bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining optical imaging of cleared tissue with mathematical modelling to predict drug delivery and therapeutic response
Authors: d’Esposito Angela , Sweeney Paul , Ali Morium , Saleh Magdy , Ramasawmy Rajiv , Roberts Thomas A , Desjardins Adrien , Lythgoe Mark F , Pedley R Barbara , Shipley Rebecca , Walker-Samuel Simon 
Published: November 2017

AbstractUnderstanding how drugs are delivered to diseased tissue, and their subsequent spatial and temporal distribution, is a key factor in the development of effective, targeted therapies. However, the interaction between the pathophysiology of diseased tissue and individual therapeutic agents can be complex, and can vary significantly between individuals. In cancer, suboptimal dosing resulting from poor delivery can cause reduced treatment efficacy, upregulation of resistance mechanisms and can even stimulate growth. Preclinical tools to better understand drug delivery are therefore urgently required, which incorporate the inherent variability and heterogeneity of human disease. To meet this need, we have combined multiscale mathematical modelling, high-resolution optical imaging of intact, optically-cleared tumour tissue from animal models, and in vivo magnetic resonance imaging (MRI). Our framework, named REANIMATE (REAlistic Numerical Image-based Modelling of biologicAl Tissue substratEs) allows large tissue samples to be investigated as if it were a living sample, in detailed, highly controlled, computational experiments. Specifically, we show that REANIMATE can be used to predict the heterogeneous delivery of specific therapeutic agents, in disparate two murine xenograft models of human colorectal carcinoma. Given the wide adoption of optical clearing equipment in biomedical research laboratories, REANIMATE enables a new paradigm in cancer drug development, which could also be applied to other disease areas.
Changes in global brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor
Authors: Preller Katrin H. , Burt Joshua B. , Ji Jie Lisa , Schleifer Charles , Adkinson Brendan , Stämpfli Philipp , Repovs Grega , Krystal John H. , Murray John D. , Vollenweider Franz X. , Anticevic Alan 
Published: November 2017

ABSTRACTLysergic acid diethylamide (LSD) is a psychedelic drug with predominantly agonist activity at various serotonin (5-HT) and dopamine receptors. Despite the therapeutic and scientific interest in LSD, the specific receptor contributions to its neurobiological effects remain largely unknown. To address this knowledge gap, we conducted a double-blind, randomized, counterbalanced, cross-over study during which 24 healthy participants received either i) placebo+placebo, ii) placebo+LSD (100 μg po), or iii) ketanserin – a selective 5-HT2A receptor antagonist. Here we focus on resting-state fMRI, a measure of spontaneous neural fluctuations that can map functional brain connectivity. We collected resting-state data 75 and 300 minutes after LSD/placebo administration. We quantified resting-state functional connectivity via a fully data-driven global brain connectivity (GBC) method to comprehensively map LSD neuropharmacological effects. LSD administration caused widespread GBC alterations that followed a specific topography: LSD reduced connectivity in associative areas, but concurrently increased connectivity across sensory and somatomotor areas. The 5-HT2A receptor antagonist, ketanserin, fully blocked the subjective and neural LSD effects. We show that whole-brain data-driven spatial patterns of LSD effects matched 5-HT2A receptor cortical gene expression in humans, which along with ketanserin effects, strongly implicates the 5-HT2A receptor in LSD’s neuropharmacology. Critically, the LSD-induced subjective effects were associated with somatomotor networks GBC changes. These data-driven neuropharmacological results pinpoint the critical role of 5-HT2A in LSD’s mechanism, which informs its neurobiology and guides rational development of psychedelic-based therapeutics
SMN1 and SMN2 Copy Number Determination by droplet digital PCR (ddPCR) based on Extreme Value Theory for Threshold Estimation
Authors: Niknazar Mohammad , Jansen Michael , Puig Oscar 
Published: November 2017

AbstractSpinal muscular atrophy (SMA) is the most frequent genetic cause of infantile death. Homozygous deletion screening of survival of motor neuron (SMN1) represents the first tier in diagnostic testing. In this work, we adopted and optimized a method to increase the accuracy of SMN1 and SMN2 copy number determination on ddPCR platform. This method, which makes no assumption about the distribution of the fluorescence readouts, was shown to significantly increase accuracy and outperform QuantaSoft software on problematic SMN1 samples.Method SummaryIn order to increase the accuracy of SMN1 and SMN2 copy number determination by ddPCR, we adopted and optimized a method based on extreme value theory for threshold estimation. Our method increases total accuracy and improves resolution of problematic samples.
Latent variable model for aligning barcoded short-reads improves downstream analyses
Authors: Shajii Ariya , Numanagić Ibrahim , Berger Bonnie 
Published: November 2017

AbstractRecent years have seen the emergence of several “third-generation” sequencing platforms, each of which aims to address shortcomings of standard next-generation short-read sequencing by producing data that capture long-range information, thereby allowing us to access regions of the genome that are inaccessible with short-reads alone. These technologies either produce physically longer reads typically with higher error rates or instead capture long-range information at low error rates by virtue of read “barcodes” as in 10x Genomics’ Chromium platform. As with virtually all sequencing data, sequence alignment for third-generation sequencing data is the foundation on which all downstream analyses are based. Here we introduce a latent variable model for improving barcoded read alignment, thereby enabling improved downstream genotyping and phasing. We demonstrate the feasibility of this approach through developing EMerAld— or EMA for short— and testing it on the barcoded short-reads produced by 10x’s sequencing technologies. EMA not only produces more accurate alignments, but unlike other methods also assigns interpretable probabilities to the alignments it generates. We show that genotypes called from EMA’s alignments contain over 30% fewer false positives than those called from Lariat’s (the current 10x alignment tool), with a fewer number of false negatives, on datasets of NA12878 and NA24385 as compared to NIST GIAB gold standard variant calls. Moreover, we demonstrate that EMA is able to effectively resolve alignments in regions containing nearby homologous elements— a particularly challenging problem in read mapping— through the introduction of a novel statistical binning optimization framework, which allows us to find variants in the pharmacogenomically important CYP2D region that go undetected when using Lariat or BWA. Lastly, we show that EMA’s alignments improve phasing performance compared to Lariat’s in both NA12878 and NA24385, producing fewer switch/mismatch errors and larger phase blocks on average.EMA software and datasets used are available at http://ema.csail.mit.edu.
Decision by sampling implements efficient coding of psychoeconomic functions
Authors: Bhui Rahul , Gershman Samuel J. 
Published: November 2017

AbstractThe theory of decision by sampling (DbS) proposes that an attribute’s subjective value is its rank within a sample of attribute values retrieved from memory. This can account for instances of context dependence beyond the reach of classic theories which assume stable preferences. In this paper, we provide a normative justification for DbS that is based on the principle of efficient coding. The efficient representation of information in a noiseless communication channel is characterized by a uniform response distribution, which the rank transformation implements. However, cognitive limitations imply that decision samples are finite, introducing noise. Efficient coding in a noisy channel requires smoothing of the signal, a principle that leads to a new generalization of DbS. This generalization is closely connected to range-frequency theory, and helps descriptively account for a wider set of behavioral observations, such as how context sensitivity varies with the number of available response categories.
Temporal neural mechanisms underlying conscious access to different levels of facial stimulus contents
Authors: Hsu Shen-Mou , Yang Yu-Fang 
Published: November 2017

ABSTRACTAn important issue facing the empirical study of consciousness concerns how the contents of incoming stimuli gain access to conscious processing. According to classic theories, facial stimuli are processed in a hierarchical manner. However, it remains unclear how the brain determines which level of stimulus contents is consciously accessible when facing an incoming facial stimulus. Accordingly, with a magnetoencephalography technique, this study aims to investigate the temporal dynamics of the neural mechanism mediating which level of stimulus content is consciously accessible. Participants were instructed to view masked target faces at threshold, so that according to behavioral responses, their perceptual awareness alternated from consciously accessing facial identity in some trials to being able to consciously access facial configuration features but not facial identity in other trials. Conscious access at these two levels of facial contents were associated with a series of differential neural events. Before target presentation, different patterns of phase angle adjustment were observed between the two types of conscious access. This effect was followed by stronger phase clustering for awareness of facial identity immediately during stimulus presentation. After target onset, conscious access to facial identity, as opposed to facial configural features, was able to elicit more robust late positivity. In conclusion, we suggest that the stages of neural events, ranging from prestimulus to stimulus-related activities, may operate in combination to determine which level of stimulus contents is consciously accessed. Conscious access may thus be better construed as comprising various forms that depend on the level of stimulus contents accessed.
Bases of antisense IncRNA-associated regulation of gene expression in fission yeast
Authors: Wery Maxime , Gautier Camille , Descrimes Marc , Yoda Mayuko , Migeot Valérie , Hermand Damien , Morillon Antonin 
Published: November 2017

ABSTRACTAntisense (as)lncRNAs can regulate gene expression but the underlying mechanisms and the different cofactors involved remain unclear. Using Native Elongating Transcript sequencing, here we show that stabilization of antisense Exo2-sensitivite IncRNAs (XUTs) results in the attenuation, at the nascent transcription level, of a subset of highly expressed genes displaying prominent promoter-proximal nucleosome depletion and histone acetylation. Mechanistic investigations on the catalase genectt1revealed that its induction following oxidative stress is impaired in Exo2-deficient cells, correlating with the accumulation of an asXUT. Interestingly, expression of this asXUT was also activated in wild-type cells upon oxidative stress, concomitant toctt1induction, indicating a potential attenuation feedback. This attenuation correlates with asXUT abundance, it is transcriptional, characterized by low RNAPII-ser5 phosphorylation, and it requires an histone deacetylase activity and the conserved Set2 histone methyltransferase. Finally, we identified Dicer as another RNA processing factor acting onctt1induction, but independently of Exo2. We propose that asXUTs could modulate the expression of their paired-sense genes when it exceeds a critical threshold, using a conserved mechanism independent of RNAi.AUTHOR SUMMARYExamples of regulatory antisense (as)lncRNAs acting on gene expression have been reported in multiple model organisms. However, despite their regulatory importance, aslncRNAs have been poorly studied, and the molecular bases for aslncRNAs-mediated regulation remain incomplete. One reason for the lack of global information on aslncRNAs appears to be their low cellular abundance. Indeed, our previous studies in budding and fission yeasts revealed that aslncRNAs are actively degraded by the Xrn1/Exo2-dependent cytoplasmic 5′-3′ RNA decay pathway. Using a combination of single-gene and genome-wide analyses in fission yeast, here we report that the stabilization of a set of Exo2-sensitive aslncRNAs correlates with attenuation of paired-sense genes transcription. Our work provides fundamental insights into the mechanism by which aslncRNAs could regulate gene expression. It also highlights for the first time that the level of sense gene transcription and the presence of specific chromatin features could define the potential of aslncRNA-mediated attenuation, raising the idea that aslncRNAs only attenuate those genes with expression levels above a “regulatory threshold”. This opens novel perspectives regarding what the potential determinants of aslncRNA-dependent regulation, as previous models in budding yeast rather proposed that aslncRNA-mediated repression is restricted to lowly expressed genes.
Allele-specific control of replication timing and genome organization during development
Authors: Rivera-Mulia Juan Carlos , Dimond Andrew , Vera Daniel , Trevilla-Garcia Claudia , Sasaki Takayo , Zimmerman Jared , Dupont Catherine , Gribnau Joost , Fraser Peter , Gilbert David M. 
Published: November 2017

AbstractDNA replication occurs in a defined temporal order known as the replication-timing (RT) program. RT is regulated during development in discrete chromosomal units, coordinated with transcriptional activity and 3D genome organization. Here, we derived distinct cell types from F1 hybrid musculus X castaneus mouse crosses and exploited the high single nucleotide polymorphism (SNP) density to characterize allelic differences in RT (Repli-seq), genome organization (Hi-C and promoter-capture Hi-C), gene expression (nuclear RNA-seq) and chromatin accessibility (ATAC-seq). We also presentHARP: a new computational tool for sorting SNPs in phased genomes to efficiently measure allele-specific genome-wide data. Analysis of 6 different hybrid mESC clones with different genomes (C57BL/6, 129/sv and CAST/Ei), parental configurations and gender revealed significant RT asynchrony between alleles across ~12 % of the autosomal genome linked to sub-species genomes but not to parental origin, growth conditions or gender. RT asynchrony in mESCs strongly correlated with changes in Hi-C compartments between alleles but not SNP density, gene expression, imprinting or chromatin accessibility. We then tracked mESC RT asynchronous regions during development by analyzing differentiated cell types including extraembryonic endoderm stem (XEN) cells, 4 male and female primary mouse embryonic fibroblasts (MEFs) and neural precursors (NPCs) differentiatedin vitrofrom mESCs with opposite parental configurations. Surprisingly, we found that RT asynchrony and allelic discordance in Hi-C compartments seen in mESCs was largely lost in all differentiated cell types, coordinated with a more uniform Hi-C compartment arrangement, suggesting that genome organization of homologues converges to similar folding patterns during cell fate commitment.
Fronto-limbic dysconnectivity leads to impaired brain network controllability in young people with bipolar disorder and those at high genetic risk
Authors: Jeganathan Jayson , Perry Alistair , Bassett Danielle S. , Roberts Gloria , Mitchell Philip B. , Breakspear Michael 
Published: November 2017

AbstractRecent investigations have used diffusion-weighted imaging to reveal disturbances in the neurocircuitry that underlie cognitive-emotional control in bipolar disorder (BD) and in unaffected siblings or children at high genetic risk (HR). It has been difficult to quantify the mechanism by which structural changes disrupt the superimposed brain dynamics, leading to the emotional lability that is characteristic of BD. Average controllability is a concept from network control theory that extends structural connectivity data to estimate the manner in which local neuronal fluctuations spread from a node or subnetwork to alter the state of the rest of the brain. We used this theory to ask whether structural connectivity deficits previously observed in HR (n=84, mean age 22.4) individuals, patients with BD (n=38, mean age 23.9), and age- and gender-matched controls (n=96, mean age 22.6) translate to differences in the ability of brain systems to be manipulated between states. Localized impairments in network controllability were seen in the left parahippocampal, left middle occipital, left superior frontal, right inferior frontal, and right precentral gyri in BD and HR groups. Subjects with BD had distributed deficits in a subnetwork containing the left superior and inferior frontal gyri, postcentral gyrus, and insula (p=0.004). HR participants had controllability deficits in a right-lateralized subnetwork involving connections between the dorsomedial and ventrolateral prefrontal cortex, the superior temporal pole, putamen, and caudate nucleus (p=0.008). Between-group controllability differences were attenuated after removal of topological factors by network randomization. Some previously reported differences in network connectivity were not associated with controllability-differences, likely reflecting the contribution of more complex brain network properties. These analyses highlight the potential functional consequences of altered brain networks in BD, and may guide future clinical interventions.HighlightsControl theory estimates how neuronal fluctuations spread from local networks.We compare brain controllability in bipolar disorder and their high-risk relatives.These groups have impaired controllability in networks supporting cognitive and emotional control.Weaker connectivity as well as topological alterations contribute to these changes.
cycleX: multi-dimensional pseudotime reveals cell cycle and differentiation relationship of dendritic cell progenitors
Authors: Tan Yong Kee , Zhang Xiaomeng , Chen Jinmiao 
Published: November 2017

AbstractAdvances in single-cell RNA-sequencing have helped reveal the previously underappreciated level of cellular heterogeneity present during cellular differentiation. A static snapshot of single-cell transcriptomes provides a good representation of the various stages of differentiation as differentiation is rarely synchronized between cells. Data from numerous single-cell analyses has suggested that cellular differentiation and development can be conceptualized as continuous processes. Consequently, computational algorithms have been developed to infer pseudotimes and re-ordered cells along developmental trajectories. However, existing pseudotime inference methods generate one-dimensional pseudotime in an unsupervised manner, which is inadequate to elucidate the effects of individual biological processes such as cell cycle and differentiation and the links between them. Here we present a method called cycleX which infers multi-dimensional pseudotimes to reveal putative relationship between cell cycle and differentiation during dendritic cell development. cycleX can be also applied to generate multi-dimensional pseudotime for the relationship among cell cycle, differentiation, trafficking, activation, metabolism and etc.
Investigating on relationship between effective quantum efficiency and irradiance
Authors: Ye Zi-Piao , Zhou Shuang-Xi , Yang Xiao-Long , Kang Hua-Jing , Robakowski Piotr 
Published: November 2017

AbstractModels describing the relationship between effective quantum efficiency of PS II (ΦPSII) and irradiance (I) are routinely used to determine how irradiance influences effective quantum efficiency and photosynthetic electron transport rate (ETR). However, with no single model one can accurately describe the relationship betweenΦPSIIand I, and explain the interdependence betweenΦPSIIand biophysical properties of photosynthetic pigments, especially in plants growing under low level irradiances. Basing on the mechanistic model of photosynthetic electron transport rate we have developed the model of the relationship betweenΦPSIIandI. The new model reveals thatΦPSIIincreases with photochemistry (kP) and heat dissipation (kD). Furthermore, the values of key parameters calculated using the new model were compared with the values calculated with two other empirical models. The new model was perfectly fitted to the light-response curves ofΦPSII. The key calculated photosynthetic parameters: maximumΦPSII, maximumETRand their corresponding saturation irradiance were close to the measured values. In addition, our model associatesΦPSIIwith intrinsic features of photosynthetic pigments. We concluded thatΦPSIIdecreased with increasingIdue to the decrease in the effective absorption cross-section of photosynthetic pigments molecules.HighlightA model of the relationship between effective quantum efficiency of PS II (ΦPSII) and irradiance (I) has been developed. Using this new model it was found thatΦPSIIdecreased with increasingIdue to the decrease in the effective absorption cross-section of photosynthetic pigments molecules.AbbreviationsETRElectron transport rateETRmaxMaximum electron transport rateFSteady-state fluorescenceFm′Maximum fluorescence in the lightFvVariable fluorescence yield of the dark-adapted leafgiDegeneration of energy level of photosynthetic pigment molecules in the ground stateigkDegeneration of energy level of photosynthetic pigment molecules in the excited statekIIrradianceNPQNon-photochemical quenchingN0Total light-harvesting pigment moleculesPARsatSaturation irradiance corresponding toETRmaxkPRate of photochemical reactionkDRate of non-radiative heat dissipationPS IIPhotosystem IIaeInitial slope of light-response curve of electron transport rateα′Fraction of light absorbed by PS IIβ′Leaf absorptanceξ1Probability of photochemistryξ2Probability of non-radiative heat dissipationξ3Probability of fluorescenceσikEigen-absorption cross-section of photosynthetic pigment from ground stateito excited statekdue to light illuminationEffective optical absorption cross-section of photosynthetic pigment molecule from ground stateito excited statekdue to light illuminationφExciton-use efficiency in PS IIτAverage lifetime of the photosynthetic pigment molecules in the lowest excited stateΣPSIIEffective quantum efficiency of PS II
Higher eukaryote-specific APC/C composition is a determinant of spindle assembly checkpoint importance
Authors: Wild Thomas , Budzowska Magda , Karemore Gopal , Choudhary Chunaram 
Published: November 2017

AbstractThe multisubunit ubiquitin ligase APC/C (anaphase promoting complex/cyclosome) is essential for mitosis by promoting timely degradation of cyclin B1. Proper timing of APC/C activation is regulated by the spindle assembly checkpoint (SAC), which is initiated by the kinase MPS1 and implemented by MAD2-dependent inhibition of the APC/C. Here we analysed the contribution of the higher eukaryote-specific APC/C subunits APC7 and APC16 to APC/C composition, function and regulation. APC16 is required for APC7 assembly into the APC/C, while APC16 assembles independently of APC7. ΔAPC7 and ΔAPC16 cells display no major defects in mitotic progression, cyclin B1 degradation or SAC response. Strikingly, however, deletion of either APC7 or APC16 is sufficient to provide synthetic viability to MAD2 deletion. ΔAPC7ΔMAD2 cells display an accelerated mitosis and require SAC-independent MPS1 function for maintaining their genome stability. Overall, these results show how human APC/C composition critically influences the cellular fate upon loss of SAC activity.