bluuebunny/crossref_metadata_2025_split huggingface dataset:
BORIS/CTCFL promotes a switch from a proliferative towards an invasive phenotype in melanoma cells
Authors: Janssen Sanne Marlijn , Moscona Roy , Elchebly Mounib , Papadakis Andreas Ioannis , Redpath Margaret , Wang Hangjun , Rubin Eitan , van Kempen Léon Cornelis , Spatz Alan 
Published: February 2020

AbstractMelanoma is among the most aggressive cancers due to its tendency to metastasize early. Phenotype switching between a proliferative and an invasive state has been suggested as a critical process for metastasis, though the mechanisms that regulate state transitions are complex and remain poorly understood. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcriptional modulator that becomes aberrantly expressed in melanoma. Yet, the role of BORIS in melanoma remains elusive. Here, we show that BORIS is involved in melanoma phenotype switching. Genetic modification of BORIS expression in melanoma cells combined with whole-transcriptome analysis indicated that BORIS expression contributes to an invasion-associated transcriptome. In line with these findings, inducible BORIS overexpression in melanoma cells reduced proliferation and increased migration and invasion, demonstrating that the transcriptional switch is accompanied by a phenotypic switch. Mechanistically, we reveal that BORIS binds near the promoter of transforming growth factor-beta 1 (TFGB1), a well-recognized factor involved in the transition towards an invasive state, which coincided with increased expression of TGFB1. Overall, our study indicates a pro-invasive role for BORIS in melanoma via transcriptional reprogramming.
NF90 stabilizes cyclin E1 mRNA through phosphorylation of NF90-Ser382 by CDK2
Authors: Ding Donglin , Huang Huixing , Li Quanfu , Yu Wenbo , Wang Chenji , Ma Haijie , Wu Jiaxue , Dang Yongjun , Yu Long , Jiang Wei 
Published: February 2020

AbstractNuclear factor 90 (NF90), an RNA-binding protein, has been implicated in regulating interleukin-2 (IL-2) and the immune response. It was recently reported that NF90 is upregulated in hepatocellular carcinoma (HCC) tissues and promotes HCC proliferation through upregulating cyclin E1 at the posttranscription level. However, the regulation of NF90 in HCC remains unclear. We demonstrate here that cyclin-dependent kinase (CDK) 2 interacts with NF90 and phosphorylated it at serine382. Mechanistically, phosphorylation of NF90-Ser382 determines the nuclear export of NF90 and stabilization of cyclin E1 mRNA. We also demonstrate that the phosphorylation deficient mutant NF90-S382A inhibits cell growth and induces cell cycle arrest at the G1 phase in HCC cells. Moreover, an NF90-S382A xenograft tumor had a decreased size and weight compared with the wildtype NF90. The NF90-S382A xenograft contained a significantly lower level of the proliferation marker Ki-67. Additionally, in HCC patients, NF90-Ser382 phosphorylation was stronger in tumor than in non-tumor tissues. Clinically, phosphorylation of NF90-Ser382 is significantly associated with larger tumor sizes, higher AFP levels, and shorter overall survival rates. These results suggest NF90-Ser382 phosphorylation serves as a potential diagnosis and prognostic marker and a promising pharmacological target for HCC.
Phenotypic high-throughput screening platform identifies novel chemotypes for necroptosis inhibition
Authors: Brito Hugo , Marques Vanda , Afonso Marta B. , Brown Dean G. , Börjesson Ulf , Selmi Nidhal , Smith David M. , Roberts Ieuan O. , Fitzek Martina , Aniceto Natália , Guedes Rita C. , Moreira Rui , Rodrigues Cecília M. P. 
Published: February 2020

AbstractRegulated necrosis or necroptosis, mediated by receptor-interacting kinase 1 (RIPK1), RIPK3 and pseudokinase mixed lineage kinase domain-like protein (MLKL), contributes to the pathogenesis of inflammatory, infectious and degenerative diseases. Recently identified necroptosis inhibitors display moderate specificity, suboptimal pharmacokinetics, off-target effects and toxicity, preventing these molecules from reaching the clinic. Here, we developed a cell-based high-throughput screening (HTS) cascade for the identification of small-molecule inhibitors of necroptosis. From the initial library of over 250,000 compounds, the primary screening phase identified 356 compounds that strongly inhibited TNF-α-induced necroptosis, but not apoptosis, in human and murine cell systems, with EC50 < 6.7 μM. From these, 251 compounds were tested for RIPK1 and/or RIPK3 kinase inhibitory activity; some were active and several have novel mechanisms of action. Based on specific chemical descriptors, 110 compounds proceeded into the secondary screening cascade, which then identified seven compounds with maximum ability to reduce MLKL activation, IC50 >100 μM, EC50 2.5–11.5 μM under long-term necroptosis execution in murine fibroblast L929 cells, and full protection from ATP depletion and membrane leakage in human and murine cells. As a proof of concept, compound SN-6109, with binding mode to RIPK1 similar to that of necrostatin-1, confirmed RIPK1 inhibitory activity and appropriate pharmacokinetic properties. SN-6109 was further tested in mice, showing efficacy against TNF-α-induced systemic inflammatory response syndrome. In conclusion, a phenotypic-driven HTS cascade promptly identified robust necroptosis inhibitors with in vivo activity, currently undergoing further medicinal chemistry optimization. Notably, the novel hits highlight the opportunity to identify new molecular mechanisms of action in necroptosis.
A computational platform for high-throughput analysis of RNA sequences and modifications by mass spectrometry
Authors: Wein Samuel , Andrews Byron , Sachsenberg Timo , Santos-Rosa Helena , Kohlbacher Oliver , Kouzarides Tony , Garcia Benjamin A. , Weisser Hendrik 
Published: February 2020

AbstractThe field of epitranscriptomics continues to reveal how post-transcriptional modification of RNA affects a wide variety of biological phenomena. A pivotal challenge in this area is the identification of modified RNA residues within their sequence contexts. Mass spectrometry (MS) offers a comprehensive solution by using analogous approaches to shotgun proteomics. However, software support for the analysis of RNA MS data is inadequate at present and does not allow high-throughput processing. Existing software solutions lack the raw performance and statistical grounding to efficiently handle the numerous modifications found on RNA. We present a free and open-source database search engine for RNA MS data, called NucleicAcidSearchEngine (NASE), that addresses these shortcomings. We demonstrate the capability of NASE to reliably identify a wide range of modified RNA sequences in four original datasets of varying complexity. In human tRNA, we characterize over 20 different modification types simultaneously and find many cases of incomplete modification.
Inhibiting WNT and NOTCH in renal cancer stem cells and the implications for human patients
Authors: Fendler Annika , Bauer Daniel , Busch Jonas , Jung Klaus , Wulf-Goldenberg Annika , Kunz Severine , Song Kun , Myszczyszyn Adam , Elezkurtaj Sefer , Erguen Bettina , Jung Simone , Chen Wei , Birchmeier Walter 
Published: February 2020

AbstractCurrent treatments for clear cell renal cell cancer (ccRCC) are insufficient because two-thirds of patients with metastases progress within two years. Here we report the identification and characterization of a cancer stem cell (CSC) population in ccRCC. CSCs are quantitatively correlated with tumor aggressiveness and metastasis. Transcriptional profiling and single cell sequencing reveal that these CSCs exhibit an activation of WNT and NOTCH signaling. A significant obstacle to the development of rational treatments has been the discrepancy between model systems and the in vivo situation of patients. To address this, we use CSCs to establish non-adherent sphere cultures, 3D tumor organoids, and xenografts. Treatment with WNT and NOTCH inhibitors blocks the proliferation and self-renewal of CSCs in sphere cultures and organoids, and impairs tumor growth in patient-derived xenografts in mice. These findings suggest that our approach is a promising route towards the development of personalized treatments for individual patients.
Chromosomal origin of replication coordinates logically distinct types of bacterial genetic regulation
Authors: Kosmidis Kosmas , Jablonski Kim Philipp , Muskhelishvili Georgi , Hütt Marc-Thorsten 
Published: February 2020

AbstractFor a long time it has been hypothesized that bacterial gene regulation involves an intricate interplay of the transcriptional regulatory network (TRN) and the spatial organization of genes in the chromosome. Here we explore this hypothesis both on a structural and on a functional level. On the structural level, we study the TRN as a spatially embedded network. On the functional level, we analyze gene expression patterns from a network perspective (“digital control”), as well as from the perspective of the spatial organization of the chromosome (“analog control”). Our structural analysis reveals the outstanding relevance of the symmetry axis defined by the origin (Ori) and terminus (Ter) of replication for the network embedding and, thus, suggests the co-evolution of two regulatory infrastructures, namely the transcriptional regulatory network and the spatial arrangement of genes on the chromosome, to optimize the cross-talk between two fundamental biological processes: genomic expression and replication. This observation is confirmed by the functional analysis based on the differential gene expression patterns of more than 4000 pairs of microarray and RNA-Seq datasets for E. coli from the Colombos Database using complex network and machine learning methods. This large-scale analysis supports the notion that two logically distinct types of genetic control are cooperating to regulate gene expression in a complementary manner. Moreover, we find that the position of the gene relative to the Ori is a feature of very high predictive value for gene expression, indicating that the Ori–Ter symmetry axis coordinates the action of distinct genetic control mechanisms.
High-resolution T2-FLAIR and non-contrast CT brain atlas of the elderly
Authors: Rajashekar Deepthi , Wilms Matthias , MacDonald M. Ethan , Ehrhardt Jan , Mouches Pauline , Frayne Richard , Hill Michael D. , Forkert Nils D. 
Published: February 2020

AbstractNormative brain atlases are a standard tool for neuroscience research and are, for example, used for spatial normalization of image datasets prior to voxel-based analyses of brain morphology and function. Although many different atlases are publicly available, they are usually biased with respect to an imaging modality and the age distribution. Both effects are well known to negatively impact the accuracy and reliability of the spatial normalization process using non-linear image registration methods. An important and very active neuroscience area that lacks appropriate atlases is lesion-related research in elderly populations (e.g. stroke, multiple sclerosis) for which FLAIR MRI and non-contrast CT are often the clinical imaging modalities of choice. To overcome the lack of atlases for these tasks and modalities, this paper presents high-resolution, age-specific FLAIR and non-contrast CT atlases of the elderly generated using clinical images.
Machine Learning and Bioinformatics Models to Identify Pathways that Mediate Influences of Welding Fumes on Cancer Progression
Authors: Rana Humayan Kabir , Akhtar Mst. Rashida , Islam M. Babul , Ahmed Mohammad Boshir , Lió Pietro , Huq Fazlul , Quinn Julian M. W. , Moni Mohammad Ali 
Published: February 2020

AbstractWelding generates and releases fumes that are hazardous to human health. Welding fumes (WFs) are a complex mix of metallic oxides, fluorides and silicates that can cause or exacerbate health problems in exposed individuals. In particular, WF inhalation over an extended period carries an increased risk of cancer, but how WFs may influence cancer behaviour or growth is unclear. To address this issue we employed a quantitative analytical framework to identify the gene expression effects of WFs that may affect the subsequent behaviour of the cancers. We examined datasets of transcript analyses made using microarray studies of WF-exposed tissues and of cancers, including datasets from colorectal cancer (CC), prostate cancer (PC), lung cancer (LC) and gastric cancer (GC). We constructed gene-disease association networks, identified signaling and ontological pathways, clustered protein-protein interaction network using multilayer network topology, and analyzed survival function of the significant genes using Cox proportional hazards (Cox PH) model and product-limit (PL) estimator. We observed that WF exposure causes altered expression of many genes (36, 13, 25 and 17 respectively) whose expression are also altered in CC, PC, LC and GC. Gene-disease association networks, signaling and ontological pathways, protein-protein interaction network, and survival functions of the significant genes suggest ways that WFs may influence the progression of CC, PC, LC and GC. This quantitative analytical framework has identified potentially novel mechanisms by which tissue WF exposure may lead to gene expression changes in tissue gene expression that affect cancer behaviour and, thus, cancer progression, growth or establishment.
The role of faceting and elongation on the magnetic anisotropy of magnetite Fe3O4 nanocrystals
Authors: Moreno Roberto , Poyser Samuel , Meilak Daniel , Meo Andrea , Jenkins Sarah , Lazarov Vlado K. , Vallejo-Fernandez Gonzalo , Majetich Sara , Evans Richard F. L. 
Published: February 2020

AbstractFe3O4 nanoparticles are one of the most promising candidates for biomedical applications such as magnetic hyperthermia and theranostics due to their bio-compatibility, structural stability and good magnetic properties. However, much is unknown about the nanoscale origins of the observed magnetic properties of particles due to the dominance of surface and finite size effects. Here we have developed an atomistic spin model of elongated magnetite nanocrystals to specifically address the role of faceting and elongation on the magnetic shape anisotropy. We find that for faceted particles simple analytical formulae overestimate the magnetic shape anisotropy and that the underlying cubic anisotropy makes a significant contribution to the energy barrier for moderately elongated particles. Our results enable a better estimation of the effective magnetic anisotropy of highly crystalline magnetite nanoparticles and is a step towards quantitative prediction of the heating effects of magnetic nanoparticles.
Early-life microbiota transplantation affects behavioural responses, serotonin and immune characteristics in chicken lines divergently selected on feather pecking
Authors: van der Eijk Jerine A. J. , Rodenburg T. Bas , de Vries Hugo , Kjaer Joergen B. , Smidt Hauke , Naguib Marc , Kemp Bas , Lammers Aart 
Published: February 2020

AbstractGut microbiota influences host behaviour and physiology, such as anxiety, stress, serotonergic and immune systems. These behavioural and physiological characteristics are related to feather pecking (FP), a damaging behaviour in chickens that reduces animal welfare and productivity. Moreover, high FP (HFP) and low FP (LFP) lines differed in microbiota composition. However, it is unknown whether microbiota can influence the development of FP. For the first time, we identified the effects of microbiota transplantation on FP, and behavioural and physiological characteristics related to FP. HFP and LFP chicks received sterile saline (control), HFP or LFP microbiota transplantation during the first two weeks post-hatch. Microbiota transplantation influenced behavioural responses of the HFP line during treatment and of the LFP line after treatment. In both lines, homologous microbiota transplantation (i.e., receiving microbiota from their line) resulted in more active behavioural responses. Furthermore, microbiota transplantation influenced immune characteristics (natural antibodies) in both lines and peripheral serotonin in the LFP line. However, limited effects on microbiota composition, stress response (corticosterone) and FP were noted. Thus, early-life microbiota transplantation had immediate and long-term effects on behavioural responses and long-term effects on immune characteristics and peripheral serotonin; however, the effects were dependent on host genotype. Since early-life microbiota transplantation influenced behavioural and physiological characteristics that are related to FP, it could thus influence the development of FP later in life.
Charge mobility calculation of organic semiconductors without use of experimental single-crystal data
Authors: Ishii Hiroyuki , Obata Shigeaki , Niitsu Naoyuki , Watanabe Shun , Goto Hitoshi , Hirose Kenji , Kobayashi Nobuhiko , Okamoto Toshihiro , Takeya Jun 
Published: February 2020

AbstractPrediction of material properties of newly designed molecules is a long-term goal in organic electronics. In general, it is a difficult problem, because the material properties are dominated by the unknown packing structure. We present a practical method to obtain charge transport properties of organic single crystals, without use of experimental single-crystal data. As a demonstration, we employ the promising molecule C10–DNBDT. We succeeded in quantitative evaluation of charge mobility of the single crystal using our quantum wave-packet dynamical simulation method. Here, the single-crystal data is computationally obtained by searching possible packing structures from structural formula of the molecule. We increase accuracy in identifying the actual crystal structure from suggested ones by using not only crystal energy but also similarity between calculated and experimental powder X-ray diffraction patterns. The proposed methodology can be a theoretical design technique for efficiently developing new high-performance organic semiconductors, since it can estimate the charge transport properties at early stage in the process of material development.
Analysis of TET2 and EZH2 gene functions in chromosome instability in acute myeloid leukemia
Authors: Wang Jingyi , He Na , Wang Ruiqing , Tian Tian , Han Fengjiao , Zhong Chaoqin , Zhang Chen , Hua Mingqiang , Ji Chunyan , Ma Daoxin 
Published: February 2020

AbstractTET2 and EZH2 play important roles in the epigenetic regulation in many cancers. However, their specific roles in acute myeloid leukemia (AML) pathogenesis remain unknown. Here, the expression, methylation or mutation of EZH2 and TET2 was determined and further correlated with the levels of the chromosome instability (CIN) genes MAD2 and CDC20. We down-regulated EZH2 and TET2 in AML cell lines and assessed the effect on CIN using fluorescence in situ hybridization (FISH). Our results showed that TET2, EZH2, MAD2 and CDC20 were aberrantly expressed in AML patients. The expression level of MAD2 or CDC20 was positively correlated with that of TET2 or EZH2. Hypermethylation of the TET2 gene down-regulated its transcription. Down-regulation of EZH2 or TET2 expression inhibited apoptosis, affected MAD2 and CDC20 expression, and promoted CIN in AML cells. Decitabine treatment restored TET2 methylation and EZH2 transcription and ameliorated CIN in AML. Therefore, TET2 and EZH2 play a tumor-inhibiting role in AML that affects CIN via MAD2 and CDC20.
Modelling of pancreatic cancer biology: transcriptomic signature for 3D PDX-derived organoids and primary cell line organoid development
Authors: Nelson Shannon R. , Zhang Chenxi , Roche Sandra , O’Neill Fiona , Swan Niall , Luo Yonglun , Larkin AnneMarie , Crown John , Walsh Naomi 
Published: February 2020

AbstractWith a five-year survival rate of 9%, pancreatic ductal adenocarcinoma (PDAC) is the deadliest of all cancers. The rapid mortality makes PDAC difficult to research, and inspires a resolve to create reliable, tractable cellular models for preclinical cancer research. Organoids are increasingly used to model PDAC as they maintain the differentiation status, molecular and genomic signatures of the original tumour. In this paper, we present novel methodologies and experimental approaches to develop PDAC organoids from PDX tumours, and the simultaneous development of matched primary cell lines. Moreover, we also present a method of recapitulating primary cell line cultures to organoids (CLOs). We highlight the usefulness of CLOs as PDAC organoid models, as they maintain similar transcriptomic signatures as their matched patient-derived organoids and patient derived xenografts (PDX)s. These models provide a manageable, expandable in vitro resource for downstream applications such as high throughput screening, functional genomics, and tumour microenvironment studies.
Chemically labeled toxins or bioactive peptides show a heterogeneous intracellular distribution and low spatial overlap with autofluorescence in bloom-forming cyanobacteria
Authors: Kurmayer Rainer , Entfellner Elisabeth , Weisse Thomas , Offterdinger Martin , Rentmeister Andrea , Deng Li 
Published: February 2020

AbstractHarmful algal blooms formed by colony-forming cyanobacteria deteriorate water resources by producing cyanotoxins, which frequently occur at high intracellular concentrations. We aimed to localize toxic microcystins (MCs) and bioactive anabaenopeptins (APs) at the subcellular level under noninvasive conditions. Since both metabolites are synthesized nonribosomally, the relaxed specificity of key enzymes catalyzing substrate activation allowed chemical labeling through a standard copper-catalyzed click chemistry reaction. The genera Planktothrix and Microcystis specifically incorporated unnatural amino acids such as N-propargyloxy-carbonyl-L-lysine or O-propargyl-L-tyrosine, resulting in modified AP or MC peptides carrying the incorporated alkyne moiety. The labeled cells were quantitatively differentiated from the unlabeled control cells. MCs and APs occurred intracellularly as distinct entities showing a cell-wide distribution but a lowered spatial overlap with natural autofluorescence. Using the immunofluorescence technique, colocalization with markers of individual organelles was utilized to relate the distribution of labeled MCs to cellular compartments, e.g., using RbcL and FtsZ (cytosol) and PsbA (thylakoids). The colocalization correlation coefficients calculated pairwise between organelles and autofluorescence were highly positive as opposed to the relatively low positive indices derived from labeled MCs. The lower correlation coefficients imply that only a portion of the labeled MC molecules were related spatially to the organelles in the cell.
Flat Wall Proximity Effect on Micro-Particle Sedimentation in Non-Newtonian Fluids
Authors: Farzam Rad Vahideh , Moradi Ali-Reza 
Published: February 2020

AbstractWe investigate the sedimentation of colloidal micro-spheres and red blood cells (RBCs) in non-Newtonian fluid - silicone oil with different viscosities. We use digital holographic microscopy (DHM) to obtain volumetric information of the sedimenting micro-objects. Especially, the numerical refocusing feature of DHM is used to extract the depth information of multiple particles moving inside the fluid. The effects of proximity to a flat wall and the non-Newtonian behavior on the sedimenting micro-spheres and RBCs are studied by trajectory analyzing and velocimetry. We observe that for lower viscosity values the proximity effect is more pronounced. The variation rate of the particle falling velocities versus their distance to the flat wall decreases by increasing the viscosity of the fluid. For RBCs, however, the decreasing of the velocity variations have a smoother trend. The experimental results verify the theoretical prediction that, similar to Newtonian case, a correction factor in Stokes’ law suffices for describing the wall effect.