bluuebunny/crossref_metadata_2025_split huggingface dataset:
MicroRNA-421 confers paclitaxel resistance by binding to the KEAP1 3′UTR and predicts poor survival in non-small cell lung cancer
Authors: Duan Fu-Gang , Wang Mei-Fang , Cao Ya-Bing , Dan Li  , Li Run-Ze , Fan Xing-Xing , Khan Imran , Lai Huan-Ling , Zhang Yi-Zhong , Hsiao Wendy Wen-Luan , Yao Xiao-Jun , Wu Qi-Biao , Liu Liang , Tang Yi-Jun , Leung Elaine Lai-Han 
Published: October 2019

AbstractMicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated protein 1(KEAP1) expression by targeting its 3′-untranslated region (3′UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, β-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting β-catenin reduced miR-421 levels in A549 cells. In addition, β-catenin upregulation enhanced miR-421 expression, indicating that β-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.
Truncated PPM1D impairs stem cell response to genotoxic stress and promotes growth of APC-deficient tumors in the mouse colon
Authors: Burocziova Monika , Burdova Kamila , Martinikova Andra S. , Kasparek Petr , Kleiblova Petra , Danielsen Stine A. , Borecka Marianna , Jenikova Gabriela , Janečková Lucie , Pavel Jozef , Zemankova Petra , Schneiderova Michaela , Schwarzova Lucie , Ticha Ivana , Sun Xiao-Feng , Jiraskova Katerina , Liska Vaclav , Vodickova Ludmila , Vodicka Pavel , Sedlacek Radislav , Kleibl Zdenek , Lothe Ragnhild A. , Korinek Vladimír , Macurek Libor 
Published: October 2019

AbstractProtein phosphatase magnesium-dependent 1 delta (PPM1D) terminates cell response to genotoxic stress by negatively regulating the tumor suppressor p53 and other targets at chromatin. Mutations in the exon 6 of the PPM1D result in production of a highly stable, C-terminally truncated PPM1D. These gain-of-function PPM1D mutations are present in various human cancers but their role in tumorigenesis remains unresolved. Here we show that truncated PPM1D impairs activation of the cell cycle checkpoints in human non-transformed RPE cells and allows proliferation in the presence of DNA damage. Next, we developed a mouse model by introducing a truncating mutation in the PPM1D locus and tested contribution of the oncogenic PPM1DT allele to colon tumorigenesis. We found that p53 pathway was suppressed in colon stem cells harboring PPM1DT resulting in proliferation advantage under genotoxic stress condition. In addition, truncated PPM1D promoted tumor growth in the colon in Apcmin mice and diminished survival. Moreover, tumor organoids derived from colon of the ApcminPpm1dT/+ mice were less sensitive to 5-fluorouracil when compared to ApcminPpm1d+/+and the sensitivity to 5-fluorouracil was restored by inhibition of PPM1D. Finally, we screened colorectal cancer patients and identified recurrent somatic PPM1D mutations in a fraction of colon adenocarcinomas that are p53 proficient and show defects in mismatch DNA repair. In summary, we provide the first in vivo evidence that truncated PPM1D can promote tumor growth and modulate sensitivity to chemotherapy.
MicroRNA-18a promotes cancer progression through SMG1 suppression and mTOR pathway activation in nasopharyngeal carcinoma
Authors: Mai ShiJuan , Xiao RuoWen , Shi Lu , Zhou XiaoMin , Yang Te , Zhang MeiYin , Weng NuoQing , Zhao XinGe , Wang RuiQi , Liu Ji , Sun Rui , Qin HaiDe , Wang HuiYun 
Published: October 2019

AbstractmiR-18a has been reported to be upregulated in nasopharyngeal carcinoma (NPC) tissues by microarray assays. However, the roles and the underlying mechanisms of miR-18a in NPC remain poorly understood. Here we demonstrated by real-time RT-PCR that miR-18a expression is upregulated in NPC tissues, and positively correlated with tumor size and TNM stage. Moreover, miR-18a expression could be upregulated by NF-κB activation or Epstein-Barr virus encoded latent membrane protein 1 expression. The ectopic expression of miR-18a promoted NPC cell proliferation, migration and invasion, while the repression of miR-18a had opposite effects. Candidate genes under regulation by miR-18a were screened out through a whole-genome microarray assay, further identified by a reporter assay and verified in clinical samples. SMG1, a member of the phosphoinositide 3-kinase-related kinases family and an mTOR antagonist, was identified as functional target of miR-18a. Our results confirmed that miR-18a exerts its oncogenic role through suppression of SMG1 and activation of mTOR pathway in NPC cells. Importantly, in vivo xenograft tumor growth in nude mice was effectively inhibited by intratumor injection of miR-18a antagomir. Our data support an oncogenic role of miR-18a through a novel miR-18a/SMG1/mTOR axis and suggest that the antitumor effects of antagomir-18a may make it suitable for NPC therapy.
Hydralazine targets cAMP-dependent protein kinase leading to sirtuin1/5 activation and lifespan extension in C. elegans
Authors: Dehghan Esmaeil , Goodarzi Mohammad , Saremi Bahar , Lin Rueyling , Mirzaei Hamid 
Published: October 2019

AbstractTherapeutic activation of mitochondrial function has been suggested as an effective strategy to combat aging. Hydralazine is an FDA-approved drug used in the treatment of hypertension, heart failure and cancer. Hydralazine has been recently shown to promote lifespan inC. elegans, rotifer and yeast through a mechanism which has remained elusive. Here we report cAMP-dependent protein kinase (PKA) as the direct target of hydralazine. Using in vitro and in vivo models, we demonstrate a mechanism in which binding and stabilization of a catalytic subunit of PKA by hydralazine lead to improved mitochondrial function and metabolic homeostasis via the SIRT1/SIRT5 axis, which underlies hydralazine’s prolongevity and stress resistance benefits. Hydralazine also protects mitochondrial metabolism and function resulting in restoration of health and lifespan inC. elegansunder high glucose and other stress conditions. Our data also provide new insights into the mechanism(s) that explain various other known beneficial effects of hydralazine.
A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers
Authors: Akerberg Brynn N. , Gu Fei , VanDusen Nathan J. , Zhang Xiaoran , Dong Rui , Li Kai , Zhang Bing , Zhou Bin , Sethi Isha , Ma Qing , Wasson Lauren , Wen Tong , Liu Jinhua , Dong Kunzhe , Conlon Frank L. , Zhou Jiliang , Yuan Guo-Cheng , Zhou Pingzhu , Pu William T. 
Published: October 2019

AbstractMapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development.
Modification of boron nitride nanocages by titanium doping results unexpectedly in exohedral complexes
Authors: Li Ruyi , Wang Yang 
Published: October 2019

AbstractDespite their early experimental production and observation, the unambiguous molecular structures of metal-containing boron nitride (BN) nanocages still remain mysterious. It has been commonly assumed that this family of compounds has the metal atom confined inside the cage, just like their isoelectronic cousins, carbon metallofullerenes do. Here, we demonstrate that Ti(BN)n ($$n$$
n
= 12–24) complexes have, unexpectedly, an exohedral structure instead of an endohedral one, which could be verified by collision-induced dissociation experiments. The predicted global minimum structures exhibit some common bonding features accounting for their high stability, and could be readily synthesized under typical conditions for generating BN nanoclusters. The Ti doping dramatically changes not only the cage topology, but the arrangement of B and N atoms, endowing the resultant compounds with potential for $${\mathrm{CO}}_{2}$$

CO

2

capture and nitrogen fixation. These findings may expand or alter the understanding of BN nanostructures functionalized with other transition metals.
Broad-spectrum resistance to bacterial blight in rice using genome editing
Authors: Oliva Ricardo , Ji Chonghui , Atienza-Grande Genelou , Huguet-Tapia José C. , Perez-Quintero Alvaro , Li Ting , Eom Joon-Seob , Li Chenhao , Nguyen Hanna , Liu Bo , Auguy Florence , Sciallano Coline , Luu Van T. , Dossa Gerbert S. , Cunnac Sébastien , Schmidt Sarah M. , Slamet-Loedin Inez H. , Vera Cruz Casiana , Szurek Boris , Frommer Wolf B. , White Frank F. , Yang Bing 
Published: October 2019

AbstractBacterial blight of rice is an important disease in Asia and Africa. The pathogen,Xanthomonas oryzaepv.oryzae(Xoo), secretes one or more of six known transcription-activator-like effectors (TALes) that bind specific promoter sequences and induce, at minimum, one of the three host sucrose transporter genesSWEET11,SWEET13andSWEET14, the expression of which is required for disease susceptibility. We used CRISPR–Cas9-mediated genome editing to introduce mutations in all threeSWEETgene promoters. Editing was further informed by sequence analyses of TALe genes in 63Xoostrains, which revealed multiple TALe variants forSWEET13alleles. Mutations were also created inSWEET14, which is also targeted by two TALes from an AfricanXoolineage. A total of five promoter mutations were simultaneously introduced into the rice line Kitaake and the elite mega varieties IR64 and Ciherang-Sub1. Paddy trials showed that genome-editedSWEETpromoters endow rice lines with robust, broad-spectrum resistance.
CO3+1 network formation in ultra-high pressure carbonate liquids
Authors: Wilding Martin , Bingham Paul A. , Wilson Mark , Kono Yoshio , Drewitt James W. E. , Brooker Richard A. , Parise John B. 
Published: October 2019

AbstractCarbonate liquids are an important class of molten salts, not just for industrial applications, but also in geological processes. Carbonates are generally expected to be simple liquids, in terms of ionic interactions between the molecular carbonate anions and metal cations, and therefore relatively structureless compared to more “polymerized” silicate melts. But there is increasing evidence from phase relations, metal solubility, glass spectroscopy and simulations to suggest the emergence of carbonate “networks” at length scales longer than the component molecular anions. The stability of these emergent structures are known to be sensitive to temperature, but are also predicted to be favoured by pressure. This is important as a recent study suggests that subducted surface carbonate may melt near the Earth’s transition zone (~44 km), representing a barrier to the deep carbon cycle depending on the buoyancy and viscosity of these liquids. In this study we demonstrate a major advance in our understanding of carbonate liquids by combining simulations and high pressure measurements on a carbonate glass, (K2CO3-MgCO3) to pressures in excess of 40 GPa, far higher than any previous in situ study. We show the clear formation of extended low-dimensional carbonate networks of close CO32− pairs and the emergence of a “three plus one” local coordination environment, producing an unexpected increase in viscosity with pressure. Although carbonate melts may still be buoyant in the lower mantle, an increased viscosity by at least three orders of magnitude will restrict the upward mobility, possibly resulting in entrainment by the down-going slab.
Monitoring spawning migrations of potamodromous fish species via eDNA
Authors: Thalinger Bettina , Wolf Elisabeth , Traugott Michael , Wanzenböck Josef 
Published: October 2019

AbstractPotamodromous fish are considered important indicators of habitat connectivity in freshwater ecosystems, but they are globally threatened by anthropogenic impacts. Hence, non-invasive techniques are necessary for monitoring during spawning migrations. The use of environmental DNA (eDNA) potentially facilitates these efforts, albeit quantitative examinations of spawning migrations remain so far mostly uncharted. Here, we investigated spawning migrations of Danube bleak, Alburnus mento, and Vimba bream, Vimba vimba, and found a strong correlation between daily visual fish counts and downstream eDNA signals obtained from filtered water samples analysed with digital PCR and end-point PCR coupled with capillary electrophoresis. By accounting for daily discharge fluctuations, it was possible to predict eDNA signal strength from the number of migrating fish: first, the whole spawning reach was taken into account. Second, the model was validated using eDNA signals and fish counts obtained from the upper half of the examined river stretch. Consequently, fish counts and their day-to-day changes could be described via an eDNA-based time series model for the whole migration period. Our findings highlight the capability of eDNA beyond delivering simple presence/absence data towards efficient and informative monitoring of highly dynamic aquatic processes such as spawning migrations of potamodromous fish species.
Fractal nature of groundwater level fluctuations affected by riparian zone vegetation water use and river stage variations
Authors: Sun HongGuang , Gu Xiufen , Zhu Jianting , Yu Zhongbo , Zhang Yong 
Published: October 2019

AbstractGroundwater systems affected by various factors can exhibit complex fractal behaviors, whose reliable characterization however is not straightforward. This study explores the fractal scaling behavior of the groundwater systems affected by plant water use and river stage fluctuations in the riparian zone, using multifractal detrended fluctuation analysis (MFDFA). The multifractal spectrum based on the local Hurst exponent is used to quantify the complexity of fractal nature. Results show that the water level variations at the riparian zone of the Colorado River, USA, exhibit multifractal characteristics mainly caused by the memory of time series of the water level fluctuations. The groundwater level at the monitoring well close to the river characterizes the season-dependent scaling behavior, including persistence from December to February and anti-persistence from March to November. For the site with high-density plants (Tamarisk ramosissima, which requires direct access to groundwater as its source of water), the groundwater level fluctuation becomes persistent in spring and summer, since the plants have the most significant and sustained influence on the groundwater in these seasons, which can result in stronger memory of the water level fluctuation. Results also show that the high-density plants weaken the complexity of the multifractal property of the groundwater system. In addition, the groundwater level variations at the site close to the river exhibit the most complex multifractality due to the influence of the river stage fluctuation.
Interacting effects of vessel noise and shallow river depth elevate metabolic stress in Ganges river dolphins
Authors: Dey Mayukh , Krishnaswamy Jagdish , Morisaka Tadamichi , Kelkar Nachiket 
Published: October 2019

AbstractIn riverine ‘soundscapes’, complex interactions between sound, substrate type, and depth create difficulties in assessing impacts of anthropogenic noise pollution on freshwater fauna. Underwater noise from vessels can negatively affect endangered Ganges river dolphins (Platanista gangetica), which are ‘almost blind’ and rely entirely on high-frequency echolocation clicks to sense their environment. We conducted field-based acoustic recordings and modelling to assess acoustic responses ofPlatanistato underwater noise exposure from vessels in the Ganga River (India), which is now being transformed into a major waterway. Dolphins showed enhanced activity during acute noise exposure and suppressed activity during chronic exposure. Increase in ambient noise levels altered dolphin acoustic responses, strongly masked echolocation clicks, and more than doubled metabolic stress. Noise impacts were further aggravated during dry-season river depth reduction. Maintaining ecological flows, downscaling of vessel traffic, and propeller modifications to reduce cavitation noise, could help mitigate noise impacts on Ganges river dolphins.
Grandmothers’ smoking in pregnancy is associated with a reduced prevalence of early-onset myopia
Authors: Williams Cathy , Suderman Matthew , Guggenheim Jeremy A. , Ellis Genette , Gregory Steve , Iles-Caven Yasmin , Northstone Kate , Golding Jean , Pembrey Marcus 
Published: October 2019

AbstractMyopia (near sightedness) is the most common vision disorder resulting in visual impairment worldwide. We tested the hypothesis that intergenerational, non-genetic heritable effects influence refractive development, using grandparental prenatal smoking as a candidate exposure. Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we found that the prevalence of myopia at age 7 was lower if the paternal grandmother had smoked in pregnancy, an association primarily found among grandsons compared to granddaughters. There was a weaker, non-sex-specific, reduction in the prevalence of myopia at age 7 if the maternal grandmother had smoked in pregnancy. For children who became myopic later (between 7 and 15 years of age) there were no associations with either grandmother smoking. Differences between early and late-onset myopia were confirmed with DNA methylation patterns: there were very distinct and strong associations with methylation for early-onset but not later-onset myopia.
Brain-derived neurotrophic factor is related with adverse cardiac remodeling and high NTproBNP
Authors: Bahls Martin , Könemann Stephanie , Markus Marcello R. P. , Wenzel Kristin , Friedrich Nele , Nauck Matthias , Völzke Henry , Steveling Antje , Janowitz Deborah , Grabe Hans-Jörgen , Felix Stephan B. , Dörr Marcus 
Published: October 2019

AbstractThe brain-derived neurotrophic factor (BDNF) is a neuronal growth factor essential for normal cardiac contraction and relaxation. Alterations in BDNF signaling are related to the development of cardiovascular disease. Whether BDNF is related to subclinical cardiac remodeling is unclear. We related BDNF with echocardiographic parameters and NTproBNP in a large population-based cohort (n = 2,976, median age 48 years; 45% male). Transthoracic echocardiography was performed on all subjects and BDNF was measured by ELISA. Study participants with severe kidney dysfunction, previous myocardial infarction, and LV ejection fraction <40% were excluded. Linear regression models were adjusted for age, sex, lean mass, fat mass, current smoking, systolic blood pressure and depression. Low BDNF was associated with high NTproBNP. A 10,000 pg/ml lower BDNF was related with a 2.5 g higher (95%-confidence interval [CI]: 0.2 to 4.9; p = 0.036) LV mass, 0.01 cm posterior wall thickness (0.003 to 0.022; p = 0.007) and 0.02 E/A ratio (0.003 to 0.042, p = 0.026). Here we show that low BDNF levels are related with adverse cardiac remodeling and higher levels of NTproBNP. Further research is warranted to assess if BDNF may be used to monitor neuronal-cardiac damage during CVD progression.
Rare variants in non-coding regulatory regions of the genome that affect gene expression in systemic lupus erythematosus
Authors: Jones Sarah A. , Cantsilieris Stuart , Fan Huapeng , Cheng Qiang , Russ Brendan E. , Tucker Elena J. , Harris James , Rudloff Ina , Nold Marcel , Northcott Melissa , Dankers Wendy , Toh Andrew E. J. , White Stefan J. , Morand Eric F. 
Published: October 2019

AbstractPersonalized medicine approaches are increasingly sought for diseases with a heritable component. Systemic lupus erythematosus (SLE) is the prototypic autoimmune disease resulting from loss of immunologic tolerance, but the genetic basis of SLE remains incompletely understood. Genome wide association studies (GWAS) identify regions associated with disease, based on common single nucleotide polymorphisms (SNPs) within them, but these SNPs may simply be markers in linkage disequilibrium with other, causative mutations. Here we use an hierarchical screening approach for prediction and testing of true functional variants within regions identified in GWAS; this involved bioinformatic identification of putative regulatory elements within close proximity to SLE SNPs, screening those regions for potentially causative mutations by high resolution melt analysis, and functional validation using reporter assays. Using this approach, we screened 15 SLE associated loci in 143 SLE patients, identifying 7 new variants including 5 SNPs and 2 insertions. Reporter assays revealed that the 5 SNPs were functional, altering enhancer activity. One novel variant was linked to the relatively well characterized rs9888739 SNP at the ITGAM locus, and may explain some of the SLE heritability at this site. Our study demonstrates that non-coding regulatory elements can contain private sequence variants affecting gene expression, which may explain part of the heritability of SLE.