bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large-scale correlations between eight key double strand break related data sets over the whole human genome
Authors: Brahme Anders , Hultén Maj , Bengtsson Carin , Hultgren Andreas , Zetterberg Anders 
Published: March 2019

AbstractEight different data sets, covering the whole human genome are compared with regard to their genomic distribution. A close correlation between cytological detected chiasma and MLH1 immunofluorescence sites with the recombination density distribution from the HapMap project was found. Sites with a high probability of chromatid breakage after exposure to low and high ionization density radiations are often located inside common and rare Fragile Sites (FSs) indicating that the common Radiation-Induced Breakpoint sites (RIBs) may be a new kind of more local fragility. Furthermore, Oncogenes and other cancer-related genes are commonly located in regions with an increased probability of rearrangements during genomic recombination, or in regions with high probability of copy number changes, possibly since these processes may be involved in oncogene activation and cancer induction. An increased CpG density is linked to regions of high gene density to secure high fidelity reproduction and survival. To minimize cancer induction these genes are often located in regions of decreased recombination density and/or higher than average CpG density. Interestingly, copy number changes occur predominantly at common RIBs and/or FSs at least for breast cancers with poor prognosis and they decrease weakly but significantly in regions with increasing recombination density and CpG density. It is compelling that all these datasets are influenced by the cells handling of double strand breaks and more generally DNA damage on its genome. In fact, the DNA repair genes are systematically avoiding regions with a high recombination density. This may be a consequence of natural selection, as they need to be intact to accurately handle repairable DNA lesions.
Crystal structure of the LRR ectodomain of the plant immune receptor kinase SOBIR1
Authors: Hohmann Ulrich , Hothorn Michael 
Published: March 2019

AbstractPlant unique membrane receptor kinases with leucine-rich repeat (LRR) extracellular domains are key regulators of development and immune responses. Here we present the 1.55 Å resolution crystal structure of the immune receptor kinase SOBIR1 from Arabidopsis. The ectodomain structure reveals the presence of 5 LRRs sandwiched between non-canonical capping domains. The disulphide bond-stabilized N-terminal cap harbors an unusual β-hairpin structure. The C-terminal cap features a highly positively charged linear motif which we find largely disordered in our structure. Size-exclusion chromatography and right-angle light scattering experiments suggest that SOBIR1 is a monomer in solution. The protruding β-hairpin, a set of highly conserved basic residues at the inner surface of the SOBIR LRR domain and the presence of a genetic missense allele in LRR2, together suggest that the SOBIR1 ectodomain may mediate protein – protein interaction in plant immune signalling.SynopsisThe ectodomain structure of a novel plant membrane receptor kinase with unusual capping domains is reported.
Predicting the effects of SNPs on transcription factor binding affinity
Authors: Nishizaki Sierra S , Ng Natalie , Dong Shengcheng , Morterud Cody , Williams Colten , Boyle Alan P 
Published: March 2019

AbstractGWAS have revealed that 88% of disease associated SNPs reside in noncoding regions. However, noncoding SNPs remain understudied, partly because they are challenging to prioritize for experimental validation. To address this deficiency, we developed the SNP effect matrix pipeline (SEMpl). SEMpl estimates transcription factor binding affinity by observing differences in ChIP-seq signal intensity for SNPs within functional transcription factor binding sites genome-wide. By cataloging the effects of every possible mutation within the transcription factor binding site motif, SEMpl can predict the consequences of SNPs to transcription factor binding. This knowledge can be used to identify potential disease-causing regulatory loci.
Neural signals to violations of abstract rules using speech-like stimuli
Authors: Vidal Yamil , Brusini Perrine , Bonfieni Michela , Mehler Jacques , Bekinschtein Tristan 
Published: March 2019

AbstractAs the evidence of predictive processes playing a role in a wide variety of cognitive domains increases, the brain as a predictive machine becomes a central idea in neuroscience. In auditory processing a considerable amount of progress has been made using variations of the Oddball design, but most of the existing work seems restricted to predictions based on physical features or conditional rules linking successive stimuli. To characterise the predictive capacity of the brain to abstract rules, we present here two experiments that use speech-like stimuli to overcome limitations and avoid common confounds. Pseudowords were presented in isolation, intermixed with infrequent deviants that contained unexpected phoneme sequences. As hypothesized, the occurrence of unexpected sequences of phonemes reliably elicited an early prediction error signal. These prediction error signals do not seemed to be modulated by attentional manipulations due to different task instructions, suggesting that the predictions are deployed even when the task at hand does not volitionally involve error detection. In contrast, the amount of syllables congruent with a standard pseudoword presented before the point of deviance exerted a strong modulation. Prediction error’s amplitude doubled when two congruent syllables were presented instead of one, despite keeping local transitional probabilities constant. This suggest that auditory predictions can be built integrating information beyond the immediate past. In sum, the results presented here further contribute to the understanding of the predictive capabilities of the human auditory system when facing complex stimuli and abstract rules.Significance StatementThe generation of predictions seem to be a prevalent brain computation. In the case of auditory processing this information is intrinsically temporal. The study of auditory predictions has been largely circumscribed to unexpected physical stimuli features or rules connecting consecutive stimuli. In contrast, our everyday experience suggest that the human auditory system is capable of more sophisticated predictions. This becomes evident in the case of speech processing, where abstract rules with long range dependencies are universal. In this article, we present two electroencephalography experiments that use speech-like stimuli to explore the predictive capabilities of the human auditory system. The results presented here increase the understanding of the ability of our auditory system to implement predictions using information beyond the immediate past.
Overlapping transcriptional expression response of wheat zinc-induced facilitator-like transporters emphasize important role during Fe and Zn stress
Authors: Sharma Shivani , Kaur Gazaldeep , Kumar Anil , Kaur Jaspreet , Pandey Ajay Kumar 
Published: March 2019

AbstractBackgroundHexaploid wheat is an important cereal crop that has been targeted to enhance grain micronutrient content including zinc and iron. In this direction, modulating the expression of plant transporters involved in Fe and Zn homeostasis could be one of the promising approaches. Therefore, the present work was undertaken to identify bread wheatZinc–InducedFacilitator-Like (ZIFL) family of transporters and study their transcriptional expression response during micronutrient fluctuations and exposure to multiple heavy metals.ResultsThe genome-wide analyses resulted in identification of thirty-five putativeTaZIFLgenes, which were distributed only on Chromosome 3, 4 and 5. Wheat ZIFL proteins subjected to the phylogenetic analysis showed the uniform distribution along with rice,Arabidopsisand maize.In-silicoanalysis of the promoters of the wheat ZIFL genes suggested the presence of multiple metal binding sites including those which are involved in Fe homeostasis. QRT-PCR analysis of wheatZIFLgenes suggested the differential regulation of the transcripts in roots and shoots under surplus Zn and also during Fe starvation. Specifically, in roots,TaZIFL2.3, TaZIFL4.1, TaZIFL4.2, TaZIFL5, TaZIFL6.1andTaZIFL6.2were significantly up-regulated by both Zn and Fe. This suggested that ZIFL could possibly be regulated by both the nutrient stress in a tissue specific manner. Interestingly, upon exposure to heavy metals,TaZIFL4.2andTaZIFL7.1showed significant up-regulation, whereasTaZIFL5andTaZIFL6.2remained almost unaffected.ConclusionThis is the first report with detailed analysis of wheat ZIFL genes. Our study also identifies closest ortholog for transporter of mugineic acid, a chelator required for Fe uptake. Comprehensive transcript expression pattern during development of wheat seedlings and against various abiotic/biotic stresses resulted in tissue specific responses. Overall, this work addresses the role of wheatZIFLduring the interplay between micronutrient and heavy metal stress in a tissue specific manner.
Coronary atherosclerosis: Un-altered physiology
Authors: de Groot Paul , Veldhuizen Roel W 
Published: March 2019

AbstractBackgroundEnd-stage coronary artery atherosclerosis has been studied extensively but the exact mechanisms of initiation and progression have not been defined fully. The aim of this study was to mathematically describe luminal change in relation to coronary vessel wall thickness in its progression from normal to atherosclerotic to establish whether these explain the pathophysiology.MethodsOne hundred coronary artery sections were graded histologically as ‘normal’ to ‘highly atherosclerotic’. Random systemic sampling by image analysis yielded 32 measurements (lumen radius and intima, medial, and adventitial thickness) from each section along 32 evenly spaced radii.ResultsThe raw data follow an undulating course in relation to successive segments in all sections analyzed, pointing to a dynamic and well-ordered system. The calculated values, studied in triplets, followed a non-synchronized parabolic course, which was converted to linearity by taking the change in numbers (n-(n-1)=Δ) into account. The course and sign of ‘Δvessel wall’ (resulting from summed Δintima, Δmedia, Δadventitia) and ‘Δlumen radius’ values were unique for each triplet. Triplets order according to ‘Δlumen radius minus Δvessel wall’ and its course given by the trendline a-value presented stages in which increased Δvessel wall resulted in increased Δlumen radius in stages 1 and 3 and decreased Δlumen radius in stage 2. This phenomenon was found in all sections regardless of histological indication and independent of vessel wall constituent parts (intima, media, adventitia).ConclusionsSimilar basic processes are defined in all sections regardless of histological rating, indicating un-altered physiology. As such, coronary atherosclerosis can only be defined by a large to small shift of the triplets Δvessel wall trendline a-value. Consequently, no parameter of vessel wall pathology exists in absolute terms. Vessel wall composition has no importance for Δlumen radius.
Transitions in brain-network level information processing dynamics are driven by alterations in neural gain
Authors: Li Mike , Han Yinuo , Aburn Matthew J. , Breakspear Michael , Poldrack Russell A. , Shine James M. , Lizier Joseph T. 
Published: March 2019

AbstractA key component of the flexibility and complexity of the brain is its ability to dynamically adapt its functional network structure between integrated and segregated brain states depending on the demands of different cognitive tasks. Integrated states are prevalent when performing tasks of high complexity, such as maintaining items in working memory, consistent with models of a global workspace architecture. Recent work has suggested that the balance between integration and segregation is under the control of ascending neuromodulatory systems, such as the noradrenergic system. In a previous large-scale nonlinear oscillator model of neuronal network dynamics, we showed that manipulating neural gain led to a ‘critical’ transition in phase synchrony that was associated with a shift from segregated to integrated topology, thus confirming our original prediction. In this study, we advance these results by demonstrating that the gain-mediated phase transition is characterized by a shift in the underlying dynamics of neural information processing. Specifically, the dynamics of the subcritical (segregated) regime are dominated by information storage, whereas the supercritical (integrated) regime is associated with increased information transfer (measured via transfer entropy). Operating near to the critical regime with respect to modulating neural gain would thus appear to provide computational advantages, offering flexibility in the information processing that can be performed with only subtle changes in gain control. Our results thus link studies of whole-brain network topology and the ascending arousal system with information processing dynamics, and suggest that the constraints imposed by the ascending arousal system constrain low-dimensional modes of information processing within the brain.Author summaryHigher brain function relies on a dynamic balance between functional integration and segregation. Previous work has shown that this balance is mediated in part by alterations in neural gain, which are thought to relate to projections from ascending neuromodulatory nuclei, such as the locus coeruleus. Here, we extend this work by demonstrating that the modulation of neural gain alters the information processing dynamics of the neural components of a biophysical neural model. Specifically, we find that low levels of neural gain are characterized by high Active Information Storage, whereas higher levels of neural gain are associated with an increase in inter-regional Transfer Entropy. Our results suggest that the modulation of neural gain via the ascending arousal system may fundamentally alter the information processing mode of the brain, which in turn has important implications for understanding the biophysical basis of cognition.
A game theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways
Authors: Ghosh Preetam , Rana Pratip , Rangachari Vijayaraghavan , Saha Jhinuk , Steen Edward , Vaidya Ashwin 
Published: March 2019

AbstractAggregation of amyloidβ(Aβ) peptides is a significant event that underpins Alzheimer disease (AD). Aβaggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behavior. In this paper, we use our previously established investigations on heterotypic interactions between Aβand fatty acids (FAs) that adopt off-fibril formation pathway under the control ofFAconcentrations, to develop a mathematical framework in defining this complex mechanism. We bring forth the use of novel game theoretic framework based on the principles of Nash equilibria to define and simulate the competing on- and off-pathways of Aβaggregation. Together with detailed simulations and biophysical experiments, our mathematical models define the dynamics involved in the mechanisms of Aβaggregation in the presence ofFAs to adopt multiple pathways. Specifically, our game theoretic model indicates that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constant parameters, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on usingFAas a heterotypic partner to modulate temporal parameters. Predicting spatiotemporal landscape along competing pathways for a given heterotypic partner such as biological lipids is a first step towards simulating physiological scenarios in which the generation of specific conformeric strains of Aβcould be predicted. Such an approach could be profoundly significant in deciphering the biophysics of amyloid aggregation and oligomer generation, which is ubiquitously observed in many neurodegenerative diseases.
The structural evolution of host-pathogen protein interactions: an integrative approach
Authors: Brito Anderson F. , Pinney John W. 
Published: March 2019

ABSTRACTThe evolution of protein-protein interactions (PPIs) is directly influenced by the evolutionary histories of the genes and the species encoding the interacting proteins. When it comes to PPIs of host-pathogen systems, the complexity of their evolution is much higher, as two independent, but biologically associated entities, are involved. In this work, an integrative approach combining phylogenetics, tree reconciliations, ancestral sequence reconstructions, and homology modelling is proposed for studying the evolution of host-pathogen PPIs. As a case study, we analysed the evolution of interactions between herpesviral glycoproteins gD/gG and the cell membrane proteins nectins. By modelling the structures of more than 12,000 ancestral states of these virus-host complexes it was found that in early times of their evolution, these proteins were unable to interact, most probably due to electrostatic incompatibilities between their interfaces. After the event of gene duplication that gave rise to a paralog of gD (known as gG), both protein lineages evolved following distinct functional constraints, with most gD reaching high binding affinities towards nectins, while gG lost such ability, most probably due to a process of neofunctionalization. Based on their favourable interaction energies (negative ΔG), it is possible to hypothesize that apart from nectins 1 and 2, some alphaherpesviruses might also use nectins 3 and 4 as cell receptors. These findings show that the proposed integrative method is suitable for modelling the evolution of host-pathogen protein interactions, and useful for raising new hypotheses that broaden our understanding about the evolutionary history of PPIs, and their molecular functioning.
Ring canals permit extensive cytoplasm sharing among germline cells independent of fusomes inDrosophilatestes
Authors: Kaufman Ronit S. , Price Kari L. , Mannix Katelynn M. , Ayers Kathleen , Hudson Andrew M. , Cooley Lynn 
Published: March 2019

AbstractIntercellular bridges, also called ring canals (RCs), connect germline cells during gametogenesis in males and females. They form as a consequence of incomplete cytokinesis during cell division leaving groups of daughter cells connected in syncytia. InDrosophilafemales, RCs are required for oocyte growth but little is known about the role of RCs during spermatogenesis. Using live imaging, we document extensive intercellular movement of GFP and a subset of endogenous proteins through RCs during spermatogenesis from two-cell diploid spermatogonia to clusters of 64 post-meiotic haploid spermatids. Loss of the fusome, a large cytoplasmic structure extending through RCs that is known to be important during oogenesis, has minimal impact on RC development or intercellular protein movement during spermatogenesis. Our results reveal that male germline RCs remain persistently open and mediate extensive sharing of cytoplasmic information, supporting multiple roles for RCs throughout sperm development.
Macrophage Activation by a Substituted Pyrimido[5,4-b]Indole Increases Anti-Cancer Activity
Authors: Hardie Joseph , Mas-Rosario Javier A. , Ha Siyoung , Rizzo Erik M. , Farkas Michelle E. 
Published: March 2019

ABSTRACTImmunotherapy has become a promising new approach for cancer treatment due to the immune system’s ability to remove tumors in a safe and specific manner. Many tumors express anti-inflammatory factors that deactivate the local immune response or recruit peripheral macrophages into pro-tumor roles. Because of this, effective and specific ways of activating macrophages into anti-tumor phenotypes is highly desirable for immunotherapy purposes. Here, the use of a small molecule TLR agonist as a macrophage activator for anti-cancer therapy is reported. This compound, referred to as PBI1, demonstrated unique activation characteristics and expression patterns compared to treatment with LPS, through activation of TLR4. Furthermore, PBI1 treatment resulted in anti-tumor immune behavior, enhancing macrophage phagocytic efficiency five-fold versus non-treated macrophages. Additive effects were observed via use of a complementary strategy (anti-CD47 antibody), resulting in ∼10-fold enhancement of phagocytosis, suggesting this small molecule approach could be used in conjunction with other therapeutics.
De novo Identification of Essential Protein Domains from CRISPR/Cas9 Tiling-sgRNA Knockout Screens
Authors: He Wei , Zhang Liang , Villarreal Oscar D. , Fu Rongjie , Bedford Ella , Dou Jingzhuang , Bedford Mark T. , Shi Xiaobing , Chen Taiping , Bartholomew Blaine , Xu Han 
Published: March 2019

AbstractHigh-throughput CRISPR/Cas9 knockout screens using a tiling-sgRNA design permit in situ evaluation of protein domain function. To facilitate de novo identification of essential protein domains from such screens, we developed ProTiler, a computational method for the robust mapping of CRISPR knockout hyper-sensitive (CKHS) regions, which refers to the protein regions that are associated with strong sgRNA dropout effect in the screens. We used ProTiler to analyze a published CRISPR tiling screen dataset, and identified 175 CKHS regions in 83 proteins. Of these CKHS regions, more than 80% overlapped with annotated Pfam domains, including all of the 15 known drug targets in the dataset. ProTiler also revealed unannotated essential domains, including the N-terminus of the SWI/SNF subunit SMARCB1, which we validated experimentally. Surprisingly, the CKHS regions were negatively correlated with phosphorylation and acetylation sites, suggesting that protein domains and post-translational modification sites have distinct sensitivities to CRISPR/Cas9 mediated amino acids loss.
KHNYN is essential for ZAP-mediated restriction of HIV-1 containing clustered CpG dinucleotides
Authors: Ficarelli Mattia , Wilson Harry , Galão Rui Pedro , Neil Stuart J D , Swanson Chad M 
Published: March 2019

AbstractCpG dinucleotides are suppressed in most vertebrate RNA viruses, including HIV-1, and introducing CpGs into RNA virus genomes inhibits their replication. The zinc-finger antiviral protein (ZAP) binds regions of viral RNA containing CpGs and targets them for degradation. ZAP does not have enzymatic activity and recruits other cellular proteins to inhibit viral replication. Here we show that KHNYN, a protein with no previously known function, interacts with ZAP. KHNYN overexpression selectively inhibits HIV-1 containing clustered CpG dinucleotides and this requires ZAP and its cofactor TRIM25. KHNYN requires both its KH-like domain and NYN endonuclease domain for antiviral activity. Crucially, depletion of KHNYN eliminated the deleterious effect of CpG dinucleotides on HIV-1 RNA abundance and infectious virus production indicating that KHNYN is required for this antiviral pathway. Overall, we have identified KHNYN as a novel ZAP cofactor that is essential for innate immune destruction of CpG containing viral RNA.