bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer brain metastases show increased levels of genomic aberration based homologous recombination deficiency scores relative to their corresponding primary tumors
Authors: Diossy M. , Reiniger L. , Sztupinszki Zs. , Krzystanek M. , Timms K. M. , Neff C. , Solimeno C. , Pruss D. , Eklund A. C. , Tóth E. , Kiss O. , Rusz O. , Cserni G. , Zombori T. , Székely B. , Csabai I. , Szallasi Z. 
Published: January 2018

AbstractDue to its mechanism of action, PARP inhibitor therapy is expected to benefit mainly tumor cases with homologous recombination deficiency (HRD). Various measures of genomic scarring based HRD scores were developed as a companion diagnostic in order to correlate it with PARP inhibitor sensitivity. We compared a variety of HRD scores in primary tumors and their corresponding brain metastases and found a significant increase in this measure in brain metastases for all measures of HRD that were tested. This discrepancy warrants further investigation to assess whether this observation is common to other metastatic sites, and potentially a significant adjustment of strategy in the application of HRD measures in clinical trials for the prioritization of patients for PARP inhibitor therapy.Key messageWe quantified homologous recombination deficiency (HRD) in paired primary breast cancer and brain metastases samples based on a previously published data set. We showed that HRD significantly increases in the brain metastases relative to its paired primary tumor. An independent validation was also performed on another set of primary breast cancer and brain metastasis pairs using the “my choice” HRD score in collaboration with Myriad Genetics.These confirmatory results suggest that brain metastases of breast cancer tend to have significantly higher HRD scores, which would prioritize those patients for PARP inhibitor therapy with those agents that cross the blood brain barrier such as veliparib and niraparib.
Cross-modal and non-monotonic representations of statistical regularity are encoded in local neural response patterns
Authors: Nastase Samuel A. , Davis Ben , Hasson Uri 
Published: January 2018

AbstractCurrent neurobiological models assign a central role to predictive processes calibrated to environmental statistics. Neuroimaging studies examining the encoding of stimulus uncertainty have relied almost exclusively on manipulations in which stimuli were presented in a single sensory modality, and further assumed that neural responses vary monotonically with uncertainty. This has left a gap in theoretical development with respect to two core issues: i) are there cross-modal brain systems that encode input uncertainty in way that generalizes across sensory modalities, and ii) are there brain systems that track input uncertainty in a non-monotonic fashion? We used multivariate pattern analysis to address these two issues using auditory, visual and audiovisual inputs. We found signatures of cross-modal encoding in frontoparietal, orbitofrontal, and association cortices using a searchlight cross-classification analysis where classifiers trained to discriminate levels of uncertainty in one modality were tested in another modality. Additionally, we found widespread systems encoding uncertainty non-monotonically using classifiers trained to discriminate intermediate levels of uncertainty from both the highest and lowest uncertainty levels. These findings comprise the first comprehensive report of cross-modal and non-monotonic neural sensitivity to statistical regularities in the environment, and suggest that conventional paradigms testing for monotonic responses to uncertainty in a single sensory modality may have limited generalizability.
Modelling Signalling Networks from Perturbation Data
Authors: Dorel Mathurin , Klinger Bertram , Sieber Anja , Prahallad Anirudh , Gross Torsten , Bosdriesz Evert , Wessels Lodewyk , Blüthgen Nils 
Published: January 2018

AbstractMotivationIntracellular signalling is realized by complex signalling networks which are almost impossible to understand without network models, especially if feedbacks are involved. Modular Response Analysis (MRA) is a convenient modelling method to study signalling networks in various contexts.ResultsWe developed a derivative of MRA that is suited to model signalling networks from incomplete perturbation schemes and multi-perturbation data. We applied the method to study the effect of SHP2, a protein that has been implicated in resistance to targeted therapy in colon cancer, using data from a knock out and parental colon cancer cell line. We find that SHP2 is required for MAPK signalling, whereas AKT signalling only partially depends on SHP2.AvailabilityAn R-package is available at https://github.com/MathurinD/STASNetContactnils.bluethgen@charite.de
TheRhodobacter sphaeroidesmethionine sulfoxide reductase MsrP can reduceR- andS-diastereomers of methionine sulfoxide from a broad-spectrum of protein substrates
Authors: Tarrago Lionel , Grosse Sandrine , Siponen Marina I. , Lemaire David , Alonso Béatrice , Miotello Guylaine , Armengaud Jean , Arnoux Pascal , Pignol David , Sabaty Monique 
Published: January 2018

SummaryMethionine (Met) is prone to oxidation and can be converted to Met sulfoxide (MetO), which exists as R- and S-diastereomers. MetO can be reduced back to Met by the ubiquitous methionine sulfoxide reductase (Msr) enzymes. Canonical MsrA and MsrB were shown as absolutely stereospecific for the reduction of S- and R-diastereomer, respectively. Recently, the molybdenum-containing protein MsrP, conserved in all gram-negative bacteria, was shown to be able to reduce MetO of periplasmic proteins without apparent stereospecificity inEscherichia coli.Here, we describe the substrate specificity of theRhodobacter sphaeroidesMsrP. Proteomics analysis coupled to enzymology approaches indicate that it reduces a broad spectrum of periplasmic oxidized proteins. Moreover, using model proteins, we demonstrated that RsMsrP preferentially reduces unfolded oxidized proteins and we confirmed that this enzyme, like itsE. colihomolog, can reduce bothR-andS-diastereomers of MetO with similar efficiency.
Fine mapping chromatin contacts in capture Hi-C data
Authors: Eijsbouts Christiaan , Burren Oliver , Newcombe Paul , Wallace Chris 
Published: January 2018

ABSTRACTHi-C and capture Hi-C (CHi-C) are used to map physical contacts between chromatin regions in cell nuclei using high-throughput sequencing. Analysis typically proceeds considering the evidence for contacts between each possible pair of fragments independent from other pairs. This can produce long runs of fragments which appear to all make contact with the same baited fragment of interest. We hypothesised that these long runs could result from a smaller subset of direct contacts and propose a new method, based on a Bayesian sparse variable selection approach, which attempts to fine map these direct contacts.Our model is conceptually novel, exploiting the spatial pattern of counts in CHi-C data, and prioritises fragments with biological properties that would be expected of true contacts. For bait fragments corresponding to gene promoters, we identify contact fragments with active chromatin and contacts that correspond to edges found in previously defined enhancer-target networks; conversely, for intergenic bait fragments, we identify contact fragments corresponding to promoters for genes expressed in that cell type. We show that long runs of apparently co-contacting fragments can typically be explained using a subset of direct contacts consisting of < 10% of the number in the full run, suggesting that greater resolution can be extracted from existing datasets. Our results appear largely complementary to the those from a per-fragment analytical approach, suggesting that they provide an additional level of interpretation that may be used to increase resolution for mapping direct contacts in CHi-C experiments.
Efficacy and dynamics of self-targeting CRISPR/Cas constructs for gene editing in the retina
Authors: Li Fan , Hung Sandy S.C. , Wang Jiang-Hui , Chrysostomou Vicki , Wong Vickie H.Y. , Bender James A. , Tu Leilei , Pébay Alice , King Anna E , Cook Anthony L. , Wong Raymond C.B. , Bui Bang V. , Hewitt Alex W. , Liu Guei-Sheung 
Published: January 2018

ABSTRACTSafe delivery of CRISPR/Cas endonucleases remains one of the major barriers to the widespread application ofin vivogenome editing including the anticipatory treatment of monogenic retinal diseases. We previously reported the utility of adeno-associated virus (AAV)-mediated CRISPR/Cas genome editing in the retina; however, with this type of viral delivery system, active endonucleases will remain in the retina for an extended period, making genotoxicity a significant consideration in clinical applications. To address this issue, we have designed a self-destructing “kamikaze” CRISPR/Cas system that disrupts the Cas enzyme itself following expression. Four guide RNAs (sgRNAs) were designed to targetStreptococcus pyogenesCas9 (SpCas9), afterin situvalidation, the selected sgRNAs were cloned into a dual AAV vector. One construct was used to deliver SpCas9 and the other delivered sgRNAs directed against SpCas9 and the target locus (yellow fluorescent protein, YFP), in the presence of mCherry. Both constructs were packaged into AAV2 vector and intravitreally administered in C57BL/6 andThy1-YFPtransgenic mice. After 8 weeks the expression of SpCas9, the efficacy ofYFPgene disruption was quantified. A reduction of SpCas9 mRNA was found in retinas treated with AAV2-mediated-YFP/SpCas9 targeting CRISPR/Cas compared to those treated with YFP targeting CRISPR/Cas alone. We also show that AAV2-mediated delivery of YFP/SpCas9 targeting CRISPR/Cas significantly reduced the number of YFP fluorescent cells among mCherry-expressing cells (~85.5% reduction compared to LacZ/SpCas9 targeting CRISPR/Cas) in transfected retina ofThy1-YFPtransgenic mice. In conclusion, our data suggest that a self-destructive “kamikaze” CRISPR/Cas system can be used as a robust tool for refined genome editing in the retina, without compromising on-target efficiency.
CCA based multi-view feature selection for multi-omics data integration
Authors: El-Manzalawy Yasser 
Published: January 2018

AbstractRecent technological advances in high-throughput omics technologies and their applications in genomic medicine have opened up outstanding opportunities for individualized medicine. However, several challenges arise in the integrative analysis of such data including heterogeneity and high dimensionality of the omics data. In this study, we present a novel multi-view feature selection algorithm based on the well-known canonical correlation analysis (CCA) statistical method for jointly selecting discriminative features from multi-omics data sources (multi-views). Our results demonstrate that models for predicting kidney renal clear cell carcinoma (KIRC) survival using our proposed method for jointly selecting discriminative features from copy number alteration (CNA), gene expression RNA-Seq, and reverse-phase protein arrays (RPPA) views outperform models trained using single-view data as well as three integrated models developed using data fusion approaches including CCA-based feature fusion.
Impacts of Simultaneous Multislice Acquisition on Sensitivity and Specificity in fMRI
Authors: Risk Benjamin B. , Kociuba Mary C. , Rowe Daniel B. 
Published: January 2018

AbstractSimultaneous multislice (SMS) acquisition can be used to decrease the time between acquisition of fMRI volumes, which can increase sensitivity by facilitating the removal of higher-frequency artifacts and boosting effective sample size. The technique requires an additional processing step in which the slices are separated, or unaliased, to recover the whole brain volume. However, this may result in signal “leakage” between aliased locations, i.e., slice “leakage,” and lead to spurious activation (decreased specificity). SMS can also lead to noise amplification, which can reduce the benefits of decreased repetition time. In this study, we evaluate the original slice-GRAPPA (no leak block) reconstruction algorithm and acquisition scenarios used in the young adult Human Connectome Project (HCP), as well as split slice-GRAPPA (leak block). In addition to slice leakage, signal leakage can result from spatial smoothing, i.e., smoothing leakage, which leads to inflated regions of activation. Previous studies have generally found that SMS acquisition results in higher test statistics and/or a greater number of activated voxels. Here, we use simulations to disentangle this phenomenon into true positives (sensitivity) and false positives (decreased specificity). Slice leakage was greatly decreased by split slice-GRAPPA. Noise amplification was decreased by using moderate acceleration factors (AF = 4). We examined slice leakage in unprocessed fMRI motor task data from the HCP, which used the original slice-GRAPPA. When data were smoothed, we found evidence of slice leakage in some, but not all, subjects. We also found evidence of SMS noise amplification in unprocessed task and processed resting-state HCP data.
The histone variant H2A.Z and chromatin remodeler BRAHMA act coordinately and antagonistically to regulate transcription and nucleosome dynamics in Arabidopsis
Authors: Torres E. Shannon , Deal Roger B. 
Published: January 2018

ABSTRACTPlants adapt to changes in their environment by regulating transcription and chromatin organization. The histone H2A variant H2A.Z and the SWI2/SNF2 ATPase BRAHMA have overlapping roles in positively and negatively regulating environmentally responsive genes in Arabidopsis, but the extent of this overlap was uncharacterized. Both have been associated with various changes in nucleosome positioning and stability in different contexts, but their specific roles in transcriptional regulation and chromatin organization need further characterization. We show that H2A.Z and BRM act both cooperatively and antagonistically to contribute directly to transcriptional repression and activation of genes involved in development and response to environmental stimuli. We identified 8 classes of genes that show distinct relationships between H2A.Z and BRM and their roles in transcription. We found that H2A.Z contributes to a range of different nucleosome properties, while BRM stabilizes nucleosomes where it binds and destabilizes and/or repositions flanking nucleosomes. H2A.Z and BRM contribute to +1 nucleosome destabilization, especially where they coordinately regulate transcription. We also found that at genes regulated by both BRM and H2A.Z, both factors overlap with the binding sites of light-regulated transcription factors PIF4, PIF5, and FRS9, and that some of the FRS9 binding sites are dependent on H2A.Z and BRM for accessibility. Collectively, we comprehensively characterized the antagonistic and cooperative contributions of H2A.Z and BRM to transcriptional regulation, and illuminated their interrelated roles in chromatin organization. The variability observed in their individual functions implies that both BRM and H2A.Z have more context-specific roles within diverse chromatin environments than previously assumed.
Contribution of the axon initial segment to action potentials recorded extracellularly
Authors: Teleńczuk Maria , Brette Romain , Destexhe Alain , Teleńczuk Bartosz 
Published: January 2018

AbstractAction potentials (APs) are electric phenomena that are recorded both intracellularly and extracellularly. APs are usually initiated in the short segment of the axon called the axon initial segment (AIS). It was recently proposed that at onset of an AP the soma and the AIS form a dipole. We study the extracellular signature (the extracellular action potential, EAP) generated by such a dipole. First, we demonstrate the formation of the dipole and its extracellular signature in detailed morphological models of a reconstructed pyramidal neuron. Then, we study the EAP waveform and its spatial dependence in models with axonal AP initiation and contrast it with the EAP obtained in models with somatic AP initiation. We show that in the models with axonal AP initiation the dipole forms between somatodendritic compartments and the AIS, and not between soma and dendrites as in the classical models. Soma-dendrites dipole is present only in models with somatic AP initiation. Our study has consequences for interpreting extracellular recordings of single-neuron activity and determining electrophysiological neuron types, but also for better understanding the origins of the high-frequency macroscopic electric fields recorded in the brain.New & NoteworthyWe studied the consequences of the action potential (AP) initiation site on the extracellular signatures of APs. We show that: (1) at the time of AP initiation the action initial segment (AIS) forms a dipole with the soma, (2) the width but not (3) amplitude of the extracellular AP generated by this dipole increases with the soma-AIS distance. This may help to monitor dynamic changes in the AIS position in experimental in vivo recordings.
epiTAD: a web application for visualizing high throughput chromosome conformation capture data in the context of genetic epidemiology
Authors: Creed Jordan H. , Aden-Buie Garrick , Monteiro Alvaro N. , Gerke Travis A. 
Published: January 2018

AbstractThe increasing availability of public data resources coupled with advancements in genomic technology has created greater opportunities for researchers to examine the genome on a large and complex scale. To meet the need for integrative genome wide exploration, we present epiTAD. This web-based tool enables researchers to compare genomic structures and annotations across multiple databases and platforms in an interactive manner in order to facilitate in silico discovery. epiTAD can be accessed at https://apps.gerkelab.com/epiTAD/.
BOFdat: generating biomass objective function stoichiometric coefficients from experimental data
Authors: Lachance Jean-Christophe , Monk Jonathan M. , Lloyd Colton J. , Seif Yara , Palsson Bernhard O. , Rodrigue Sébastien , Feist Adam M. , King Zachary A. , Jacques Pierre-Étienne 
Published: January 2018

AbstractGenome-scale models (GEMs) rely on a biomass objective function (BOF) to predict phenotype from genotype. Here we present BOFdat, a Python package that offers functions to generate biomass objective function stoichiometric coefficients (BOFsc) from macromolecular cell composition and relative abundances of macromolecules obtained from omic datasets. Growth-associated and non-growth associated maintenance (GAM and NGAM) costs can also be calculated by BOFdat.BOFdat is freely available on the Python Package Index (pip install BOFdat). The source code and an example usage (Jupyter Notebook and example files) are available on GitHub (https://github.com/jclachance/BOFdat). The documentation and API are available through ReadTheDocs (https://bofdat.readthedocs.io).Contactjean-christophe.lachance@usherbrooke.ca, zaking@eng.ucsd.edu, pierre-etienne.jacques@usherbrooke.ca
Differential impact of reward and punishment on functional connectivity after skill learning
Authors: Steel Adam , Silson Edward H. , Stagg Charlotte J. , Baker Chris I. 
Published: January 2018

AbstractReward and punishment shape behavior, but the mechanisms underlying their effect on skill learning are not well understood. Here, we tested whether the functional connectivity of premotor cortex (PMC), a region known to be critical for learning of sequencing skills, is altered after training by reward or punishment given during training. Resting-state fMRI was collected in two experiments before and after participants trained on either a serial reaction time task (SRTT; n = 36) or force-tracking task (FTT; n = 36) with reward, punishment, or control feedback. In each experiment, training-related change in PMC functional connectivity was compared across feedback groups. In both tasks, reward and punishment differentially affected PMC functional connectivity. On the SRTT, participants trained with reward showed an increase in functional connectivity between PMC and cerebellum as well as PMC and striatum, while participants trained with punishment showed an increase in functional connectivity between PMC and medial temporal lobe connectivity. After training on the FTT, subjects trained with control and reward showed increases in PMC connectivity with parietal and temporal cortices after training, while subjects trained with punishment showed increased PMC connectivity with ventral striatum. While the results from the two experiments overlapped in some areas, including ventral pallidum, temporal lobe, and cerebellum, these regions showed diverging patterns of results across the two tasks for the different feedback conditions. These findings suggest that reward and punishment strongly influence spontaneous brain activity after training, and that the regions implicated depend on the task learned.
Transcriptome assembly and annotation of johnsongrass (Sorghum halepense) rhizomes identifies candidate rhizome-specific genes
Authors: Ryder Nathan , Dorn Kevin M. , Huitsing Mark , Adams Micah , Ploegstra Jeff , DeHaan Lee , Larson Steve , Tintle Nathan L. 
Published: January 2018

AbstractRhizomes facilitate the wintering and vegetative propagation of many perennial grasses. Sorghum halepense (johnsongrass) is an aggressive perennial grass that relies on a robust rhizome system to persist through winters and reproduce asexually from its rootstock nodes. This study aimed to sequence and assemble expressed transcripts within the johnsongrass rhizome. A de novo transcriptome assembly was generated from a single johnsongrass rhizome meristem tissue sample. A total of 141,176 probable protein-coding sequences from the assembly were identified and assigned gene ontology terms using Blast2GO. The johnsongrass assembly was compared to Sorghum bicolor, a related non-rhizomatous species, along with an assembly of similar rhizome tissue from the perennial grain crop Thinopyrum intermedium. The presence/absence analysis yielded a set of 259 johnsongrass contigs that are likely associated with rhizome development.