bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventing Jacob-induced transcriptional inactivation of CREB protects synapses from β-amyloid in Alzheimer’s Disease
Authors: Grochowska Katarzyna M. , Gomes Guilherme M. , Raman Rajeev , Kaushik Rahul , Sosulina Liudmila , Kaneko Hiroshi , Oelschlegel Anja M. , Yuanxiang PingAn , Reyes-Resina Irene , Bayraktar Gonca , Samer Sebastian , Spilker Christina , Woo Marcel S. , Morawski Markus , Goldschmidt Jürgen , Friese Manuel A. , Rossner Steffen , Navarro Brugal Gemma , Remy Stefan , Reissner Carsten , Karpova Anna , Kreutz Michael R. 
Published: January 2020

AbstractSynaptic dysfunction caused by soluble β-Amyloid (Aβ) is a hallmark of the early stage of Alzheimer’s disease (AD) and is tightly linked to cognitive decline. Aβ induces by yet unknown mechanisms disruption of transcriptional activity of cAMP– responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Aβ elicits cytonuclear trafficking of Jacob, a protein serves as a mobile signaling hub that docks a signalosome to CREB, which induces transcriptional inactivation and subsequent synapse impairment and eventually loss in AD. The small chemical compound Nitarsone selectively hinders assembly of this signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest that targeting Jacob induced CREB shutoff is a therapeutic avenue against early synaptic dysfunction in AD.
CD4+follicular helper-like T cells are key players in anti-tumor immunity
Authors: Singh D , Ganesan AP , Panwar B , Eschweiler S , Hanley CJ , Madrigal A , Ramírez-Suástegui C , Wang A , Clarke J , Wood O , Garrido-Martin EM , Chee SJ , Seumois G , Belanger S , Alzetani A , Woo E , Friedmann PS , Crotty S , Thomas GJ , Sanchez-Elsner T , Ay F , Ottensmeier CH , Vijayanand P 
Published: January 2020

ABSTRACTTo determine the nature of CD4+T cells that provide ‘help’ for generating robust anti-tumor CD8+cytotoxic T cell (CTL) responses, we profiled the transcriptomes of patient-matched CD4+and CD8+T cells present in the tumor micro-environment (TME) and analyzed them jointly using integrated weighted gene correlation network analysis. We found the follicular helper T cell (TFH) program in CD4+T cells was strongly associated with proliferation and tissue-residency in CD8+CTLs. Single-cell analysis demonstrated the presence of TFH-like cells and features linked to cytotoxic function and their provision of CD8+T cell ‘help’. Tumor-infiltrating TFH-like cells expressed PD-1 and were enriched in tumors following checkpoint blockade, suggesting that they may respond to anti-PD-1 therapy. Adoptive transfer or induction of TFHcells in mouse models resulted in augmented CD8+CTL responses and impairment of tumor growth, indicating an important role of TFH-like CD4+T cells in anti-tumor immunity.
4DNvestigator: Time Series Genomic Data Analysis Toolbox
Authors: Lindsly Stephen , Chen Can , Liu Sijia , Ronquist Scott , Dilworth Samuel , Perlman Michael , Rajapakse Indika 
Published: January 2020

AbstractData on genome organization and output over time, or the 4D Nucleome (4DN), require synthesis for meaningful interpretation. Development of tools for the efficient integration of these data is needed, especially for the time dimension. We present the “4DNvestigator”, a user-friendly network based toolbox for the analysis of time series genome-wide genome structure (Hi-C) and gene expression (RNA-seq) data. Additionally, we provide methods to quantify network entropy, tensor entropy, and statistically significant changes in time series Hi-C data at different genomic scales.Availabilityhttps://github.com/lindsly/4DNvestigator
Taxonomic classification method for metagenomics based on core protein families with Core-Kaiju
Authors: Tovo Anna , Menzel Peter , Krogh Anders , Lagomarsino Marco Cosentino , Suweis Samir 
Published: January 2020

ABSTRACTCharacterizing species diversity and composition of bacteria hosted by biota is revolutionizing our understanding of the role of symbiotic interactions in ecosystems. However, determining microbiomes diversity implies the classification of taxa composition within the sampled community, which is often done via the assignment of individual reads to taxa by comparison to reference databases. Although computational methods aimed at identifying the microbe(s) taxa are available, it is well known that inferences using different methods can vary widely depending on various biases. In this study, we first apply and compare different bioinformatics methods based on 16S ribosomal RNA gene and whole genome shotgun sequencing for taxonomic classification to three small mock communities of bacteria, of which the compositions are known. We show that none of these methods can infer both the true number of taxa and their abundances. We thus propose a novel approach, named Core-Kaiju, which combines the power of shotgun metagenomics data with a more focused marker gene classification method similar to 16S, but based on emergent statistics of core protein domain families. We thus test the proposed method on the three small mock communities and also on medium- and highly complex mock community datasets taken from the Critical Assessment of Metagenome Interpretation challenge. We show that Core-Kaiju reliably predicts both number of taxa and abundance of the analysed mock bacterial communities. Finally we apply our method on human gut samples, showing how Core-Kaiju may give more accurate ecological characterization and fresh view on real microbiomes.
Intergenic RNA mainly derives from nascent transcripts of known genes
Authors: Federico Agostini , Julian Zagalak , Jan Attig , Jernej Ule , Luscombe Nicholas M. 
Published: January 2020

AbstractBackgroundEukaryotic genomes undergo pervasive transcription, leading to the production of many types of stable and unstable RNAs. Transcription is not restricted to regions with annotated gene features but includes almost any genomic context. Currently, the source and function of most RNAs originating from intergenic regions in the human genome remains unclear.ResultsWe hypothesised that many intergenic RNA can be ascribed to the presence of as-yet unannotated genes or the ‘fuzzy’ transcription of known genes that extends beyond the annotated boundaries. To elucidate the contributions of these two sources, we assembled a dataset of >2.5 billion publicly available RNA-seq reads across 5 human cell lines and multiple cellular compartments to annotate transcriptional units in the human genome. About 80% of transcripts from unannotated intergenic regions can be attributed to the fuzzy transcription of existing genes; the remaining transcripts originate mainly from putative long non-coding RNA loci that are rarely spliced. We validated the transcriptional activity of these intergenic RNA using independent measurements, including transcriptional start sites, chromatin signatures, and genomic occupancies of RNA polymerase II in various phosphorylation states. We also analysed the nuclear localisation and sensitivities of intergenic transcripts to nucleases to illustrate that they tend to be rapidly degraded either ‘on-chromatin’ by XRN2 or ‘off-chromatin’ by the exosome.ConclusionsWe provide a curated atlas of intergenic RNAs that distinguishes between alternative processing of well annotated genes from independent transcriptional units based on the combined analysis of chromatin signatures, nuclear RNA localisation and degradation pathways.
HDAC inhibitor Givinostat targets DNA-binding of human CGGBP1
Authors: Patel Manthan , Patel Divyesh , Datta Subhamoy , Singh Umashankar 
Published: January 2020

ABSTRACTThe antineoplastic agent Givinostat inhibits histone deacetylases. We present here our finding that the DNA-binding of human CGGBP1 is also inhibited by Givinostat. CGGBP1, a DNA-binding protein, is required for cancer cell proliferation. In our quest to exploit the potential anti-proliferative effects of CGGBP1 inhibition, we have developed a simple screening assay to identify chemical inhibitors of DNA-protein interactions. We have applied this screen for human CGGBP1 on a library of 1685 compounds and found that Givinostat is a direct inhibitor of CGGBP1-DNA interaction. The mechanism of action of Givinostat should thus extend beyond HDACs to include the inhibition of the myriad functions of CGGBP1 that depend on its binding to the DNA.
Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells
Authors: Armento Angela , Honisch Sabina , Panagiotakopoulou Vasiliki , Sonntag Inga , Jacob Anke , Kilger Ellen , Deleidi Michela , Clark Simon , Ueffing Marius 
Published: January 2020

AbstractAge-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. About 50% of AMD patients present polymorphisms in the Complement Factor H (CFH) gene, coding for Factor H protein (FH). AMD-associatedCFHrisk variants, Y402H in particular, impair FH function leading to complement overactivation. In AMD, retinal homeostasis is compromised due to dysfunction of retinal pigment epithelium (RPE) cells. Whether FH contributes to AMD pathogenesis only via complement system dysregulation remains unclear. To investigate the potential role of FH on energy metabolism and oxidative stress in RPE cells, we silencedCFHin human hTERT-RPE1 cells. FH-deprived RPE cells exposed to oxidative insult, showed altered metabolic homeostasis, including reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation. Our data suggest that FH protects RPE cells from oxidative stress and metabolic reprogramming, highlighting a novel function for FH in AMD pathogenesis.Graphical abstract
Transcriptional elongation machinery controls vulnerability of breast cancer cells to PRC2 inhibitors
Authors: Chan Ngai Ting , Liu Peng , Huang Junfeng , Wang Yidan , Ong Irene , Li Lingjun , Xu Wei 
Published: January 2020

ABSTRACTCTR9 is the scaffold subunit in Paf1c, a multifunctional complex regulating multiple steps of RNA Pol II-mediated transcription. Using inducible and stable CTR9 knockdown breast cancer cell lines, we discovered that the expression of a subset of KDMs, including KDM6A and Jarid2, is strictly controlled by CTR9. Global analyses of histone modifications revealed a significant increase of H3K27me3 upon loss of CTR9. Loss of CTR9 results in a decrease of H3K4me3 and H3K36me3 in gene bodies, and elevated levels and genome-wide expansion of H3K27me3. Mechanistically, CTR9 depletion triggers a PRC2 subtype switching from PRC2.2 to PRC2.1. As a consequence, CTR9 depletion generates vulnerability that renders breast cancer cells hypersensitive to PRC2 inhibitors. Our findings that CTR9 demarcates PRC2-mediated H3K27me3 levels and genomic distribution, provide a unique mechanism of transition from transcriptionally active to repressive chromatin states and sheds light on the biological functions of CTR9 in development and cancer.
A working memory intervention weakens the reconsolidation of a threat memory and its biases processing towards threat
Authors: Picco Soledad , Bavassi Luz , Fernández Rodrigo S. , Pedreira María E. 
Published: January 2020

ABSTRACTBACKGROUNDThreat-conditioning (TC) memory plays a central role in anxiety disorders, but not in a simple way. This memory impacts on complex cognitive systems by modifying behavioral responses with a bias to fearful stimuli and overestimating potential threats. In this study we proposed a global approach analyzing the scope of disrupting TC memory reconsolidation in the implicit memory, the declarative contingency and the cognitive biases.METHODSDay 1: Subjects were trained on TC. Day 2: after Threat-memory reactivation, one group performed a high demanding working memory task (HWM) and the other a low demanding working memory task (LWM). The last group, only performed the HWM task. Day 3: TC memory was tested by an extinction session followed by reinstatement. Finally, all subjects completed tasks targeting stimuli representation, valuation and attentional bias towards threat.RESULTSDisrupting reconsolidation of TC memory with a HWM weakened the implicit memory retention and faded the representation and valuation towards threat but it had no effect on attentional bias. Moreover, we revealed that subjects’ performance during the working memory task was specifically associated in TC memory retention.CONCLUSIONSOur findings reveal a strong impairment of the threat-memory restabilization and associated emotional biases. This may result from the competition between defensive survival and central-executive control networks. Our results fits with Experimental Psychopathology approach, disentangling the relation between the implicit memory, cognitive, valenced systems and the possibility to weaken both the threatening memory and the systems associated with the maintenance of anxiety profile.
Assessing the Intra- and Inter-Subject Reliability of the Perturbational Complexity Index (PCI) of Consciousness for Three Brain Regions Using TMS-EEG
Authors: Caulfield Kevin A. , Savoca Matthew T. , Lopez James W. , Summers Philipp M. , Li Xingbao , Fecchio Matteo , Casarotto Silvia , Massimini Marcello , George Mark S. 
Published: January 2020

AbstractBackgroundThe perturbational complexity index (PCI) is a useful measure of consciousness that combines transcranial magnetic stimulation (TMS) with electroencephalography (EEG). However, the PCI has not been assessed for reliability between sessions nor is there a clear best stimulation target to acquire a PCI.Objective/HypothesisWe assessed the reliability of within-subject PCIs between 3 sessions with stimulation over the same premotor, motor, and parietal targets between visits, hypothesizing that we could determine a most reliable TMS-EEG target to acquire PCIs in healthy, conscious adults.MethodsPCIs were acquired for 9 participants (5 women) over 3 sessions within a week. A 64 channel EEG system was used with all electrode impedances ≤ 10kΩ. Premotor, motor, and parietal stimulation targets were identified using a real-time Matlab graphical user interface (GUI). Neuronavigation using an MRI-template brain ensured that every TMS pulse was delivered within 3.0mm and 5° of the stimulation target.ResultsPremotor, motor, and parietal PCIs all had significant PCIs (all p < 0.05). However, parietal and motor PCIs had excellent reliability (ICCs = 0.927 and 0.857 respectively) whereas premotor PCIs had good reliability (ICC = 0.737). PCIs were similar between brain sites within each subject in a single visit, but with only a moderate effect (p = 0.024, ICC = 0.480). PCIs on a group level did not differ between brain sites (p = 0.589).ConclusionsThe PCI is a reliable measure over this timeframe within each subject for single brain targets. PCIs for parietal and motor sites are most similar between visits. Due to only moderate similarity between PCIs from three brain sites within each session, PCIs should be acquired over at least two brain sites, with parietal and motor regions as the top candidates.
Red Panda: A novel method for detecting variants in single-cell RNA sequencing
Authors: Cornish Adam , Roychoudhury Shrabasti , Sarma Krishna , Pramanik Suravi , Bhakat Kishor , Dudley Andrew , Mishra Nitish K , Guda Chittibabu 
Published: January 2020

AbstractSingle-cell sequencing enables us to better understand genetic diseases, such as cancer or autoimmune disorders, which are often affected by changes in rare cells. Currently, no existing software is aimed at identifying single nucleotide variations or micro (1-50bp) insertions and deletions in single-cell RNA sequencing (scRNA-seq) data. Generating high-quality variant data is vital to the study of the aforementioned diseases, among others. In this study, we report the design and implementation of Red Panda, a novel method to accurately identify variants in scRNA-seq data. Variants were called on scRNA-seq data from human articular chondrocytes, mouse embryonic fibroblasts (MEFs), and simulated data stemming from the MEF alignments. Red Panda had the highest Positive Predictive Value at 45.0%, while other tools—FreeBayes, GATK HaplotypeCaller, GATK UnifiedGenotyper, Monovar, and Platypus—ranged from 5.8%-41.53%. From the simulated data, Red Panda had the highest sensitivity at 72.44%. We show that our method provides a novel and improved mechanism to identify variants in scRNA-seq as compared to currently-existing software.AvailabilitySource code freely available under the MIT License athttps://github.com/adambioi/red_panda, and is supported on Linux
Serum cytokine levels are modulated by specific frequencies, amplitudes, and pulse widths of vagus nerve stimulation
Authors: Tsaava Téa , Datta-Chaudhuri Timir , Addorisio Meghan E. , Masi Emily Battinelli , Silverman Harold A. , Newman Justin E. , Imperato Gavin H. , Bouton Chad , Tracey Kevin J. , Chavan Sangeeta S. , Chang Eric H. 
Published: January 2020

ABSTRACTElectrical stimulation of peripheral nerves is a widely used technique to treat a variety of conditions including chronic pain, motor impairment, headaches, and epilepsy. Nerve stimulation to achieve efficacious symptomatic relief depends on the proper selection of electrical stimulation parameters to recruit the appropriate fibers within a nerve. Recently, electrical stimulation of the vagus nerve has shown promise for controlling inflammation and clinical trials have demonstrated efficacy for the treatment of inflammatory disorders. This application of vagus nerve stimulation activates the inflammatory reflex, reducing levels of inflammatory cytokines during inflammation. Here, we wanted to test whether altering the parameters of electrical vagus nerve stimulation would change circulating cytokine levels of normal healthy animals in the absence of increased inflammation. To examine this, we systematically tested a set of electrical stimulation parameters and measured serum cytokine levels in healthy mice. Surprisingly, we found that specific combinations of pulse width, pulse amplitude, and frequency produced significant increases of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFα), while other parameters selectively lowered serum TNFα levels, as compared to sham-stimulated mice. In addition, serum levels of the anti-inflammatory cytokine interleukin-10 (IL-10) were significantly increased by select parameters of electrical stimulation but remained unchanged with others. These results indicate that electrical stimulation parameter selection is critically important for the modulation of cytokines via the cervical vagus nerve and that specific cytokines can be increased by electrical stimulation in the absence of inflammation. As the next generation of bioelectronic therapies and devices are developed to capitalize on the neural regulation of inflammation, the selection of nerve stimulation parameters will be a critically important variable for achieving cytokine-specific changes.
TheGossypium longicalyxgenome as a resource for cotton breeding and evolution
Authors: Grover Corrinne E. , Pan Mengqiao , Yuan Daojun , Arick Mark A. , Hu Guanjing , Brase Logan , Stelly David M. , Lu Zefu , Schmitz Robert J. , Peterson Daniel G. , Wendel Jonathan F. , Udall Joshua A. 
Published: January 2020

AbstractCotton is an important crop that has made significant gains in production over the last century. Emerging pests such as the reniform nematode have threatened cotton production. The rare African diploid speciesGossypium longicalyxis a wild species that has been used as an important source of reniform nematode immunity. While mapping and breeding efforts have made some strides in transferring this immunity to the cultivated polyploid species, the complexities of interploidal transfer combined with substantial linkage drag have inhibited progress in this area. Moreover, this species shares its most recent common ancestor with the cultivated A-genome diploid cottons, thereby providing insight into the evolution of long, spinnable fiber. Here we report a newly generatedde novogenome assembly ofG. longicalyx. This high-quality genome leveraged a combination of PacBio long-read technology, Hi-C chromatin conformation capture, and BioNano optical mapping to achieve a chromosome level assembly. The utility of theG. longicalyxgenome for understanding reniform immunity and fiber evolution is discussed.
Using regions of homozygosity to evaluate the use of dogs as preclinical models in human drug development
Authors: Smieszek SP. , Polymeropoulos MP. 
Published: January 2020

AbstractAnimals are used as preclinical models for human diseases in drug development. Dogs, especially, are used in preclinical research to support the clinical safety evaluations during drug development. Comparisons of patterns of regions of homozygosity (ROH) and phenotypes between dog and human are not well known. We conducted a genome-wide homozygosity analysis (GWHA) in the human and the dog genomes.We calculated ROH patterns across distinct human cohorts including the Amish, the 1000 genomes, Wellderly, Vanda 1k genomes, and Alzheimer’s cohort. The Amish provided a large cohort of extended kinships allowing for in depth family oriented analyses. The remaining human cohorts served as statistical references. We then calculated ROH across different dog breeds with emphasis on the beagle - the preferred breed used in drug development.Out of five studied human cohorts we reported the highest mean ROH in the Amish population. We calculated the extent of the genome covered by ROH (FROH) (human 3.2Gb, dog 2.5Gb). Overall FROHdiffered significantly between the Amish and the 1000 genomes, and between the human and the beagle genomes. The mean FROHper 1Mb was ∼16kb for Amish, ∼0.6kb for Vanda 1k, and ∼128kb for beagles. This result demonstrated the highest degree of inbreeding in beagles, far above that of the Amish, one of the most inbred human populations.ROH can contribute to inbreeding depression if they contain deleterious variants that are fully or partially recessive. The differences in ROH characteristics between human and dog genomes question the applicability of dog models in preclinical research, especially when the goal is to gauge the subtle effects on the organism’s physiology produced by candidate therapeutic agents. Importantly, there are huge differences in a subset of ADME genes, specifically cytochrome P450 family (CYPs), constituting major enzymes involved in drug metabolism. We should hesitate to generalize from dog to human, even if human and beagle are relatively close species phylogenetically