bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cancer Associated Fibroblasts Mediate Cancer Progression and Remodel the Tumouroid Stroma
Authors: Pape Judith , Magdeldin Tarig , Stamati Katerina , Nyga Agata , Loizidou Marilena , Emberton Mark , Cheema Umber 
Published: December 2019

ObjectiveCancer associated fibroblasts (CAFs) are highly differentiated and heterogenous cancer stromal cells that promote tumour growth, angiogenesis and matrix remodelling.DesignWe utilised a novel 3D in vitro model of colorectal cancer, composed of a cancer mass and surrounding stromal compartment. We compared cancer invasion with an acellular stromal surround, a ‘healthy’ or normal cellular stroma and a cancerous stroma. For the cancerous stroma we incorporated six patient-derived CAF samples to study their differential effects on cancer growth, vascular network formation, and remodelling.ResultsCAFs enhanced the distance and surface area of the invasive cancer mass whilst inhibiting vascular-like network formation. These processes were driven by the upregulation of hepatocyte growth factor (HFG), metallopeptidase inhibitor 1 (TIMP1) and fibulin 5 (FBLN5).Remodelling appeared to occur through the process of disruption of complex networks and was associated with the up upregulation of vascular endothelial growth factor (VEGFA) and down-regulation in vascular endothelial cadherin (VE-Cadherin).ConclusionThese results support, within a biomimetic 3D, in vitro framework, the direct role of CAFs in promoting cancer invasion and that CAFs are also key components in driving vasculogenesis and angiogenesis.
Structural basis of RNA polymerase III transcription repression by Maf1
Authors: Vorländer Matthias K. , Baudin Florence , Moir Robyn D. , Wetzel René , Hagen Wim J. H. , Willis Ian M. , Müller Christoph W. 
Published: December 2019

ABSTRACTMaf1 is a highly conserved central regulator of transcription by RNA polymerase III (Pol III), and Maf1 activity influences a wide range of phenotypes from metabolic efficiency to lifespan. Here, we present a 3.3 Å cryo-EM structure of yeast Maf1 bound to Pol III, which establishes how Maf1 achieves transcription repression. In the Maf1-bound state, Pol III elements that are involved in transcription initiation are sequestered, and the active site is sealed off due to ordering of the mobile C34 winged helix 2 domain. Specifically, the Maf1 binding site overlaps with the binding site of the Pol III transcription factor TFIIIB and DNA in the pre-initiation complex, rationalizing that binding of Maf1 and TFIIIB to Pol III are mutually exclusive. We validate our structure using variants of Maf1 with impaired transcription-inhibition activity. These results reveal the exact mechanism of Pol III inhibition by Maf1, and rationalize previous biochemical data.
DeepSleep: Fast and Accurate Delineation of Sleep Arousals at Millisecond Resolution by Deep Learning
Authors: Li Hongyang , Guan Yuanfang 
Published: December 2019

AbstractSleep arousals are transient periods of wakefulness punctuated into sleep. Excessive sleep arousals are associated with many negative effects including daytime sleepiness and sleep disorders. High-quality annotation of polysomnographic recordings is crucial for the diagnosis of sleep arousal disorders. Currently, sleep arousals are mainly annotated by human experts through looking at millions of data points manually, which requires considerable time and effort. Here we present a deep learning approach, DeepSleep, which ranked first in the 2018 PhysioNet Challenge for automatically segmenting sleep arousal regions based on polysomnographic recordings. DeepSleep features accurate (area under receiver operating characteristic curve of 0.93), high-resolution (5-millisecond resolution), and fast (10 seconds per sleep record) delineation of sleep arousals.
Dissecting chronic myeloid leukaemia overlapping transcriptome with TIF-Seq2
Authors: Wang Jingwen , Li Bingnan , Marques Sueli , Steinmetz Lars M. , Wei Wu , Pelechano Vicent 
Published: December 2019

ABSTRACTEukaryotic transcriptomes are complex involving thousands of overlapping transcripts. The interleaved nature of the transcriptome limits our ability to identify regulatory regions and, in some cases, can lead to misinterpretation of gene expression. To improve the understanding of the overlapping transcriptome, we have developed an optimized method, TIF-Seq2, able to sequence simultaneously the 5’ and 3’ ends of individual RNA molecules at single-nucleotide resolution. We investigated the transcriptome of a well characterized human cell line (K562) and identify thousands of unannotated transcript isoforms. By focusing on transcripts which are challenging to be investigated with RNA-seq, we accurately defined boundaries of lowly expressed unannotated and read-though transcripts putatively encoding fusion genes. We validated our results by targeted long-read sequencing and standard RNA-Seq for chronic myeloid leukaemia patient samples. Taking the advantage of TIF-Seq2, we explore transcription regulation among the overlapping units and investigate their crosstalk. We show that most overlapping upstream transcripts use poly(A) sites within the first 2 kb of the downstream transcription unit. Our work shows that, by paring the 5’ and 3’ end of each RNA, TIF-Seq2 can improve the annotation of complex genomes, facilitates accurate assignment of promoters to genes and easily identify transcriptionally fused genes.Key pointsStudy of TSS-PAS co-occurrence allows dissecting complex overlapping transcription units.Partially overlapping transcription units in human commonly use PAS within the first 2Kb.TIF-Seq2 facilitates the identification of lowly expressed and transcriptionally fused genes.
Cascading Epigenomic Analysis for Identifying Disease Genes from the Regulatory Landscape of GWAS Variants
Authors: Ng Bernard , Casazza William , Kim Nam Hee , Wang Chendi , Farhadi Farnush , Tasaki Shinya , Bennett David A. , De Jager Philip L. , Gaiteri Christopher , Mostafavi Sara 
Published: December 2019

AbstractThe majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for linkingcisgenetic effects to epigenomic variation and another for linkingcisepigenomic variation to gene expression. Applying these models in cascade to GWAS summary statistics generates gene level statistics that reflect genetically-driven epigenomic effects. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes. CEWAS thus presents a novel means for exploring the regulatory landscape of GWAS variants in uncovering disease mechanisms.SummaryThe majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, combines the effect of genetic variants on DNA methylation as well as gene expression. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes.
SUSD4 Controls Activity-Dependent Degradation of AMPA Receptor GLUA2 and Synaptic Plasticity
Authors: González-Calvo I. , Iyer K. , Carquin M. , Khayachi A. , Giuliani F.A. , Vincent J. , Séveno M. , Sigoillot S.M. , Veleanu M. , Tahraoui S. , Albert M. , Vigy O. , Nadjar Y. , Dumoulin A. , Triller A. , Bessereau J.-L. , Rondi-Reig L. , Isope P. , Selimi F. 
Published: December 2019

SummaryAt excitatory synapses, the choice between recycling or degradation of glutamate AMPA receptors controls the direction of synaptic plasticity. In this context, how the degradation machinery is targeted to specific synaptic substrates in an activity-dependent manner is not understood. Here we show that SUSD4, a complement-related transmembrane protein, is a tether for HECT ubiquitin ligases of the NEDD4 subfamily, which promote the degradation of a large number of cellular substrates. SUSD4 is expressed by many neuronal populations starting at the time of synapse formation. Loss-of-function ofSusd4in the mouse prevents activity-dependent degradation of the GLUA2 AMPA receptor subunit and long-term depression at cerebellar synapses, and leads to impairment in motor coordination adaptation and learning. SUSD4 could thus act as an adaptor targeting NEDD4 ubiquitin ligases to AMPA receptors during long-term synaptic plasticity. These findings shed light on the potential contribution ofSUSD4mutations to the etiology of neurodevelopmental diseases.
Methylphenidate boosts choices of mental labor over leisure depending on baseline striatal dopamine
Authors: Hofmans Lieke , Papadopetraki Danae , van den Bosch Ruben , Määttä Jessica I. , Froböse Monja I. , Zandbelt Bram. B. , Westbrook Andrew , Verkes Robbert-Jan , Cools Roshan 
Published: December 2019

ABSTRACTThe cognitive enhancing effects of methylphenidate are well established, but the mechanisms remain unclear. We recently demonstrated that methylphenidate boosts cognitive motivation by enhancing the weight on the benefits of a cognitive task in a manner that depended on striatal dopamine. Here we considered the complementary hypothesis that methylphenidate might also act by changing the weight on the opportunity cost of a cognitive task. To this end, fifty healthy participants (25 women) completed a novel cognitive effort discounting task that was sensitive to opportunity cost, and required choices between task and leisure. They were tested on methylphenidate, sulpiride or placebo and also underwent an [18F]DOPA PET scan to quantify baseline dopamine synthesis capacity. Methylphenidate boosted choices of cognitive effort over leisure across the group, and this effect was greatest in participants with more striatal dopamine at baseline. The effects of sulpiride did not reach significance. This study strengthens the motivational account of methylphenidate’s effects on cognition and suggests that methylphenidate reduces the cost of mental labor by increasing striatal dopamine.
Topologically Dependent Abundance of Spontaneous DNA Damage in Single Human Cells
Authors: Zhu Qiangyuan , Niu Yichi , Gundry Michael , Sheng Kuanwei , Niu Muchun , Zong Chenghang 
Published: December 2019

AbstractIn the studies of single-cell genomics, the large endeavor has been focused on the detection of the permanent changes in the genome. On the other hand, spontaneous DNA damage frequently occurs and results in transient single-stranded changes to the genome until they are repaired. So far, successful profiling of these dynamic changes has not been demonstrated by single-cell whole-genome amplification methods. Here we reported a novel single-cell WGA method: Linearly Produced Semiamplicon based Split Amplification Reaction (LPSSAR), which allows, for the first time, the genome-wide detection of the DNA damage associated single nucleotide variants (dSNVs) in single human cells. The sequence-based detection of dSNVs allows the direct characterization of the major damage signature that occurred in human cells. In the analysis of the abundance of dSNVs along the genome, we observed two modules of dSNV abundance, instead of a homogeneous abundance of dSNVs. Interestingly, we found that the two modules are associated with the A/B topological compartments of the genome. This result suggests that the genome topology directly influences genome stability. Furthermore, with the detection of a large number of dSNVs in single cells, we showed that only under a stringent filtering condition, can we distinguish the de novo mutations from the dSNVs and achieve a reliable estimation of the total level of de novo mutations in a single cell.
Characterization of transcription activation domain of EcaICE1 and its interaction with EcaSIZ1 in Eucalyptus camaldulensis
Authors: Zhang Ziyang , Cheng Ling , Zhang Weihua , Hu Jianlin , Liu Yan , Lin Yuanzhen 
Published: December 2019

AbstractSUMOylation in plants is associated with biotic and abiotic stress responses, flowering and other aspects of development, and ICE1 protein SUMOylation by SUMO E3 ligase SIZ1 plays important roles in plant cold tolerance. Here, we reported the subcellular localization of EcaICE1 and its interaction with EcaSIZ1 in Eucalyptus camaldulensis. The genes EcaICE1 and EcaSIZ1 were isolated by homologous cloning. The subcellular localization analysis showed that EcaICE1 was located in nucleus. Bimolecular fluorescence complementation (BiFC) analysis revealed that EcaICE1 could interact with EcaSIZ1 in the nucleus of Nicotiana benthamiana leaves. Moreover, yeast two-hybrid assay confirmed that the amino acid region from position 84 to 126 in EcaICE1 was critical for the strong transactivation activity of EcaICE1 and that the C terminal region from position 361 to 557 in EcaICE1 was the key region for its interaction with EcaSIZ1 by using different truncated lengths of non-transactivation activity of EcaICE1 as the bait protein. Collectively, our results showed that EcaICE1 may have a SUMOylation pathway similar to Arabidopsis thaliana.
Functional magnetic resonance imaging of regional impaired cerebrovascular reactivity for migraineurs in the interictal state
Authors: Chan Suk-tak , Evans Karleyton C. , Song Tian-yue , Gupta Rajiv , Rosen Bruce R. , Singhal Aneesh , Kwong Kenneth K. 
Published: December 2019

ABSTRACTThere is still an unmet need of mapping the potential impairment of cerebrovascular reactivity (CVR) in episodic migraineurs in the interictal state. We mapped CVR of 6 episodic migraineurs and 5 headache-free controls (HC) with blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) under carbon dioxide (CO2) challenge of 30-second epochs with elevated end-tidal partial pressure of CO2 (PETCO2) by 4-8mmHg. Three migraineurs have migraine without aura (MOA) and the other three have migraine with aura (MA). We found that only MOA subjects showed a reduced or negative BOLD response to CO2 at the red nucleus. All 3 MOA subjects were characterized by bilateral posterior communicating artery hypoplasia (bPCAH) identified by MR angiography (MRA). MOA and HC subjects did not show any significant difference in BOLD responses to CO2 challenge in cortical and white matter while MA subjects showed poor positive association between BOLD responses and PETCO2 in large territories of the cortex and white matter tracts. The combined use of fMRI under CO2 challenge and MRA presented a unique approach to investigate the mechanisms of episodic migraine in the interictal state demonstrating for the first time negative CVR at the red nucleus of the midbrain in patients with MOA. CVR maps obtained from both the midbrain and cortical regions provided various signatures to explore the differences between migraineurs and HC and between MOA and MA.
Task rule and choice are reflected by layer-specific processing in rodent auditory cortical microcircuits
Authors: Zempeltzi Marina M. , Kisse Martin , Brunk Michael G. K. , Glemser Claudia , Aksit Sümeyra , Deane Katrina E. , Maurya Shivam , Schneider Lina , Ohl Frank W. , Deliano Matthias , Happel Max F. K. 
Published: December 2019

AbstractThe primary auditory cortex (A1) is an essential node in the integrative brain network that encodes the behavioral relevance of acoustic stimuli, predictions, and auditory-guided decision making. Previous studies have revealed task-related information being present at both the single-unit and population activity. However, its realization with respect to the cortical microcircuitry is less well understood. In this study, we used chronic, laminar current source density (CSD) analysis from the A1 of behaving Mongolian gerbils (Meriones unguiculatus) in order to characterize layer-specific, spatiotemporal synaptic population activity. Animals were trained to first detect and subsequently to discriminate two pure tone frequencies in consecutive training phases in a Go/NoGo shuttle-box task. We demonstrate that not only sensory but also task- and choice-related information is represented in the mesoscopic neuronal population code distributed across cortical layers. Based on a single-trial analysis using generalized linear-mixed effect models (GLMM), we found infragranular layers to be involved in auditory-guided action initiation during tone detection. Supragranular layers, particularly, are involved in the coding of choice options during tone discrimination. Further, we found that the overall columnar synaptic network activity represents the accuracy of the opted choice. Our study thereby suggests a multiplexed representation of stimulus features in dependence of the task, action selection, and the behavioral options of the animal in preparation of correct choices. The findings expand our understanding of how individual layers contribute to the integrative circuit of the A1 in order to code task-relevant information and guide sensory-based decision making.
Mass-spectrometry based proteomics reveals mitochondrial supercomplexome plasticity
Authors: Gonzalez-Franquesa Alba , Stocks Ben , Chubanava Sabina , Hattel Helle Baltzer , Moreno-Justicia Roger , Treebak Jonas T. , Zierath Juleen R. , Deshmukh Atul S. 
Published: December 2019

SummaryMitochondrial respiratory complex subunits assemble in supercomplexes. Studies of supercomplexes have typically relied upon antibody-based protein quantification, often limited to the analysis of a single subunit per respiratory complex. To provide a deeper insight into mitochondrial and supercomplex plasticity, we combined Blue Native Polyacrylamide Gel Electrophoresis (BN-PAGE) and mass spectrometry to determine the supercomplexome of skeletal muscle from sedentary and exercise-trained mice. We quantified 422 mitochondrial proteins within ten supercomplex bands, in which we showed the debated presence of complex II and V. Upon exercise-induced mitochondrial biogenesis, non-stoichiometric changes in subunits and incorporation into supercomplexes was apparent. We uncovered the dynamics of supercomplex-related assembly proteins and mtDNA-encoded subunits within supercomplexes, as well as the complexes of ubiquinone biosynthesis enzymes and Lactb, a mitochondrial-localized protein implicated in obesity. Our approach can be applied to broad biological systems. In this instance, comprehensively analyzing respiratory supercomplexes illuminates previously undetectable complexity in mitochondrial plasticity.HighlightsComprehensive quantification of respiratory subunits within supercomplexesComplex II and V assemble within supercomplexesMitochondrial-encoded subunits display elevated upregulation upon exercise trainingExercise increases ubiquinone biosynthesis enzyme complexes
Lateral mechanical impedance rather than frontal, promotes cortical expansion of roots
Authors: Feng Xuanjun , Xiong Jing , Hu Yue , Pan Liteng , Liao Zhengqiao , Zhang Xuemei , Guo Wei , Wu Fengkai , Xu Jie , Hu Erliang , Lan Hai , Lu Yanli 
Published: December 2019

AbstractIt has long been considered that mechanical impedance on root will restrict root elongation and consequently promote radial growth. However, we did observe radial expansion but not elongation restriction in maize seedlings after short growth in sands. Mechanical impedance of soil can be classified into frontal- and lateral-type based on the interaction site of root. Therefore, we suspected that radial expansion might be mainly stimulated by lateral rather than frontal impedance. To verify our speculation, frontal and lateral impedance was provided separately. Small plastic caps were used to provide unique frontal impedance on root tip and cylindrical plastic containers were used to provide lateral impedance. Plastic caps could reduce root length remarkably. However, the radial expansion of plastic-cap-fitted roots was significantly inferior to that of the sand-cultured roots. Microstructural analysis revealed that sand-condition thickened root largely dependents on cortical expansion, whereas plastic cap did it mainly by thickening stele. In cylindrical plastic containers, mechanical impedance came only from the lateral direction and promoted the expansion of cortex just as sand-condition. Thus, we proposed that the expansion of the cortex and the consequent radial growth is mainly due to lateral impedance when growing in sands.
Evaluation of deacetylase inhibition in metaplastic breast carcinoma using multiple derivations of preclinical models of a new patient-derived tumor
Authors: Chang Tiffany C. , Matossian Margarite D. , Elliott Steven , Burks Hope E. , Sabol Rachel A. , Ucar Deniz A. , Wathieu Henri , Zabaleta Jovanny , De Valle Luis , Gill Sukhmani , Martin Elizabeth , Riker Adam I. , Miele Lucio , Bunnell Bruce A. , Burow Matthew E. , Collins-Burow Bridgette M. 
Published: December 2019

AbstractMetaplastic breast carcinoma (MBC) is a clinically aggressive and rare subtype of breast cancer, with similar features to basal-like breast cancers. Due rapid growth rates and characteristic heterogeneity, MBC is often unresponsive to standard chemotherapies; and novel targeted therapeutic discovery is urgently needed. Histone deacetylase inhibitors (DACi) suppress tumor growth and metastasis through regulation of the epithelial-to-mesenchymal transition axis in various cancers, including basal-like breast cancers.We utilized a new MBC patient-derived xenograft (PDX) to examine the effect of DACi therapy on MBC. Cell morphology, cell cycle-associated gene expressions, transwell migration, and metastasis were evaluated in patient-derived cells and tumors after treatment with romidepsin and panobinostat. Derivations of our PDX model, including cells, spheres, organoids, explants, andin vivoimplanted tumors were treated. Finally, we tested the effects of combining DACi with approved chemotherapeutics on relative cell biomass.DACi significantly suppressed the total number of lung metastasisin vivousing our PDX model, suggesting a role for DACi in preventing circulating tumor cells from seeding distal tissue sites. These data were supported by our findings that DACi reduced cell migration, populations, and expression of mesenchymal-associated genes. While DACi treatment did affect cell cycle-regulating genesin vitro,tumor growth was not affected compared to controls. Importantly, gene expression results varied depending on the cellular or tumor system used, emphasizing the importance of using multiple derivations of cancer models in preclinical therapeutic discovery research. Furthermore, DACi sensitized and produced a synergistic effect with approved oncology therapeutics on inherently resistant MBC.This study introduced a role for DACi in suppressing the migratory and mesenchymal phenotype of MBC cells through regulation of the epithelial-mesenchymal transition axis and suppression of the CTC population. Preliminary evidence that DACi treatment in combination with MEK1/2 inhibitors exerts a synergistic effect on MBC cells was also demonstrated.