considered as a consistent molecular factory, with a rather passive role in the translation process. Recent findings have shifted this obsolete view, revealing a remarkably complex and multifaceted machinery whose role is to orchestrate spatiotemporal control of gene expression. Ribosome specialization discovery has raised the interesting possibility of the existence of its malignant counterpart, an 'oncogenic' ribosome, which may promote tumor progression. Here we weigh the arguments supporting the existence of an 'oncogenic' ribosome and evaluate its role in cancer evolution. In particular, we provide an analysis and perspective on how the ribosome may play a critical role in the acquisition and maintenance of cancer stem cell phenotype.
The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [11C]-raclopride PET study with aripiprazole
Authors: Shin Sangho , Kim Seoyoung , Seo Seongho , Lee Jae Sung , Howes Oliver D. , Kim Euitae , Kwon Jun Soo 
Published: April 2018

AbstractAripiprazole’s effects on cognitive function in patients with schizophrenia are unclear because of the difficulty in disentangling specific effects on cognitive function from secondary effects due to the improvement in other schizophrenic symptoms. One approach to address this is to use an intermediate biomarker to investigate the relationship between the drug’s effect on the brain and change in cognitive function. This study aims to investigate aripiprazole’s effect on working memory by determining the correlation between dopamine D2/3 (D2/3) receptor occupancy and working memory of patients with schizophrenia. Seven patients with schizophrenia participated in the study. Serial positron emission tomography (PET) scans with [11C]raclopride were conducted at 2, 26, and 74 h after the administration of aripiprazole. The subjects performed the N-back task just after finishing the [11C]raclopride PET scan. The mean (±SD) D2/3 receptor occupancies were 66.9 ± 6.7% at 2 h, 65.0 ± 8.6% at 26, and 57.7 ± 11.2% at 74 h after administering aripiprazole. Compared with performance on the zero-back condition, performance in memory-loaded conditions (one-, two-, and three-back conditions) was significantly related to D2/3 receptor occupancy by aripiprazole (error rate: ß = −2.236, t = −6.631, df = 53.947, and p = 0.001; reaction time: ß = −9.567, t = −2.808, df = 29.967, and p = 0.009). Although the sample size was relatively small, these results suggest that aripiprazole as a dopamine-partial agonist could improve cognitive function in patients with schizophrenia.
miR-98-5p contributes to cisplatin resistance in epithelial ovarian cancer by suppressing miR-152 biogenesis via targeting Dicer1
Authors: Wang Yanan , Bao Wei , Liu Yuan , Wang Shiyu , Xu Shengjie , Li Xi , Li Yanli , Wu Sufang 
Published: April 2018

AbstractEpithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy, and cisplatin resistance is usually correlated with the poor prognosis of EOC. Increasing evidence indicates that the dysregulation of miRNAs is related to chemotherapy sensitivity. In this study, we revealed that miR-98-5p, a member of the let-7 family, was enriched in cisplatin-resistant EOC cells compared with cisplatin-sensitive cells, and could promote cisplatin resistance in EOC cells. Further studies showed that miR-98-5p could directly target the 3′-UTR of Dicer1 and suppress its expression, causing global miRNA downregulation. By miRNA array and qRT-PCR verification, we identified miR-152 as the vital downstream target of the miR-98-5p/Dicer1 axis in EOC cells. Moreover, we demonstrated that the ectopic expression of miR-152 reversed cisplatin resistance both in vitro and in vivo by targeting RAD51, a central member in homologous recombination. Importantly, miR-98-5p expression, as determined by in situ hybridization in tumor tissues, was associated with poor outcome of EOC patients. Together, these findings suggest the essential role of the miR-98-5p/Dicer1/miR-152 pathway in regulating cisplatin resistance of EOC cells and provide a potential target for EOC therapy.
Down-regulation of a pro-apoptotic pathway regulated by PCAF/ADA3 in early stage gastric cancer
Authors: Brasacchio Daniella , Busuttil Rita A. , Noori Tahereh , Johnstone Ricky W. , Boussioutas Alex , Trapani Joseph A. 
Published: April 2018

AbstractThe loss of p300/CBP-associated protein (PCAF) expression is associated with poor clinical outcome in gastric cancer, and a potential bio-marker for invasive and aggressive tumors. However, the mechanism linking loss of PCAF to the onset of gastric cancer has not been identified. Given that PCAF and its binding partner transcriptional adaptor protein 3 (ADA3) were recently shown to regulate the intrinsic (mitochondrial) pathway to apoptosis via epigenetic regulation of phosphofurin acidic cluster sorting proteins 1 and 2 (PACS1, PACS2), we analyzed PCAF, ADA3, and PACS1/2 expression in 99 patient-matched surgical samples ranging from normal gastric mucosa, through pre-malignant chronic gastritis and intestinal metaplasia to stage I–III invasive cancers. PCAF mRNA levels were not reduced in either pre-malignant state but were significantly down-regulated in all stages of gastric cancer, commencing at AJCC stage I (p < 0.05), thus linking reduced PCAF expression with early malignant change. Furthermore, patients with combined reduction of PCAF and PACS1 had significantly poorer overall survival (p = 0.0257), confirmed in an independent dataset of 359 patients (p = 5.8 × 10e-6). At the protein level, PCAF, ADA3, and PACS1 expression were all significantly down-regulated in intestinal-type gastric cancer, and correlated with reduced progression free survival. We conclude that a pro-apoptotic mechanism centered on the intrinsic (mitochondrial) pathway and regulated by PCAF/ADA3 can influence the progression from premalignant to malignant change, and thus act as a tumor suppression mechanism in gastric cancer.
Seipin deficiency in mice causes loss of dopaminergic neurons via aggregation and phosphorylation of α-synuclein and neuroinflammation
Authors: Wang Ling , Hong Juan , Wu Yajuan , Liu George , Yu Wenfeng , Chen Ling 
Published: April 2018

AbstractSeipin gene is originally found in type 2 congenital generalized lipodystrophy (CGL2) to involve lipid droplet formation. Recently, decrease of seipin expression is reported in substantia nigra of Parkinson’s disease patients. Dopaminergic neurons in substantia nigra pars compacta expressed the seipin protein. The objective of this study is to investigate influence of the seipin deficiency on dopaminergic neurons and motor behaviors. Neuronal seipin knockout (seipin-nKO) mice (3–12 months of age) displayed an age-related deficit in motor coordination. The number of dopaminergic neurons in seipin-nKO mice was age dependently reduced with increase in cleaved caspase-3. The levels of αSyn oligomers and oligomer phosphorylation (S129), but not αSyn monomers, were elevated in dopaminergic neurons and substantia nigra of seipin-nKO mice. The PPARγ expression in seipin-nKO mice was reduced. In seipin-nKO mice, the phosphorylation of GSK3β was increased at Tyr216 and was reduced at Ser9, which was corrected by the PPARγ agonist rosiglitazone. The increased IL-6 level in seipin-nKO mice was sensitive to rosiglitazone and GSK3β inhibitor AR-A014418. The enhanced phosphorylation of αSyn was prevented by rosiglitazone and AR-A014418, while the increase in αSyn oligomers was corrected only by rosiglitazone. The treatment of seipin-nKO mice with rosiglitazone and AR-A014418 rescued the death of dopaminergic neurons, which was accompanied by the improvement of motor coordination. Therefore, the results indicate that seipin deficiency causes an age-related loss of dopaminergic neurons and impairment of motor coordination through reducing PPARγ to enhance aggregation and phosphorylation of αSyn and neuroinflammation.
Long non-coding RNA MUC5B-AS1 promotes metastasis through mutually regulating MUC5B expression in lung adenocarcinoma
Authors: Yuan Shuai , Liu Qingyun , Hu Zeyao , Zhou Zhengyu , Wang Guilu , Li Chengying , Xie Weijia , Meng Gang , Xiang Ying , Wu Na , Wu Long , Yu Zubin , Bai Li , Li Yafei 
Published: April 2018

AbstractLong non-coding RNAs (lncRNAs) have been involved in the process of cancer occurrence, progression, and treatment. Lung cancer-related lncRNAs are still an emerging field, thus we sought to identify novel functional lncRNAs as candidate targets in lung cancer. Here, we identified one novel lncRNA, MUC5B-AS1 (Ensembl: ENST00000532061.2). MUC5B-AS1 was upregulated in lung adenocarcinoma tissues compared with normal lung tissues. Moreover, MUC5B-AS1 promoted lung cancer cell migration and invasion in vitro and promoted lung cancer cell metastasis in vivo. MUC5B-AS1 and its cognate sense transcript MUC5B were highly co-expressed and mutually regulated in lung adenocarcinoma. Mechanistically, MUC5B-AS1 promoted cell migration and invasion by forming an RNA–RNA duplex with MUC5B, thereby increasing MUC5B expression levels in lung adenocarcinoma. The high expression of MUC5B was significantly associated with poor outcomes in lung adenocarcinoma. Our findings highlight MUC5B-AS1 functions as an oncogenic lncRNA in tumor metastasis and implicate MUC5B-AS1 as an attractive candidate target for lung adenocarcinoma treatment.
REST, regulated by RA through miR-29a and the proteasome pathway, plays a crucial role in RPC proliferation and differentiation
Authors: Wang Yuyao , Zhang Dandan , Tang Zhimin , Zhang Yi , Gao Huiqin , Ni Ni , Shen Bingqiao , Sun Hao , Gu Ping 
Published: April 2018

AbstractOne of the primary obstacles in the application of retinal progenitor cells (RPCs) to the treatment of retinal degenerative diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP), is their limited ability to proliferate and differentiate into specific retinal neurons. In this study, we revealed that repressor element-1-silencing transcription factor (REST), whose expression could be transcriptionally and post-transcriptionally mediated by retinoic acid (RA, one isomeride of a vitamin A derivative used as a differentiation-inducing agent in many disease treatments), plays a pivotal role in the regulation of proliferation and differentiation of RPCs. Our results show that direct knockdown of endogenous REST reduced RPC proliferation but accelerated RPC differentiation toward retinal neurons, which phenocopied the observed effects of RA on RPCs. Further studies disclosed that the expression level of REST could be downregulated by RA not only through upregulating microRNA (miR)-29a, which directly interacted with the 3′-untranslated region (3′-UTR) of the REST mRNA, but also through promoting REST proteasomal degradation. These results show us a novel functional protein, REST, which regulates RPC proliferation and differentiation, can be mediated by RA. Understanding the mechanisms of REST and RA in RPC fate determination enlightens a promising future for the application of REST and RA in the treatment of retinal degeneration diseases.
Inhibition of cancer progression by a novel trans-stilbene derivative through disruption of microtubule dynamics, driving G2/M arrest, and p53-dependent apoptosis
Authors: Parida Pravat Kumar , Mahata Barun , Santra Abhisek , Chakraborty Sohini , Ghosh Zhumur , Raha Sanghamitra , Misra Anup Kumar , Biswas Kaushik , Jana Kuladip 
Published: April 2018

AbstractResveratrol, a trans-stilbene polyphenolic compound and its synthetic analogs are widely used bioactive molecules due to their remarkable chemo-preventive potential. Here, we have identified a novel synthetic trans-stilbene compound, Z-DAN-11 ((Z)-3-(3, 4-dimethoxyphenyl)-2-(3, 4, 5-trimethoxyphenyl) acrylonitrile) which shows remarkable efficacy in blocking tumor growth and progression both in vitro and in vivo. Z-DAN-11 inhibits proliferation of cancer cells in vitro through microtubule depolymerization that induced G2/M arrest and consequently leads to apoptotic cell death. More importantly, Z-DAN-11 shows limited cytotoxicity to normal cells as compared to cancer cells. Quite interestingly, we have found that Z-DAN-11-mediated ROS production helps in dramatic alteration in the mitochondrial redox status which critically contributes to the apoptosis. Mechanistic studies reveal that Z-DAN-11 induces the expression of pro-apoptotic proteins and decreases anti-apoptotic protein expression that decisively helps in the activation of caspase 8, caspase 9, and caspase 3, leading to cleavage of PARP1 and cell death via intrinsic and extrinsic pathways of apoptosis. Moreover, Z-DAN-11-mediated apoptosis of cancer cells is through a partial p53-dependent pathway, since both HCT116 p53−/− cells as well as p53-silenced cells (siRNA) were able to block apoptosis partially but significantly. Importantly, Z-DAN-11 also imparts its anti-tumorigenic effect by inhibiting clonogenic property and anchorage-independent growth potential of cancer cells at concentrations at least 10 times lower than that required for inducing apoptosis. Finally, in vivo study with immuno-competent syngeneic mice shows Z-DAN-11 to be able to impede tumor progression without any adverse side-effects. Hence, we identified a novel, synthetic trans-stilbene derivative with anti-tumorigenic potential which might tremendously help in devising potential therapeutic strategy against cancer.
The novel TRAIL-receptor agonist APG350 exerts superior therapeutic activity in pancreatic cancer cells
Authors: Legler Karen , Hauser Charlotte , Egberts Jan-Hendrik , Willms Anna , Heneweer Carola , Boretius Susann , Röcken Christoph , Glüer Claus-Christian , Becker Thomas , Kluge Michael , Hill Oliver , Gieffers Christian , Fricke Harald , Kalthoff Holger , Lemke Johannes , Trauzold Anna 
Published: April 2018

AbstractTumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has raised attention as a novel anticancer therapeutic as it induces apoptosis preferentially in tumor cells. However, first-generation TRAIL-receptor agonists (TRAs), comprising recombinant TRAIL and agonistic receptor-specific antibodies, have not demonstrated anticancer activity in clinical studies. In fact, cancer cells are often resistant to conventional TRAs. Therefore, in addition to TRAIL-sensitizing strategies, next-generation TRAs with superior apoptotic activity are warranted. APG350 is a novel, highly potent TRAIL-receptor agonist with a hexavalent binding mode allowing the clustering of six TRAIL-receptors per drug molecule. Here we report on preclinical in vitro and in vivo studies testing the activity of APG350 on pancreatic ductal adenocarcinoma (PDAC) cells. We found that APG350 potently induced apoptosis of Colo357, PancTuI and Panc89 cells in vitro. In addition, APG350 treatment activated non-canonical TRAIL signaling pathways (MAPK, p38, JNK, ERK1/ERK2 and NF-κB) and induced the secretion of IL-8. Stable overexpression of Bcl-xL inhibited APG350-induced cell death and augmented activation of non-canonical pathways. Intriguingly, pre-treatment of Bcl-xL-overexpressing cells with the BH3-mimic Navitoclax restored their sensitivity to APG350. To study the effects of APG350 on PDAC cells in vivo, we applied two different orthotopic xenotransplantation mouse models, with and without primary tumor resection, representing adjuvant and palliative treatment regimes, respectively. APG350 treatment of established tumors (palliative treatment) significantly reduced tumor burden. These effects, however, were not seen in tumors with enforced overexpression of Bcl-xL. Upon primary tumor resection and subsequent APG350 treatment (adjuvant therapy), APG350 limited recurrent tumor growth and metastases. Importantly, therapeutic efficacy of APG350 treatment was more effective compared with treatment with soluble TRAIL in both models. In conclusion, APG350 represents a promising next-generation TRA for the treatment of PDAC. Moreover, our results suggest that combining APG350 with Navitoclax might be a succesfull strategy for cancers harboring mitochondrial apoptosis resistance.