bluuebunny/crossref_metadata_2025_split huggingface dataset:
PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia
Authors: Smith Brittany M. , VanCampen Jake , Kong Garth L. , Yashar William , Tsang Yiu H. , Horton Wesley , Coleman Daniel J. , Estabrook Joseph , Lusardi Theresa A. , Mills Gordon B. , Druker Brian J. , Maxson Julia E. , Braun Theodore P. 
Published: August 2021

AbstractActivating mutations in the KIT tyrosine receptor kinase confer an adverse prognosis for patients with acute myeloid leukemia (AML). Outside of bone marrow transplantation, treatment options are limited. Here we demonstrate combined KIT and LSD1 inhibition produces synergistic cell death against KIT mutant AML cells. This combination suppresses MYC expression to drive cell cycle exit and apoptosis. This decreased MYC expression results from a loss of PU.1 binding at downstream MYC enhancers. The drug combination also inactivates PI3K/AKT/GSK3a/b signaling to decrease MYC protein abundance. KIT-mutant AML cells rapidly adapt to KIT inhibitor monotherapy by restoring PI3K/AKT activity, but cannot when treated with combined KIT and LSD1 inhibitor. In addition, we validate MYC suppression as a mechanism of synergy in KIT-mutant AML patient samples. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.Statement of significanceEffective treatment options for AML are limited. We describe the synergistic response to combined KIT and LSD1 inhibition in KIT-mutant AML and identify key biomarkers of drug response. The specificity and efficacy of this combination in cell lines and patient samples provides rationale for investigation in early phase clinical trials.
Defining dysfunction due to loss of MECP2 in Rett Patient Brain
Authors: Korsakova E , Morales A , McDaniel T , Lund A , Cooper B , Ma F , Allison TF , Plath K , Graham NA , Bhaduri A , Lowry WE 
Published: August 2021

AbstractRett Syndrome is characterized by a postnatal loss of neurophysiological function and regression of childhood development. Because the syndrome is X-linked and males with MECP2 mutations generally do not survive birth, the study of this syndrome has been complicated by the fact that in female brain, a portion of neurons express wild type MECP2, and another portion express a non-functional allele of MECP2. Therefore, bulk-RNA-sequencing of Rett brain is confounded by the presence of chimerism of neurons for functional MECP2 in neurons. We developed an approach that allows for single-nuclei transcriptional profiling of individual neurons and a direct comparison between neurons that express functional MECP2 with those that express the disease-causing allele. We found that mutant neurons from Rett brain show patterns of aberrant expression of synaptic and metabolic genes, both of which can be detected in in vitro models of Rett Syndrome. We used these resources to identify a role for POU2F1/OCT1 transcription factor in mediating the response to stress due to loss of MECP2, highlighting a potential key molecular regulator of stress in Rett neurons. Together, our new sorting approach enables us to highlight defective molecular and metabolic pathways in Rett brain neurons and suggests that in vitro models could serve as valuable tools to further study this syndrome and potentially for development of novel therapeutics.
Brominated Lipid Probes Expose Structural Asymmetries in Constricted Membranes
Authors: Moss Frank R. , Lincoff James , Tucker Maxwell , Mohammed Arshad , Grabe Michael , Frost Adam 
Published: August 2021

AbstractLipids in biological membranes are thought to be functionally organized, but few experimental tools can probe nanoscale membrane structure. Using brominated lipids as contrast probes for cryo-EM and a model ESCRT-III membrane remodeling system, we observed leaflet-level and protein-localized lipid structural patterns within highly constricted and thinned membrane nanotubes. These nanotubes differed markedly from protein-free, flat bilayers in leaflet thickness, lipid diffusion rates, and lipid compositional and conformational asymmetries. Simulations and cryo-EM imaging of brominated SDPC showed how a pair of phenylalanine residues scored the outer leaflet with a helical hydrophobic defect where polyunsaturated docosahexaenoyl (DHA) tails accumulated at the bilayer surface. Combining cryo-EM of halogenated lipids with molecular dynamics thus enables new characterizations of the composition and structure of membranes on molecular length scales.One-Sentence SummaryCryo-EM imaging of halogenated lipids and MD simulations provide molecular-scale insight into constricted bilayer structure.
Defective ORF8 dimerization in delta variant of SARS CoV2 leads to abrogation of ORF8 MHC-I interaction and overcome suppression of adaptive immune response
Authors: Chaudhari Armi M , Singh Indra , Joshi Madhvi , Patel Amrutlal , Joshi Chaitanya 
Published: August 2021

AbstractIn India, the breakthrough infections during second wave of COVID-19 pandemic was due to SARS-COV-2 delta variant (B.1.617.2). It was reported that majority of the infections were caused by the delta variant and only 9.8% percent cases required hospitalization whereas, only 0.4% fatality was observed. Sudden dropdown in COVID-19 infections was observed within a short timeframe, suggesting better host adaptation with evolved delta variant. Down regulation of host immune response against SARS-CoV-2 by ORF8 induced MHC-I degradation has been reported earlier. The Delta variant carried mutations (deletion) at Asp119 and Phe120 amino acids which are critical for ORF8 dimerization. The deletions of amino acids Asp119 and Phe120 in ORF8 of delta variant results in structural instability of ORF8 dimer caused by disruption of hydrogen bonding and salt bridges as revealed by structural analysis and MD simulation studies of ORF8 dimer. Further, flexible docking of wild type and mutant ORF8 dimer revealed reduced interaction of mutant ORF8 dimer with MHC-I as compared to wild type ORF8 dimer with MHC-1, thus implicating its possible role in MHC-I expression and host immune response against SARS-CoV-2. We thus propose that mutant ORF8 may not hindering the MHC-I expression thereby resulting in better immune response against SARS-CoV-2 delta variant, which partly explains the sudden drop of SARS-CoV-2 infection rate in the second wave of SARS-CoV-2 predominated by delta variant in IndiaGraphical Abstract
Nuclear RNA binding regulates TDP-43 nuclear localization and passive nuclear export
Authors: Duan Lauren , Zaepfel Benjamin L. , Aksenova Vasilisa , Dasso Mary , Rothstein Jeffrey D. , Kalab Petr , Hayes Lindsey R. 
Published: August 2021

AbstractNuclear clearance of the DNA/RNA-binding protein TDP-43 is a pathologic hallmark of amyotrophic lateral sclerosis and frontotemporal dementia that remains unexplained. Moreover, our current understanding of TDP-43 nucleocytoplasmic shuttling does not fully explain the predominantly nuclear localization of TDP-43 in healthy cells. Here, we used permeabilized and live-cell models to investigate TDP-43 nuclear export and the role of RNA in TDP-43 localization. We show that TDP-43 nuclear efflux occurs in low-ATP conditions and independent of active mRNA export, consistent with export by passive diffusion through nuclear pore channels. TDP-43 nuclear residence requires binding to GU-rich nuclear intronic pre-mRNAs, based on the induction of TDP-43 nuclear efflux by RNase and GU-rich oligomers and TDP-43 nuclear retention conferred by pre-mRNA splicing inhibitors. Mutation of TDP-43 RNA recognition motifs disrupts TDP-43 nuclear accumulation and abolishes transcriptional blockade-induced TDP-43 nuclear efflux, demonstrating strict dependence of TDP-43 nuclear localization on RNA binding. Thus, the nuclear abundance of GU-rich intronic pre-mRNAs, as dictated by the balance of transcription and pre-mRNA processing, regulates TDP-43 nuclear sequestration and availability for passive nuclear export.
Presence of multiple parasitoids decreases host survival under warming, but parasitoid performance also decreases
Authors: Thierry Mélanie , Pardikes Nicholas A. , Rosenbaum Benjamin , Ximénez-Embún Miguel G. , Hrček Jan 
Published: August 2021

AbstractCurrent global changes are reshaping ecological communities and modifying environmental conditions. We need to recognize the combined impact of these biotic and abiotic factors on species interactions, community dynamics, and ecosystem functioning. Specifically, the strength of predator-prey interactions often depends on the presence of other natural enemies: it weakens with competition and interference or strengthens with facilitation. Such effects of multiple predators on prey are likely to be affected by changes in the abiotic environment, altering top-down control, a key structuring force in natural and agricultural ecosystems. Here, we investigated how warming alters the effects of multiple predators on prey suppression using a dynamic model coupled with empirical laboratory experiments withDrosophila-parasitoid communities. While multiple parasitoids enhanced top-down control under warming, parasitoid performance generally declined when another parasitoid was present due to competitive interactions. This could reduce top-down control over multiple generations. Our study highlights the importance of accounting for interactive effects between abiotic and biotic factors to better predict community dynamics in a rapidly changing world and thus better preserve ecosystem functioning and services such as biological control.
MEOX2 homeobox gene promotes growth of malignant gliomas
Authors: Schönrock Anna , Heinzelmann Elisa , Steffl Bianca , Narayanan Ashwin , Krunic Damir , Bähr Marion , Park Jong-Whi , Schmidt Claudia , Özduman Koray , Pamir M. Necmettin , Wick Wolfgang , Bestvater Felix , Weichenhan Dieter , Plass Christoph , Taranda Julian , Mall Moritz , Turcan Şevin 
Published: August 2021

AbstractGlioblastoma (GBM) is an aggressive tumor that frequently exhibits gain of chromosome 7, loss of chromosome 10 and aberrantly activated receptor tyrosine kinase signaling pathways. Here, we identify mesenchyme homeobox 2 (MEOX2) on chromosome 7 with increased expression in GBM as a salient oncogenic transcription factor. Specifically, we show that MEOX2 overexpression leads to increased ERK phosphorylation, and we identify a phosphorylation site on MEOX2 that regulates its transcriptional activity by altering its subnuclear localization. We show that MEOX2 overexpression can lead to increased growth in GBM implantation models and cooperates with loss of p53 and PTEN in cerebral organoid models of human malignant gliomas to induce cell proliferation. Furthermore, using high-throughput genomics, we identify transcriptional target genes of MEOX2 in patient-derived GBM tumorsphere models and a fresh frozen GBM tumor. These analyses show that MEOX2 activates several oncogenic pathways involved in MAPK signaling and extracellular matrix organization. Furthermore, MEOX2 binds to oncogenic ETS factors and known glioma oncogenes such as FABP7. In total, we reveal a novel role for MEOX2 in GBM initiation and progression and demonstrate that MEOX2 can enhance ERK signaling through a feed-forward mechanism.Significance StatementGlioblastoma (GBM) harbors gain of chromosome 7 as an early driver event. In this study, we show that mesenchyme homeobox 2 (MEOX2), an aberrantly upregulated transcription factor on chromosome 7, is an oncogene in human glioblastoma. In contrast to GBM, MEOX2 expression is very low in normal brain. We show that MEOX2 cooperates with p53 and PTEN loss to promote tumor initiation in cerebral organoid models. In addition, we identify direct and indirect molecular targets of MEOX2 and demonstrate its role in activating the ERK signaling cascade. These findings identify a novel oncogene in GBM and highlight the transcriptional networks hijacked by these tumors to activate signaling pathways central to GBM biology.
Comparing surrogates to evaluate precisely timed higher-order spike correlations
Authors: Stella Alessandra , Bouss Peter , Palm Günther , Grün Sonja 
Published: August 2021

AbstractThe generation of surrogate data, i.e., the modification of original data to destroy a certain feature, is used for the implementation of a null-hypothesis whenever an analytical approach is not feasible. Thus, surrogate data generation has been extensively used to assess the significance of spike correlations in parallel spike trains. In this context, one of the main challenges is to properly construct the desired null-hypothesis distribution and to avoid a bias in the null-hypothesis by altering the spike train statistics.A classical surrogate technique is uniform dithering (UD), which displaces spikes locally and uniformly. In this study, we compare UD against five surrogate techniques (two newly introduced) in the context of the detection of significant spatio-temporal spike patterns. We evaluate the surrogates for their performance, first on spike trains based on point process models with constant firing rate, and second on modeled non-stationary artificial data serving as ground truth to assess the pattern detection in a more complex and realistic setting. We determine which statistical features of the original spike trains are modified and to which extent. Moreover, we find that UD fails as an appropriate surrogate because it leads to a loss of spikes in the context of binning and clipping, and thus to a large number of false-positive patterns. The other surrogates achieve a better performance in detecting precisely timed higher-order correlations. Based on these insights, we analyze experimental data from pre-/motor cortex of macaque monkeys during a reaching-and-grasping task for spatio-temporal spike patterns.Significance statementTemporal jittering or dithering of single spikes or subsections of spike trains is a common method of generating surrogate data for the statistical analysis of temporal spike correlations. We discovered a serious problem with the classical and widely used method of uniform dithering that can lead to an overestimation of significance, i.e., to false positives in the statistical evaluation of spatio-temporal spike patterns. Therefore we consider 5 other dithering methods, compare and evaluate their statistical properties. Finally, we apply a much better method (trial shifting) to the analysis of experimental multiple-unit recordings and find several highly significant patterns that also reflect different experimental situations.
Differential Analysis of RNA Structure Probing Experiments at Nucleotide Resolution: Uncovering Regulatory Functions of RNA Structure
Authors: Yu Bo , Li Pan , Zhang Qiangfeng Cliff , Hou Lin 
Published: August 2021

AbstractRNAs perform their function by forming specific structures, which can change across cellular conditions. Structure probing experiments combined with next generation sequencing technology have enabled transcriptome-wide analysis of RNA secondary structure in various cellular conditions. Differential analysis of structure probing data in different conditions can reveal the RNA structurally variable regions (SVRs), which is important for understanding RNA functions. Here, we propose DiffScan, a computational framework for normalization and differential analysis of structure probing data in high resolution. DiffScan preprocesses structure probing datasets to remove systematic bias, and then scans the transcripts to identify SVRs and adaptively determines their lengths and locations. The proposed approach is compatible with most structure probing platforms (e.g., icSHAPE, DMS-seq). When evaluated with simulated and benchmark datasets, DiffScan identifies structurally variable regions at nucleotide resolution, with substantial improvement in accuracy compared with existing SVR detection methods. Moreover, the improvement is robust when tested in multiple structure probing platforms. Application of DiffScan in a dataset of multi-subcellular RNA structurome identified multiple regions that form different structures in nucleus and cytoplasm, linking RNA structural variation to regulation of mRNAs encoding mitochondria-associated proteins. This work provides an effective tool for differential analysis of RNA secondary structure, reinforcing the power of structure probing experiments in deciphering the dynamic RNA structurome.
Electrochemical Detection of Adrenaline and Hydrogen Peroxide on Carbon Nanotube Electrodes
Authors: Khot Gaurang , Kaboli Mohsen , Celikel Tansu , Shirtcliffe Neil 
Published: August 2021

AbstractAdrenaline and hydrogen peroxide have neuromodulatory functions in the brain. Considerable interest exists in developing electrochemical sensors that can detect their levels in vivo due to their important biochemical roles. Challenges associated with electrochemical detection of hydrogen peroxide and adrenaline are that the oxidation of these molecules usually requires highly oxidising potentials (beyond 1.4 V vs Ag/AgCl) where electrode damage and biofouling are likely and the signals of adrenaline, hydrogen peroide and adenosine overlap. To address these issues we fabricated pyrolysed carbon electrodes coated with oxidised carbon nanotubes (CNTs). Using these electrodes for fast-scan cyclic voltammetric (FSCV) measurements showed that the electrode offers reduced overpotentials compared with graphite and improved resistance to biofouling. The Adrenaline peak is reached at 0.75(±0.1) V and reduced back at -0.2(±0.1) V while hydrogen peroxide is detected at 0.85(±0.1) V on this electrode. The electrodes are highly sensitive with a sensitivity of 16nA µM-1 for Adrenaline and 11nA µM-1 for hydrogen peroxide on an 80 µm2 electrode. They are also suitable to distinguish between adrenaline, hydrogen peroxide and adenosine thus these probes can be used for multimodal detection of analytes.
Host ecology regulates interspecies recombination in bacteria of the genus Campylobacter
Authors: Mourkas Evangelos , Yahara Koji , Bayliss Sion C. , Calland Jessica K. , Johansson Håkan , Mageiros Leonardos , Muñoz-Ramirez Zilia Y. , Futcher Grant , Méric Guillaume , Hitchings Matthew D. , Sandoval-Motta Santiago , Torres Javier , Jolley Keith A. , Maiden Martin C. J. , Ellström Patrik , Waldenström Jonas , Pascoe Ben , Sheppard Samuel K. 
Published: August 2021

AbstractHorizontal gene transfer (HGT) can allow traits that have evolved in one bacterial species to transfer to another. This has potential to rapidly promote new adaptive trajectories such as zoonotic transfer or antimicrobial resistance. However, for this to occur requires gaps to align in barriers to recombination within a given time frame. Chief among these barriers is the physical separation of species with distinct ecologies in separate niches. Within the genus Campylobacter there are species with divergent ecologies, from rarely isolated single host specialists to multi-host generalist species that are among the most common global causes of human bacterial gastroenteritis. Here, by characterising these contrasting ecologies, we can quantify HGT among sympatric and allopatric species in natural populations. Analysing recipient and donor population ancestry among genomes from 30 Campylobacter species we show that cohabitation in the same host can lead to a 6-fold increase in HGT between species. This accounts for up to 30% of all SNPs within a given species and identifies highly recombinogenic genes with functions including host adaptation and antimicrobial resistance. As described in some animal and plant species, ecological factors are a major evolutionary force for speciation in bacteria and changes to the host landscape can promote partial convergence of distinct species through HGT.
Regulation of ammonium acquisition and use in Oryza longistaminata ramets under nitrogen source heterogeneity
Authors: Kawai Misato , Tabata Ryo , Ohashi Miwa , Honda Haruno , Kamiya Takehiro , Kojima Mikiko , Takebayashi Yumiko , Oishi Shunsuke , Okamoto Satoru , Hachiya Takushi , Sakakibara Hitoshi 
Published: August 2021

AbstractOryza longistaminata, a wild rice, vegetatively reproduces and forms a networked clonal colony consisting of ramets connected by rhizomes. Although water, nutrients, and other molecules can be transferred between ramets via the rhizomes, inter-ramet communication in response to spatially heterogeneous nitrogen availability is not well understood. We studied the response of ramet pairs to heterogeneous nitrogen availability by using a split hydroponic system that allowed each ramet root to be exposed to different conditions. Ammonium uptake was compensatively enhanced in the sufficient-side root when roots of the ramet pairs were exposed to ammonium-sufficient and deficient conditions. Comparative transcriptome analysis revealed that a gene regulatory network for effective ammonium assimilation and amino acid biosynthesis was activated in the sufficient-side roots. Allocation of absorbed nitrogen from the nitrogen-sufficient to the deficient ramets was rather limited. Nitrogen was preferentially used for newly growing axillary buds on the sufficient-side ramets. Biosynthesis of trans-zeatin, a cytokinin, was up-regulated in response to the nitrogen supply, but trans-zeatin appears not to target the compensatory regulation. Our results also implied that the O. longistaminata ortholog of OsCEP1 plays a role as a nitrogen-deficient signal in inter-ramet communication, providing compensatory up-regulation of nitrogen assimilatory genes. These results provide insights into the molecular basis for efficient growth strategies of asexually proliferating plants growing in areas where the distribution of ammonium ions is spatially heterogeneous.One sentence summaryOryza longistaminata, a rhizomatous wild rice, systemically regulates ammonium acquisition and use in response to spatially heterogeneous nitrogen availability via inter-ramet communication.
CULTURE AND MAINTENANCE OF URINE-DERIVED, 3-DIMENSIONAL CANINE TRANSITIONAL CELL CARCINOMA ORGANOIDS
Authors: Thenuwara Savantha , Schneider Ben , Mosichuk Allison , Gabriel Vojtech , Zdyrski Christopher , Dao Kimberly , Iennarella-Servantez Chelsea , Colosimo Madeline , Sahoo Dipak , Bourgois-Mochel Agnes , Palerme Jean-Sebastien , Musser Margaret , Johannes Chad , Allenspach Karin , Mochel Jonathan P. 
Published: August 2021

ABSTRACTBladder cancer is the ninth most common malignancy in the world. Transitional cell carcinoma (TCC), also referred to as urothelial carcinoma (UC) is the most common form of bladder cancer, occurring in 90% of cases. In this study, we explore urine-derived, 3-dimensional, canine TCC organoids as a possible model to study bladder TCC ex vivo. After establishing the cell lines, we subjected the 3D cells to RNA in situ hybridization (RNA-ISH) and cell viability assays. Overall, 3D cell culture from urine samples of TCC diagnosed canines expressed RNA biomarkers in a similar manner to parent tumors via RNA-ISH and showed more sensitivity to cisplatin treatment when compared to 2D human TCC cells. With further experimentation, canine TCC organoids could become an ideal model to study TCC ex vivo.