bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structural basis of envelope and phase intrinsic coupling modes of the cerebral cortex
Authors: Messé Arnaud , Hollensteiner Karl J. , Delettre Céline , Dell Leigh-Anne , Pieper Florian , Nentwig Lena J. , Galindo-Leon Edgar E. , Larrat Benoît , Mériaux Sébastien , Mangin Jean-François , Reillo Isabel , de Juan Romero Camino , Borrell Víctor , Engler Gerhard , Toro Roberto , Engel Andreas K. , Hilgetag Claus C. 
Published: December 2018

AbstractIntrinsic coupling modes (ICMs) provide a framework for describing the interactions of ongoing brain activity at multiple spatial and temporal scales. Two families of ICMs can be distinguished: phase and envelope ICMs. The principles that shape these ICMs remain partly elusive, in particular their relation to the underlying brain structure. Here we explored structure-function relationships in the ferret brain between ICMs quantified from ongoing brain activity recorded with chronically implanted ECoG arrays and structural connectivity (SC) obtained from high-resolution diffusion MRI tractography. Large-scale computational models as well as simple topological ingredients of SC were used to explore the ability to predict both types of ICMs. Importantly, all investigations were conducted with ICM measures that are sensitive or insensitive to volume conduction effects. The results show that both types of ICMs are strongly related to SC, except when using ICM measures removing zero-lag synchronizations. Computational models are challenged to predict these ICM patterns consistently, and simple predictions from SC topological features can sometimes outperform them. Overall, the results demonstrate that patterns of cortical functional coupling as reflected in both phase and envelope ICMs bear a substantial relation to the underlying structural connectivity of the cerebral cortex.
A global overview of pleiotropy and genetic architecture in complex traits
Authors: Watanabe Kyoko , Stringer Sven , Frei Oleksandr , Mirkov Maša Umićević , Polderman Tinca J.C. , van der Sluis Sophie , Andreassen Ole A. , Neale Benjamin M. , Posthuma Danielle 
Published: December 2018

ABSTRACTAfter a decade of genome-wide association studies (GWASs), fundamental questions in human genetics are still unanswered, such as the extent of pleiotropy across the genome, the nature of trait-associated genetic variants and the disparate genetic architecture across human traits. The current availability of hundreds of GWAS results provide the unique opportunity to gain insight into these questions. In this study, we harmonized and systematically analysed 4,155 publicly available GWASs. For a subset of well-powered GWAS on 558 unique traits, we provide an extensive overview of pleiotropy and genetic architecture. We show that trait associated loci cover more than half of the genome, and 90% of those loci are associated with multiple trait domains. We further show that potential causal genetic variants are enriched in coding and flanking regions, as well as in regulatory elements, and how trait-polygenicity is related to an estimate of the required sample size to detect 90% of causal genetic variants. Our results provide novel insights into how genetic variation contributes to trait variation. All GWAS results can be queried and visualized at the GWAS ATLAS resource (http://atlas.ctglab.nl).
Functional evaluation of transposable elements as transcriptional enhancers in mouse embryonic and trophoblast stem cells
Authors: Todd Christopher D. , Deniz Özgen , Branco Miguel R. 
Published: December 2018

AbstractThe recurrent invasion and expansion of transposable elements (TEs) throughout evolution brought with it a vast array of coding and non-coding sequences that can serve as substrates for natural selection. Namely, TEs are thought to have contributed to the establishment of gene regulatory networks via their cis-acting elements. Both the embryonic and extraembryonic lineages of the early mouse embryo are thought to have benefited from the co-option of TEs as distal enhancer elements. However, there is little to no evidence that these particular TEs play significant roles in the regulation of gene expression. Here we tested for roles of TEs as enhancers in mouse embryonic and trophoblast stem cells by combining bioinformatic analyses with genetic and epigenetic editing experiments. Epigenomic and transcriptomic data from wildtype cells suggested that a large number of TEs played a role in the establishment of highly tissue-specific gene expression programmes. Through genetic editing of individual TEs we confirmed a subset of these regulatory relationships. However, a wider survey via CRISPR interference of RLTR13D6 elements in embryonic stem cells revealed that only a minority play significant roles in gene regulation. Our results suggest that a small proportion of TEs contribute to the mouse pluripotency regulatory network, and highlight the importance of functional experiments when evaluating the role of TEs in gene regulation.
Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model
Authors: Wegrzynowicz Michal , Bar-On Dana , Calo’ Laura , Anichtchik Oleg , Iovino Mariangela , Xia Jing , Ryazanov Sergey , Leonov Andrei , Giese Armin , Dalley Jeffrey W. , Griesinger Christian , Ashery Uri , Spillantini Maria Grazia 
Published: December 2018

SUMMARYParkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.
Similarities and differences between native HIV-1 envelope glycoprotein trimers and stabilized soluble trimer mimetics
Authors: la Peña Alba Torrents de , Rantalainen Kimmo , Cottrell Christopher A. , Allen Joel D. , van Gils Marit J. , Torres Jonathan L. , Crispin Max , Sanders Rogier W. , Ward Andrew B. 
Published: December 2018

AbstractThe HIV-1 envelope glycoprotein (Env) trimer is located on the surface of the virus and is the target of broadly neutralizing antibodies (bNAbs). Recombinant native-like soluble Env trimer mimetics, such as SOSIP trimers, have taken a central role in HIV-1 vaccine research aimed at inducing bNAbs. We therefore performed a direct and thorough comparison of a full-length native Env trimer containing the transmembrane domain and the cytoplasmic tail, with the sequence matched soluble SOSIP trimer, both based on an early Env sequence (AMC011) from an HIV+ individual that developed bNAbs. The structures of the full-length AMC011 trimer bound to either bNAb PGT145 or PGT151 were very similar to the structures of SOSIP trimers. Antigenically, the full-length and SOSIP trimers were comparable, but in contrast to the full-length trimer, the SOSIP trimer did not bind at all to non-neutralizing antibodies, most likely as a consequence of the intrinsic stabilization of the SOSIP trimer. Furthermore, the glycan composition of full-length and SOSIP trimers was similar overall, but the SOSIP trimer possessed slightly less complex and less extensively processed glycans, which may relate to the intrinsic stabilization as well as the absence of the membrane tether. These data provide insights into how to best use and improve membrane-associated full-length and soluble SOSIP HIV-1 Env trimers as immunogens.
Placental DNA methylation levels at CYP2E1 and IRS2 are associated with child outcome in a prospective autism study
Authors: Zhu Yihui , Mordaunt Charles E. , Yasui Dag H. , Marathe Ria , Coulson Rochelle L. , Dunaway Keith W. , Walker Cheryl K. , Ozonoff Sally , Hertz-Picciotto Irva , Schmidt Rebecca J. , LaSalle Janine M. 
Published: December 2018

AbstractDNA methylation acts at the interface of genetic and environmental factors relevant for autism spectrum disorder (ASD). Placenta, normally discarded at birth, is a potentially rich source of DNA methylation patterns predictive of ASD in the child. Here, we performed whole methylome analyses of placentas from a prospective study of high-risk pregnancies. 400 differentially methylated regions (DMRs) discriminated placentas stored from children later diagnosed with ASD compared to typical controls. These ASD DMRs were significantly enriched at promoters, mapped to 596 genes functionally enriched in neuronal development, and overlapped genetic ASD risk. ASD DMRs at CYP2E1 and IRS2 reached genome-wide significance, replicated by pyrosequencing, and correlated with expression. Methylation at CYP2E1 associated with both ASD diagnosis and cis genotype, while methylation at IRS2 was unaffected by cis genotype but modified by preconceptional maternal prenatal vitamin use. This study therefore identified two potentially useful early epigenetic markers for ASD in placenta.
Neuromusculoskeletal simulation reveals abnormal rectus femoris-gluteus medius reflex coupling in post-stroke gait
Authors: Akbas Tunc , Neptune Richard R. , Sulzer James 
Published: December 2018

ABSTRACTPost-stroke gait is often accompanied by muscle impairments that result in adaptations such as hip circumduction to compensate for lack of knee flexion. Our previous work robotically enhanced knee flexion in individuals post-stroke with Stiff-Knee Gait (SKG), however, this resulted in greater circumduction, suggesting the existence of abnormal coordination in SKG. The purpose of this work is to investigate two possible mechanisms of the abnormal coordination: 1) an involuntary coupling between stretched quadriceps and abductors, and 2) a coupling between volitionally activated knee flexors and abductors. We used previously collected kinematic, kinetic and EMG measures from nine participants with chronic stroke and five healthy controls during walking with and without the applied knee flexion torque perturbations in the pre-swing phase of gait in the neuromusculoskeletal simulation. The measured muscle activity was supplemented by simulated muscle activations to estimate the muscle states of the quadriceps, hamstrings and hip abductors. We used linear mixed models to investigate two hypotheses: H1) association between quadriceps and abductor activation during an involuntary period (reflex latency) following the perturbation and H2) association between hamstrings and abductor activation after the perturbation was removed. We observed significantly higher rectus femoris (RF) activation in stroke participants compared to healthy controls within the reflex latency period following the perturbation based on both measured (H1, p < 0.001) and simulated (H1, p = 0.022) activity. Simulated RF and gluteus medius (GMed) activations were correlated only in those with SKG, which was significantly higher compared to healthy controls (H1, p = 0.030). There was no evidence of voluntary synergistic coupling between any combination of hamstrings and hip abductors (H2, p > 0.05) when the perturbation was removed. The RF-GMed coupling suggests an underlying abnormal reflex coordination pattern in post-stroke SKG. These results challenge earlier assumptions that hip circumduction in stroke is simply a kinematic adaptation due to reduced toe clearance. Instead, abnormal coordination may underlie circumduction, illustrating the deleterious role of abnormal coordination in post-stroke gait.
Fast and accurate differential transcript usage by testing equivalence class counts
Authors: Cmero Marek , Davidson Nadia M , Oshlack Alicia 
Published: December 2018

AbstractRNA sequencing has enabled high-throughput and fine-grained quantitative analyses of the transcriptome. While differential gene expression is the most widely used application of this technology, RNA-seq data also has the resolution to infer differential transcript usage (DTU), which can elucidate the role of different transcript isoforms between experimental conditions, cell types or tissues. DTU has typically been inferred from exon-count data, which has issues with assigning reads unambiguously to counting bins, and requires alignment of reads to the genome. Recently, approaches have emerged that use transcript quantifications estimates directly for DTU. Transcript counts can be inferred from ‘pseudo’ or lightweight aligners, which are significantly faster than traditional genome alignment. However, recent evaluations show lower sensitivity in DTU analysis. Transcript abundances are estimated from equivalence classes (ECs), which determine the transcripts that any given read is compatible with. Here we propose performing DTU testing directly on equivalence class read counts. We evaluate this approach on simulated human and drosophila data, as well as on a real dataset through subset testing. We find that ECs counts have similar sensitivity and false discovery rates as exon-level counts but can be generated in a fraction of the time through the use of pseudo-aligners. We posit that equivalent class counts is a natural unit on which to perform many types of analysis.
M1 disruption delays motor processes but not deliberation about action choices
Authors: Derosiere Gerard , Thura David , Cisek Paul , Duque Julie 
Published: December 2018

AbstractDecisions about actions typically involve a period of deliberation that ends with the commitment to a choice and the motor processes overtly expressing that choice. Previous studies have shown that neural activity in sensorimotor areas, including the primary motor cortex (M1), correlates with deliberation features during action selection. Yet, the causal contribution of these areas to the decision process remains unclear. Here, we investigated whether M1 determines choice commitment, or whether it simply reflects decision signals coming from upstream structures and instead mainly contributes to the motor processes that follow commitment. To do so, we tested the impact of a disruption of M1 activity, induced by continuous theta burst stimulation (cTBS), on the behavior of human subjects in (1) a simple reaction time (SRT) task allowing us to estimate the duration of the motor processes and (2) a modified version of the tokens task (Cisek et al., 2009), which allowed us to estimate subjects’ time of commitment as well as accuracy criterion. The efficiency of cTBS was attested by a reduction in motor evoked potential amplitudes following M1 disruption, as compared to those following a sham stimulation. Furthermore, M1 cTBS lengthened SRTs, indicating that motor processes were perturbed by the intervention. Importantly, all of the behavioral results in the tokens task were similar following M1 disruption and sham stimulation, suggesting that the contribution of M1 to the deliberation process is potentially negligible. Taken together, these findings favor the view that M1 contribution is downstream of the decision process.New and noteworthyDecisions between actions are ubiquitous in the animal realm. Deliberation during action choices entails changes in the activity of the sensorimotor areas controlling those actions, but the causal role of these areas is still often debated. Using continuous theta burst stimulation, we show that disrupting the primary motor cortex (M1) delays the motor processes that follow instructed commitment but does not alter volitional deliberation, suggesting that M1 contribution may be downstream of the decision process.
Dynamic changes in the brain protein interaction network correlates with progression of Aβ42 pathology in Drosophila
Authors: Scholes Harry M. , Cryar Adam , Kerr Fiona , Sutherland David , Gethings Lee A. , Vissers Johannes P. C. , Lees Jonathan G. , Orengo Christine A. , Partridge Linda , Thalassinos Konstantinos 
Published: December 2018

AbstractAlzheimer’s disease (AD), the most prevalent form of dementia, is a progressive and devastating neurodegenerative condition for which there are no effective treatments. Understanding the molecular pathology of AD during disease progression may identify new ways to reduce neuronal damage. Here, we present a longitudinal study tracking dynamic proteomic alterations in the brains of an inducible Drosophila melanogaster model of AD expressing the Arctic mutant Aβ42 gene. We identified 3093 proteins from flies that were induced to express Aβ42 and age-matched healthy controls using label-free quantitative ion-mobility data independent analysis mass spectrometry. Of these, 228 proteins were significantly altered by Aβ42 accumulation and were enriched for AD-associated processes. Network analyses further revealed that these proteins have distinct hub and bottleneck properties in the brain protein interaction network, suggesting that several may have significant effects on brain function. Our unbiased analysis provides useful insights into the key processes governing the progression of amyloid toxicity and forms a basis for further functional analyses in model organisms and translation to mammalian systems.
Asexual reproduction drives the reduction of transposable element load
Authors: Bast Jens , Jaron Kamil S. , Schuseil Donovan , Roze Denis , Schwander Tanja 
Published: December 2018

AbstractTheory predicts that sexual reproduction can both facilitate and restrain transposable element (TE) accumulation by providing TEs with a means of spreading to all individuals in a population and facilitating TE load reduction via purifying selection. By quantifying genomic TE loads over time in experimental sexual and asexualSaccharomyces cerevisiaepopulations, we provide direct evidence that asexual reproduction drives a reduction of TE loads. We show, using simulations, that this reduction occurs via evolution of TE activity, most likely via increased excision rates. Thus, sex is a major driver of genomic TE loads and at the root of the success of TEs.
De-Novo-Designed Translational Repressors for Multi-Input Cellular Logic
Authors: Kim Jongmin , Zhou Yu , Carlson Paul , Teichmann Mario , Simmel Friedrich C. , Silver Pamela A. , Collins James J. , Lucks Julius B. , Yin Peng , Green Alexander A. 
Published: December 2018

ABSTRACTSynthetic biology aims to apply engineering principles toward the development of novel biological systems for biotechnology and medicine. Despite efforts to expand the set of high-performing parts for genetic circuits, achieving more complex circuit functions has often been limited by the idiosyncratic nature and crosstalk of commonly utilized parts. Here, we present a molecular programming strategy that implements RNA-based repression of translation usingde-novo-designed RNAs to realize high-performance orthogonal parts with mRNA detection and multi-input logic capabilities. These synthetic post-transcriptional regulators, termed toehold repressors and three-way junction (3WJ) repressors, efficiently suppress translation in response to cognate trigger RNAs with nearly arbitrary sequences using thermodynamically and kinetically favorable linear-linear RNA interactions. Automatedin silicooptimization of thermodynamic parameters yields improved toehold repressors with up to 300-fold repression, while in-cell SHAPE-Seq measurements of 3WJ repressors confirm their designed switching mechanism in living cells. Leveraging the absence of sequence constraints, we identify eight- and 15-component sets of toehold and 3WJ repressors, respectively, that provide high orthogonality. The modularity, wide dynamic range, and low crosstalk of the repressors enable their direct integration into ribocomputing devices that provide universal NAND and NOR logic capabilities and can perform multi-input RNA-based logic. We demonstrate these capabilities by implementing a four-input NAND gate and the expression NOT((A1 AND A2) OR (B1 AND B2)) inEscherichia coli. These features make toehold and 3WJ repressors important new classes of translational regulators for biotechnological applications.
ASCOT identifies key regulators of neuronal subtype-specific splicing
Authors: Ling Jonathan P , Wilks Christopher , Charles Rone , Ghosh Devlina , Jiang Lizhi , Santiago Clayton P , Pang Bo , Venkataraman Anand , Clark Brian S , Nellore Abhinav , Langmead Ben , Blackshaw Seth 
Published: December 2018

AbstractPublic archives of next-generation sequencing data are growing exponentially, but the difficulty of marshaling this data has led to its underutilization by scientists. Here we present ASCOT, a resource that allows researchers to summarize, visualize, and query alternative splicing patterns in public RNA-Seq data. ASCOT enables rapid identification of splice-variants across tens of thousands of bulk and single-cell RNA-Seq datasets in human and mouse. To demonstrate the utility of ASCOT, we first focused on the nervous system and identified many alternative exons used only by a single neuronal subtype. We then leveraged datasets from the ENCODE and GTEx consortiums to study the unique splicing patterns of rod photoreceptors and found that PTBP1 knockdown combined with overexpression of MSI1 and PCBP2 activates rod-specific exons in HepG2 liver cancer cells. Furthermore, we observed that MSI1 targets intronic UAG motifs proximal to the 5’ splice site and interacts synergistically with PTBP1 downregulation. Finally, we show that knockdown of MSI1 in the retina abolishes rod-specific splicing. This work demonstrates how large-scale analysis of public RNA-Seq datasets can yield key insights into cell type-specific control of RNA splicing and underscores the importance of considering both annotated and unannotated splicing events. ASCOT splicing and gene expression data tables, software, and interactive browser are available at http://ascot.cs.jhu.edu.