bluuebunny/crossref_metadata_2025 huggingface dataset:
An early actinopterygian ichthyofauna from the Scottish Lower Coal Measures Formation: Westphalian A (Bashkirian)
Authors: Elliott Francis M.
Published: April 2018

Ten 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

Using 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

This 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

We 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

The 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

Aripiprazole’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

Epithelial 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

The 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

Seipin 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

Long 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

One 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

Resveratrol, 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

Tumor 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.
c-Jun-mediated microRNA-302d-3p induces RPE dedifferentiation by targeting p21Waf1/Cip1
Authors: Jiang Chao , Xie Ping , Sun Ruxu , Sun Xiantao , Liu Guohua , Ding Sijia , Zhu Meidong , Yan Biao , Liu Qinghuai , Chen Xue , Zhao Chen
Published: April 2018

Dedifferentiation of retinal pigment epithelium (RPE) cells and choroidal neovascularization (CNV) contributes to the pathogenesis of age-related macular degeneration (AMD). MicroRNAs (miRNAs) have crucial roles in AMD onset and progression. We thus aim to investigate the effects of miRNAs on RPE dedifferentiation and endothelium cell (EC) behavior, and analyze its downstream pathways. We have previously identified miR-302d-3p as the most downregulated miRNA signature along with RPE differentiation. Herein, in vitro study supported that miR-302d-3p induces RPE dedifferentiation typified by reduction of RPE characteristic markers, interrupts its phagocytosis, and promotes its migration, proliferation, and cell-cycle progression. c-Jun was identified as a potential upstream transcript factor for MIR302D, which might modulate RPE function by regulating miR-302d-3p expression. P21Waf1/Cip1, a cyclin-dependent kinase inhibitor encoded by the CDKN1A gene, was identified as a downstream target of miR-302d-3p. Our data suggested that p21Waf1/Cip1 could promote RPE differentiation, and inhibit its proliferation, migration, and cell-cycle progression. We also demonstrated that miR-302d-3p suppresses RPE differentiation through directly targeting p21Waf1/Cip1. In addition, the miR-302d-3p/CDKN1A axis was also involved in regulating tube formation of ECs, indicating its potential involvement in CNV formation. Taken together, our study implies that miR-302d-3p, regulated by c-Jun, contributes to the pathogenesis of both atrophic and exudative AMD. MiR-302d-3p promotes RPE dedifferentiation, migration, proliferation and cell-cycle progression, inhibits RPE phagocytosis, and induces abnormal EC behavior by targeting p21Waf1/Cip1. Pharmacological miR-302d-3p inhibitors are prospective therapeutic options for prevention and treatment of AMD.
Starvation during pregnancy impairs fetal oogenesis and folliculogenesis in offspring in the mouse
Authors: Wang Jun-Jie , Yu Xiao-Wei , Wu Rui-Ying , Sun Xiao-Feng , Cheng Shun-Feng , Ge Wei , Liu Jing-Cai , Li Ya-Peng , Liu Jing , Zou Shu-Hua , De Felici Massimo , Shen Wei
Published: April 2018

Although it is becoming increasingly evident that maternal starvation during pregnancy can have permanent effects on a range of physiological processes in the offspring, scant information is available about the consequence of such condition for oogenesis and hence for lifetime reproductive success of progeny in mammals. In the present study, we address this topic by starving pregnant mice at the time of ovarian differentiation (12.5 days post coitum (dpc)) for three consecutive days and analyzed the consequence first on the survival of the fetal oocytes and their capability to progress throughout the stages of meiotic prophase I (MPI) and then on the postnatal folliculogenesis of the offspring. The results showed that maternal starvation increased apoptosis in the fetal ovaries, resulting in reduction of the oocyte number. Moreover, MPI progression was slowed down in the surviving oocytes and the expression of DNA repair players in the starved ovaries increased. Transcriptome analysis identified 61 differentially expressed genes between control and starved ovaries, the most part of these being involved in metabolic processes. A significant decrease in the percentage of oocytes enclosed in primordial follicles and the expression of oocyte genes critically involved in folliculogenesis such as Nobox, Lhx8 and Sohlh2 in the 3 days post partum (dpp) starved ovaries were found. Finally, at the time of juvenile period (21 dpp), the number of oocytes and antral follicles resulted significantly lower in the ovaries of the offspring from starved mothers in comparison to controls. Our findings support the notion that maternal starvation can affect ovary development in the offspring that could adversely affect their reproductive success in the adult life.
Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869
Authors: Huang Yunlong , Li Yuju , Zhang Hainan , Zhao Runze , Jing Ran , Xu Yinghua , He Miao , Peer Justin , Kim Yeong C. , Luo Jiangtao , Tong Zenghan , Zheng Jialin
Published: April 2018

Zika virus (ZIKV) is a neurotrophic flavivirus that is capable of infecting humans, leading to brain abnormalities during fetal development. The ZIKV infectivity in neural target cells remains poorly understood. Here, we found that ZIKV specifically infected glial fibrillary acidic protein- and S100B-positive primary human astrocytes derived from fetal brains. In contrast, neuron-specific Class III β-tubulin (TuJ1)-positive neurons in the astrocyte cultures and SOX2-positive neural progenitor cells derived from the fetal brains were less susceptible to ZIKV infection compared with astrocytes. The infected astrocytes released competent viral particles and manifested programmed cell death with a progressive cytopathic effect. Interestingly, ZIKV infection in human fetal astrocytes induced a significant increase of extracellular vesicles (EVs). Treatment with GW4869, a specific inhibitor of neutral sphingomyelinase-2, decreased EV levels, suppressed ZIKV propagation, and reduced the release of infectious virions in astrocytes. Therefore, ZIKV infects primary human fetal astrocytes and the infection can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Further investigation into sphingomyelin metabolism and EVs may provide insights to the therapeutic treatment of ZIKV infection.
Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese
Authors: Okada Yukinori , Momozawa Yukihide , Sakaue Saori , Kanai Masahiro , Ishigaki Kazuyoshi , Akiyama Masato , Kishikawa Toshihiro , Arai Yasumichi , Sasaki Takashi , Kosaki Kenjiro , Suematsu Makoto , Matsuda Koichi , Yamamoto Kazuhiko , Kubo Michiaki , Hirose Nobuyoshi , Kamatani Yoichiro
Published: April 2018

Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000–3000 years in multiple loci (ADH cluster, MHC region,BRAP-ALDH2,SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk.
The Gastrodia elata genome provides insights into plant adaptation to heterotrophy
Authors: Yuan Yuan , Jin Xiaohua , Liu Juan , Zhao Xing , Zhou Junhui , Wang Xin , Wang Deyi , Lai Changjiangsheng , Xu Wei , Huang Jingwen , Zha Liangping , Liu Dahui , Ma Xiao , Wang Li , Zhou Menyan , Jiang Zhi , Meng Hubiao , Peng Huasheng , Liang Yuting , Li Ruiqiang , Jiang Chao , Zhao Yuyang , Nan Tiegui , Jin Yan , Zhan Zhilai , Yang Jian , Jiang Wenkai , Huang Luqi
Published: April 2018

We present the 1.06 Gb sequenced genome of Gastrodia elata, an obligate mycoheterotrophic plant, which contains 18,969 protein-coding genes. Many genes conserved in other plant species have been deleted from the G. elata genome, including most of those for photosynthesis. Additional evidence of the influence of genome plasticity in the adaptation of this mycoheterotrophic lifestyle is evident in the large number of gene families that are expanded in G. elata, including glycoside hydrolases and urease that likely facilitate the digestion of hyphae are expanded, as are genes associated with strigolactone signaling, and ATPases that may contribute to the atypical energy metabolism. We also find that the plastid genome of G. elata is markedly smaller than that of green plant species while its mitochondrial genome is one of the largest observed to date. Our report establishes a foundation for studying adaptation to a mycoheterotrophic lifestyle.
Precisely printable and biocompatible silk fibroin bioink for digital light processing 3D printing
Authors: Kim Soon Hee , Yeon Yeung Kyu , Lee Jung Min , Chao Janet Ren , Lee Young Jin , Seo Ye Been , Sultan Md. Tipu , Lee Ok Joo , Lee Ji Seung , Yoon Sung-il , Hong In-Sun , Khang Gilson , Lee Sang Jin , Yoo James J. , Park Chan Hum
Published: April 2018

Although three-dimensional (3D) bioprinting technology has gained much attention in the field of tissue engineering, there are still several significant engineering challenges to overcome, including lack of bioink with biocompatibility and printability. Here, we show a bioink created from silk fibroin (SF) for digital light processing (DLP) 3D bioprinting in tissue engineering applications. The SF-based bioink (Sil-MA) was produced by a methacrylation process using glycidyl methacrylate (GMA) during the fabrication of SF solution. The mechanical and rheological properties of Sil-MA hydrogel proved to be outstanding in experimental testing and can be modulated by varying the Sil-MA contents. This Sil-MA bioink allowed us to build highly complex organ structures, including the heart, vessel, brain, trachea and ear with excellent structural stability and reliable biocompatibility. Sil-MA bioink is well-suited for use in DLP printing process and could be applied to tissue and organ engineering depending on the specific biological requirements.
The basic helix-loop-helix transcription factor SHARP1 is an oncogenic driver in MLL-AF6 acute myelogenous leukemia
Authors: Numata Akihiko , Kwok Hui Si , Kawasaki Akira , Li Jia , Zhou Qi-Ling , Kerry Jon , Benoukraf Touati , Bararia Deepak , Li Feng , Ballabio Erica , Tapia Marta , Deshpande Aniruddha J. , Welner Robert S. , Delwel Ruud , Yang Henry , Milne Thomas A. , Taneja Reshma , Tenen Daniel G.
Published: April 2018

Acute Myeloid Leukemia (AML) with MLL gene rearrangements demonstrate unique gene expression profiles driven by MLL-fusion proteins. Here, we identify the circadian clock transcription factor SHARP1 as a novel oncogenic target in MLL-AF6 AML, which has the worst prognosis among all subtypes of MLL-rearranged AMLs. SHARP1 is expressed solely in MLL-AF6 AML, and its expression is regulated directly by MLL-AF6/DOT1L. Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 AML cells. Genetic deletion in mice delays the development of leukemia and attenuated leukemia-initiating potential, while sparing normal hematopoiesis. Mechanistically, SHARP1 binds to transcriptionally active chromatin across the genome and activates genes critical for cell survival as well as key oncogenic targets of MLL-AF6. Our findings demonstrate the unique oncogenic role for SHARP1 in MLL-AF6 AML.
Dissociation of two-dimensional excitons in monolayer WSe2
Authors: Massicotte Mathieu , Vialla Fabien , Schmidt Peter , Lundeberg Mark B. , Latini Simone , Haastrup Sten , Danovich Mark , Davydovskaya Diana , Watanabe Kenji , Taniguchi Takashi , Fal’ko Vladimir I. , Thygesen Kristian S. , Pedersen Thomas G. , Koppens Frank H. L.
Published: April 2018

Two-dimensional (2D) semiconducting materials are promising building blocks for optoelectronic applications, many of which require efficient dissociation of excitons into free electrons and holes. However, the strongly bound excitons arising from the enhanced Coulomb interaction in these monolayers suppresses the creation of free carriers. Here, we identify the main exciton dissociation mechanism through time and spectrally resolved photocurrent measurements in a monolayer WSe2p–n junction. We find that under static in-plane electric field, excitons dissociate at a rate corresponding to the one predicted for tunnel ionization of 2D Wannier–Mott excitons. This study is essential for understanding the photoresponse of 2D semiconductors and offers design rules for the realization of efficient photodetectors, valley dependent optoelectronics, and novel quantum coherent phases.
Universality in volume-law entanglement of scrambled pure quantum states
Authors: Nakagawa Yuya O. , Watanabe Masataka , Fujita Hiroyuki , Sugiura Sho
Published: April 2018

A pure quantum state can fully describe thermal equilibrium as long as one focuses on local observables. The thermodynamic entropy can also be recovered as the entanglement entropy of small subsystems. When the size of the subsystem increases, however, quantum correlations break the correspondence and mandate a correction to this simple volume law. The elucidation of the size dependence of the entanglement entropy is thus essentially important in linking quantum physics with thermodynamics. Here we derive an analytic formula of the entanglement entropy for a class of pure states called cTPQ states representing equilibrium. We numerically find that our formula applies universally to any sufficiently scrambled pure state representing thermal equilibrium, i.e., energy eigenstates of non-integrable models and states after quantum quenches. Our formula is exploited as diagnostics for chaotic systems; it can distinguish integrable models from non-integrable models and many-body localization phases from chaotic phases.
Capping protein-controlled actin polymerization shapes lipid membranes
Authors: Dürre Katharina , Keber Felix C. , Bleicher Philip , Brauns Fridtjof , Cyron Christian J. , Faix Jan , Bausch Andreas R.
Published: April 2018

Arp2/3 complex-mediated actin assembly at cell membranes drives the formation of protrusions or endocytic vesicles. To identify the mechanism by which different membrane deformations can be achieved, we reconstitute the basic membrane deformation modes of inward and outward bending in a confined geometry by encapsulating a minimal set of cytoskeletal proteins into giant unilamellar vesicles. Formation of membrane protrusions is favoured at low capping protein (CP) concentrations, whereas the formation of negatively bent domains is promoted at high CP concentrations. Addition of non-muscle myosin II results in full fission events in the vesicle system. The different deformation modes are rationalized by simulations of the underlying transient nature of the reaction kinetics. The relevance of the regulatory mechanism is supported by CP overexpression in mouse melanoma B16-F1 cells and therefore demonstrates the importance of the quantitative understanding of microscopic kinetic balances to address the diverse functionality of the cytoskeleton.
Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers
Authors: Lanjakornsiripan Darin , Pior Baek-Jun , Kawaguchi Daichi , Furutachi Shohei , Tahara Tomoaki , Katsuyama Yu , Suzuki Yutaka , Fukazawa Yugo , Gotoh Yukiko
Published: April 2018

Non-pial neocortical astrocytes have historically been thought to comprise largely a nondiverse population of protoplasmic astrocytes. Here we show that astrocytes of the mouse somatosensory cortex manifest layer-specific morphological and molecular differences. Two- and three-dimensional observations revealed that astrocytes in the different layers possess distinct morphologies as reflected by differences in cell orientation, territorial volume, and arborization. The extent of ensheathment of synaptic clefts by astrocytes in layer II/III was greater than that by those in layer VI. Moreover, differences in gene expression were observed between upper-layer and deep-layer astrocytes. Importantly, layer-specific differences in astrocyte properties were abrogated inreelerandDab1conditional knockout mice, in which neuronal layers are disturbed, suggesting that neuronal layers are a prerequisite for the observed morphological and molecular differences of neocortical astrocytes. This study thus demonstrates the existence of layer-specific interactions between neurons and astrocytes, which may underlie their layer-specific functions.
Methylated DNMT1 and E2F1 are targeted for proteolysis by L3MBTL3 and CRL4DCAF5 ubiquitin ligase
Authors: Leng Feng , Yu Jiekai , Zhang Chunxiao , Alejo Salvador , Hoang Nam , Sun Hong , Lu Fei , Zhang Hui
Published: April 2018

Many non-histone proteins are lysine methylated and a novel function of this modification is to trigger the proteolysis of methylated proteins. Here, we report that the methylated lysine 142 of DNMT1, a major DNA methyltransferase that preserves epigenetic inheritance of DNA methylation patterns during DNA replication, is demethylated by LSD1. A novel methyl-binding protein, L3MBTL3, binds the K142-methylated DNMT1 and recruits a novel CRL4DCAF5 ubiquitin ligase to degrade DNMT1. Both LSD1 and PHF20L1 act primarily in S phase to prevent DNMT1 degradation by L3MBTL3-CRL4DCAF5. Mouse L3MBTL3/MBT-1 deletion causes accumulation of DNMT1 protein, increased genomic DNA methylation, and late embryonic lethality. DNMT1 contains a consensus methylation motif shared by many non-histone proteins including E2F1, a key transcription factor for S phase. We show that the methylation-dependent E2F1 degradation is also controlled by L3MBTL3-CRL4DCAF5. Our studies elucidate for the first time a novel mechanism by which the stability of many methylated non-histone proteins are regulated.
Molecular doping enabled scalable blading of efficient hole-transport-layer-free perovskite solar cells
Authors: Wu Wu-Qiang , Wang Qi , Fang Yanjun , Shao Yuchuan , Tang Shi , Deng Yehao , Lu Haidong , Liu Ye , Li Tao , Yang Zhibin , Gruverman Alexei , Huang Jinsong
Published: April 2018

The efficiencies of perovskite solar cells (PSCs) are now reaching such consistently high levels that scalable manufacturing at low cost is becoming critical. However, this remains challenging due to the expensive hole-transporting materials usually employed, and difficulties associated with the scalable deposition of other functional layers. By simplifying the device architecture, hole-transport-layer-free PSCs with improved photovoltaic performance are fabricated via a scalable doctor-blading process. Molecular doping of halide perovskite films improved the conductivity of the films and their electronic contact with the conductive substrate, resulting in a reduced series resistance. It facilitates the extraction of photoexcited holes from perovskite directly to the conductive substrate. The bladed hole-transport-layer-free PSCs showed a stabilized power conversion efficiency above 20.0%. This work represents a significant step towards the scalable, cost-effective manufacturing of PSCs with both high performance and simple fabrication processes.
Bio-inspired nano-traps for uranium extraction from seawater and recovery from nuclear waste
Authors: Sun Qi , Aguila Briana , Perman Jason , Ivanov Aleksandr S. , Bryantsev Vyacheslav S. , Earl Lyndsey D. , Abney Carter W. , Wojtas Lukasz , Ma Shengqian
Published: April 2018

Nature can efficiently recognize specific ions by exerting second-sphere interactions onto well-folded protein scaffolds. However, a considerable challenge remains to artificially manipulate such affinity, while being cost-effective in managing immense amounts of water samples. Here, we propose an effective approach to regulate uranyl capture performance by creating bio-inspired nano-traps, illustrated by constructing chelating moieties into porous frameworks, where the binding motif’s coordinative interaction towards uranyl is enhanced by introducing an assistant group, reminiscent of biological systems. Representatively, the porous framework bearing 2-aminobenzamidoxime is exceptional in sequestering high uranium concentrations with sufficient capacities (530 mg g−1) and trace quantities, including uranium in real seawater (4.36 mg g−1, triple the benchmark). Using a combination of spectroscopic, crystallographic, and theory calculation studies, it is revealed that the amino substituent assists in lowering the charge on uranyl in the complex and serves as a hydrogen bond acceptor, boosting the overall uranyl affinity of amidoxime.
De novo main-chain modeling for EM maps using MAINMAST
Authors: Terashi Genki , Kihara Daisuke
Published: April 2018

An increasing number of protein structures are determined by cryo-electron microscopy (cryo-EM) at near atomic resolution. However, tracing the main-chains and building full-atom models from EM maps of ~4–5 Å is still not trivial and remains a time-consuming task. Here, we introduce a fully automated de novo structure modeling method, MAINMAST, which builds three-dimensional models of a protein from a near-atomic resolution EM map. The method directly traces the protein’s main-chain and identifies Cα positions as tree-graph structures in the EM map. MAINMAST performs significantly better than existing software in building global protein structure models on data sets of 40 simulated density maps at 5 Å resolution and 30 experimentally determined maps at 2.6–4.8 Å resolution. In another benchmark of building missing fragments in protein models for EM maps, MAINMAST builds fragments of 11–161 residues long with an average RMSD of 2.68 Å.
Galectin-3 deficiency drives lupus-like disease by promoting spontaneous germinal centers formation via IFN-γ
Authors: Beccaria Cristian Gabriel , Amezcua Vesely María Carolina , Fiocca Vernengo Facundo , Gehrau Ricardo Carlos , Ramello María Cecilia , Tosello Boari Jimena , Gorosito Serrán Melisa , Mucci Juan , Piaggio Eliane , Campetella Oscar , Acosta Rodríguez Eva Virginia , Montes Carolina Lucía , Gruppi Adriana
Published: April 2018

Germinal centers (GC) are important sites for high-affinity and long-lived antibody induction. Tight regulation of GC responses is critical for maintaining self-tolerance. Here, we show that Galectin-3 (Gal-3) is involved in GC development. Compared with WT mice, Gal-3 KO mice have more GC B cells and T follicular helper cells, increased percentages of antibody-secreting cells and higher concentrations of immunoglobulins and IFN-γ in serum, and develop a lupus-like disease. IFN-γ blockade in Gal-3 KO mice reduces spontaneous GC formation, class-switch recombination, autoantibody production and renal pathology, demonstrating that IFN-γ overproduction sustains autoimmunity. The results from chimeric mice show that intrinsic Gal-3 signaling in B cells controls spontaneous GC formation. Taken together, our data provide evidence that Gal-3 acts directly on B cells to regulate GC responses via IFN-γ and implicate the potential of Gal-3 as a therapeutic target in autoimmunity.
Invasive alien pests threaten the carbon stored in Europe’s forests
Authors: Seidl Rupert , Klonner Günther , Rammer Werner , Essl Franz , Moreno Adam , Neumann Mathias , Dullinger Stefan
Published: April 2018

Forests mitigate climate change by sequestering large amounts of carbon (C). However, forest C storage is not permanent, and large pulses of tree mortality can thwart climate mitigation efforts. Forest pests are increasingly redistributed around the globe. Yet, the potential future impact of invasive alien pests on the forest C cycle remains uncertain. Here we show that large parts of Europe could be invaded by five detrimental alien pests already under current climate. Climate change increases the potential range of alien pests particularly in Northern and Eastern Europe. We estimate the live C at risk from a potential future invasion as 1027 Tg C (10% of the European total), with a C recovery time of 34 years. We show that the impact of introduced pests could be as severe as the current natural disturbance regime in Europe, calling for increased efforts to halt the introduction and spread of invasive alien species.