bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouringde novomutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families
Authors: John Jibin , Kukshal Prachi , Bhatia Triptish , Harripaul Ricardo , Nimgaonkar V L , Deshpande S N , Thelma B.K. 
Published: November 2019

AbstractClinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rarede novovariant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets withde novoprotein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease. More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.
Acute perturbation of retromer and ESCPE-1 leads to functionally distinct and temporally resolved defects in endosomal cargo sorting
Authors: Evans Ashley J. , Daly James L. , Anuar Anis N. K. , Simonetti Boris , Cullen Peter J. 
Published: November 2019

ABSTRACTThe human retromer is a stable heterotrimer of VPS35, VPS29 and VPS26 whose principal role is to orchestrate the endosomal retrieval of hundreds of internalised cargo and promote their recycling to the cell surface; a prototypical cargo being the glucose transporter GLUT1. Retromer’s role in a distinct endosomal retrieval pathway, the retrograde sorting of the cation-independent mannose 6-phosphate receptor (CI-MPR) to the trans-Golgi network (TGN), remains controversial. Here we have developed and applied knocksideways to acutely inactivate retromer and by visualising the sorting of endogenous GLUT1 and CI-MPR provide insight into the temporal dynamics of endosomal cargo sorting in HeLa and H4 human neuroglioma cells. While retromer knocksideways led to the development of time-resolved defects in cell surface sorting of GLUT1 we failed to observe defects in the sorting of the CI-MPR. In contrast knocksideways of ESCPE-1, a key regulator of retrograde CI-MPR sorting, resulted in a time-resolved defect in CI-MPR sorting. Together these data provide independent evidence consistent with a comparatively limited role for retromer in ESCPE-1 dependent CI-MPR retrograde sorting in HeLa and H4 human neuroglioma cells.
Type-2 diabetes with low LDL-C: genetic insights into a unique phenotype
Authors: Klimentidis Yann C. , Arora Amit , Newell Michelle , Zhou Jin , Ordovas Jose M. , Renquist Benjamin J. , Wood Alexis C. 
Published: November 2019

AbstractAlthough hyperlipidemia is traditionally considered a risk factor for type-2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL-C increases T2D risk. We thus sought to comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that LDL-C was negatively associated with T2D (OR=0.43[0.41, 0.45] per mmol/L unit of LDL-C), despite positive associations of LDL-C with HbA1c and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (n=431,167) and the GLGC consortium (n=188,577), and T2D from the DIAGRAM consortium (n=898,130). We identified 31 loci associated with lower LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this phenotype, and 9 have previously been implicated in non-alcoholic fatty liver disease. Finally, two-sample Mendelian randomization analyses suggest that low LDL-C causes T2D, although causal interpretations are challenging due to pleiotropy. Our findings extend our current understanding of the higher T2D risk among individuals with low LDL-C, and of the underlying mechanisms, including those underlying the diabetogenic effect of LDL-C-lowering medications.
Reversed paired-gRNA plasmid cloning strategy for efficient genome editing inEscherichia coli
Authors: Ding Tingting , Huang Chaoyong , Liang Zeyu , Ma Xiaoyan , Wang Ning , Huo Yi-Xin 
Published: November 2019

SummaryA growing number of CRISPR-Cas9 associated applications require co-expression of two distinct gRNAs. However, coexpressing paired gRNAs under the driving of independent but identical promoters in the same direction triggers plasmid instability, due to the presence of direct repeats (DRs). In this study, deletion between DRs occurred with high frequencies during plasmid construction and duplication processes, when three DRs-involved paired-gRNA plasmids cloning strategies were tested. This recombination phenomenon was RecA-independent, in agreement with the replication slippage model. To completely eliminate the DRs-induced plasmid instability, a reversed paired-gRNA plasmids (RPGPs) cloning strategy was developed by converting DRs to the more stable invert repeats (IRs). Using RPGPs, we achieved a rapid deletion of chromosome fragments up to 100 kb with high efficiency of 83.33% inEscherichia coli. This study provides general solutions to construct stable plasmids containing short DRs, which can improve the performances of CRISPR systems that relied on paired gRNAs, and also facilitate other applications involving repeated genetic parts.
Myeloarchitecture gradients in the human insula serve as blueprints for its diverse connectivity and function
Authors: Royer Jessica , Paquola Casey , Larivière Sara , de Wael Reinder Vos , Tavakol Shahin , Lowe Alexander J. , Benkarim Oualid , Evans Alan C. , Bzdok Danilo , Smallwood Jonathan , Frauscher Birgit , Bernhardt Boris C. 
Published: November 2019

AbstractInsular cortex is a core hub involved in multiple cognitive and socio-affective processes. Yet, the anatomical mechanisms that explain how it is involved in such a diverse array of functions remain incompletely understood. Here, we define a novel framework to test the hypothesis that changes in myeloarchitecture across the insular cortex explain how it can be involved in many different facets of cognitive function. Detailed intracortical profiling, performed across hundreds of insular locations on the basis of myelin-sensitive magnetic resonance imaging (MRI), was compressed into a lower-dimensional space uncovering principal axes of myeloarchitectonic variation. Leveraging two datasets with different high-resolution MRI contrasts, we obtained robust support for two principal dimensions of insular myeloarchitectonic differentiation in vivo, one running from ventral anterior to posterior banks and one radiating from dorsal anterior towards both ventral anterior and posterior subregions. Analyses of post mortem 3D histological data showed that the antero-posterior axis was mirrored in cytoarchitectural markers, even when controlling for anatomical landmarks and sulco-gyral folding. Resting-state functional connectomics in the same individuals and ad hoc meta-analyses showed that myelin gradients in the insula constrained affiliation to macroscale intrinsic functional systems, showing differential shifts in functional network embedding across each myelin-derived gradient. Collectively, our findings offer a novel approach to capture structure-function interactions of a key node of the limbic system, and suggest a multidimensional structural basis underlying the diverse functional roles of the insula.
A Bayesian predictive approach for dealing with pseudoreplication
Authors: Lazic Stanley E. , Mellor Jack R. , Ashby Michael C. , Munafo Marcus R. 
Published: November 2019

AbstractPseudoreplication occurs when the number of measured values or data points exceeds the number of genuine replicates, and when the statistical analysis treats all data points as independent and thus fully contributing to the result. By artificially inflating the sample size, pseudoreplication contributes to irreproducibility, and it is a pervasive problem in biological research. In some fields, more than half of published experiments have pseudoreplication – making it one of the biggest threats to inferential validity. Researchers may be reluctant to use appropriate statistical methods if their hypothesis is about the pseudoreplicates and not the genuine replicates; for example, when an intervention is applied to pregnant female rodents (genuine replicates) but the hypothesis is about the effect on the multiple offspring (pseudoreplicates). We propose using a Bayesian predictive approach, which enables researchers to make valid inferences about biological entities of interest, even if they are pseudoreplicates, and show the benefits of this approach using twoin vivodata sets.
Effects of coral colony morphology on turbulent flow dynamics
Authors: Hossain Md Monir , Staples Anne E. 
Published: November 2019

AbstractLocal flow dynamics play a central role in physiological processes like respiration and nutrient uptake in coral reefs. Despite the importance of corals as hosts to a quarter of all marine life, and the pervasive threats currently facing corals, little is known about the detailed hydrodynamics of branching coral colonies. Here, in order to investigate the effects of the colony branch density and surface roughness on the local flow field, three-dimensional simulations were performed using immersed boundary, large-eddy simulations for four different colony geometries under low and high unidirectional oncoming flow conditions. The first two colonies were from thePocilloporagenus, one with a densely branched geometry, and one with a comparatively loosely branched geometry. The second pair of colony geometries were derived from a scan of a singleMontipora capitatacolony, one with the verrucae covering the surface intact, and one with the verrucae removed. We found that the mean velocity profiles in the densely branched colony changed substantially in the middle of the colony, becoming significantly reduced at middle heights where flow penetration was poor, while the mean velocity profiles in the loosely branched colony remained similar in character from the front to the back of the colony, with no middle-range velocity deficit appearing at the center of the colony. When comparing the turbulent flow statistics at the surface of the rough and smoothM. capitatacolonies, we found higher Reynolds stress components for the smooth colony, indicating higher rates of mixing and transport compared to the rough colony, which must sacrifice mixing and transport efficiency in order to maintain its surface integrity in its natural high-flow environment. These results suggest that the densely branched, roughly patterned corals found in high flow areas may be more resistant not only to breakage, but also to flow penetration.
ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer
Authors: Shi Xiaoshan , Yokom Adam L. , Wang Chunxin , Young Lindsey N. , Youle Richard J. , Hurley James H. 
Published: November 2019

AbstractThe autophagy-initiating human ULK complex consists of the kinase ULK1/2, FIP200, ATG13, and ATG101. Hydrogen-deuterium exchange mass spectrometry was used to map their mutual interactions. The N-terminal 640 residues (NTD) of FIP200 interact with the C-terminal IDR of ATG13. Mutations in these regions abolish their interaction. Negative stain electron microscopy (EM) and multiangle light scattering showed that FIP200 is a dimer whilst a single molecule each of the other subunits is present. The FIP200 NTD is flexible in the absence of ATG13, but in its presence adopts the shape of the letter C ~20 nm across. The ULK1 EAT domain interacts loosely with the NTD dimer, while the ATG13-ATG101 HORMA dimer does not contact the NTD. Cryo-EM of the NTD dimer revealed a structure similarity to the scaffold domain of TBK1, suggesting an evolutionary similarity between the autophagy initiating TBK1 kinase and the ULK1 kinase complex.SummaryThe human ULK complex consists of ULK1/2, FIP200, ATG13, and ATG101. We found that the FIP200 N-terminal domain is a C-shaped dimer that binds directly to a single ATG13 molecule and serves as the organizing hub of the complex.
Recurrent Processes Emulate a Cascade of Hierarchical Decisions: Evidence from Spatio-Temporal Decoding of Human Brain Activity
Authors: Gwilliams Laura , King Jean-Remi 
Published: November 2019

AbstractMounting evidence suggests that perception depends on a largely-feedforward brain network. However, the discrepancy between (i) the latency of the corresponding feedforward responses (150-200 ms) and (ii) the time it takes human subjects to recognize brief images (often >500 ms) suggests that recurrent neuronal activity is critical to visual processing. Here, we use magneto-encephalography to localize, track and decode the feedforward and recurrent responses elicited by brief presentations of variably-ambiguous letters and digits. We first confirm that these stimuli trigger, within the first 200 ms, a feedforward response in the ventral and dorsal cortical pathways. The subsequent activity is distributed across temporal, parietal and prefrontal cortices and leads to a slow and incremental cascade of representations culminating in action-specific motor signals. We introduce an analytical framework to show that these brain responses are best accounted for by a hierarchy of recurrent neural assemblies. An accumulation of computational delays across specific processing stages explains subjects’ reaction times. Finally, the slow convergence of neural representations towards perceptual categories is quickly followed by all-or-none motor decision signals. Together, these results show how recurrent processes generate, over extended time periods, a cascade of hierarchical decisions that ultimately predicts subjects’ perceptual reports.
Loss of m1acp3Ψ ribosomal RNA modification is a major feature of cancer
Authors: Babaian Artem , Rothe Katharina , Girodat Dylan , Minia Igor , Djondovic Sara , Milek Miha , Spencer Miko Sandra E. , Wieden Hans-Joachim , Landthaler Markus , Morin Gregg , Mager Dixie L. 
Published: November 2019

SummaryThe ribosome is an RNA-protein complex essential for translation in all domains of life. The structural and catalytic core of the ribosome is its ribosomal RNA (rRNA). While mutations in ribosomal protein (RP) genes are known drivers of oncogenesis, oncogenic rRNA variants have remained elusive. We discovered a cancer-specific single nucleotide variation in 18S rRNA at nucleotide 1248.U in up to 45.9% of colorectal carcinoma (CRC) patients and present across >22 cancer types. This is the site of a unique hyper-modified base, 1-methyl-3-α-amino-α-carboxyl-propyl pseudouridine (m1acp3Ψ), a >1 billion years conserved RNA modification at the ribosome’s peptidyl decoding-site. A sub-set of CRC tumors we term ‘hypo-m1acp3Ψ’, show sub-stoichiometric m1acp3Ψ-modification unlike normal control tissues. A m1acp3Ψ knockout model and hypo-m1acp3Ψ patient tumors share a translational signature, characterized by highly abundant ribosomal proteins. Thus, m1acp3Ψ-deficient rRNA forms an uncharacterized class of ‘onco-ribosome’ which may serve as a chemotherapeutic target for treating cancer patients.
Presynaptic depression maintains stable synaptic strength in developmentally arrested Drosophila larvae
Authors: Perry Sarah , Goel Pragya , Miller Daniel , Ganetzky Barry , Dickman Dion 
Published: November 2019

ABSTRACTPositive and negative modes of regulation typically constrain synaptic growth and function within narrow physiological ranges. However, it is unclear how synaptic strength is maintained when both pre- and post-synaptic compartments continue to grow beyond stages imposed by typical developmental programs. To address whether and how synapses can adjust to a novel life stage for which they were never molded by evolution, we have characterized synaptic growth, structure and function at the Drosophila neuromuscular junction (NMJ) under conditions where larvae are terminally arrested at the third instar stage. While wild type larvae transition to pupae after 5 days, arrested third instar (ATI) larvae persist for up to 35 days, during which NMJs exhibit extensive overgrowth in muscle size, presynaptic release sites, and postsynaptic glutamate receptors. Remarkably, despite this exuberant growth of both pre- and post-synaptic structures, stable neurotransmission is maintained throughout the ATI lifespan through a potent homeostatic reduction in presynaptic neurotransmitter release. Arrest of the larval stage in stathmin mutants reveals a degree of progressive instability and neurodegeneration that was not apparent during the typical larval period. Hence, during a period of unconstrained synaptic growth through an extended developmental period, a robust and adaptive form of presynaptic homeostatic depression can stabilize neurotransmission. More generally, the ATI manipulation provides an attractive system for studying neurodegeneration and plasticity across longer time scales.SIGNIFICANCE STATEMENTIt is unclear whether and how synapses adjust to a novel life stage for which they were never molded by evolution. We have characterized synaptic plasticity at the Drosophila neuromuscular junction in third instar larvae arrested in development for over 35 days. This approach has revealed that homeostatic depression stabilizes synaptic strength throughout the life of arrested third instars to compensate for excessive pre- and post-synaptic growth. This system also now opens the way for the study of synapses and degeneration over long time scales in this powerful model synapse.
Comparative transcriptomics reveal distinct patterns of gene expression conservation through vertebrate embryogenesis
Authors: Chan Megan E. , Bhamidipati Pranav S. , Goldsby Heather J. , Hintze Arend , Hofmann Hans A. , Young Rebecca L. 
Published: November 2019

AbstractDespite life’s diversity, studies of variation across animals often remind us of our shared evolutionary past. Abundant genome sequencing over the last ~25 years reveals remarkable conservation of genes and recent analyses of gene regulatory networks illustrate that not only genes but entire pathways are conserved, reused, and elaborated in the evolution of diversity. Predating these discoveries, 19th-century embryologists observed that though morphology at birth varies tremendously, certain stages of embryogenesis appear remarkably similar across vertebrates. Specifically, while early and late stages are variable across species, anatomy of mid-stages embryos (the ‘phylotypic’ stage) is conserved. This model of vertebrate development and diversification has found mixed support in recent analyses comparing gene expression across species possibly owing to differences across studies in species, embryonic stages, and gene sets compared. Here we perform a comparative analysis using 186 microarray and RNA-seq expression data sets covering embryogenesis in six vertebrate species spanning ~420 million years of evolution. We use an unbiased clustering approach to group stages of embryogenesis by transcriptomic similarity and ask whether gene expression similarity of clustered embryonic stages deviates from the null hypothesis of no relationship between timing and diversification. We use a phylogenetic comparative approach to characterize expression conservation pattern (i.e., early conservation, hourglass, inverse hourglass, late conservation, or no relationship) of each gene at each evolutionary node. Across vertebrates, we find an enrichment of genes exhibiting early conservation, hourglass, late conservation patterns and a large depletion of gene exhibiting no distinguishable pattern of conservation in both microarray and RNA-seq data sets. Enrichment of genes showing patterned conservation through embryogenesis indicates diversification of embryogenesis may be temporally constrained. However, the circumstances (e.g., gene groups, evolutionary nodes, species) under which each pattern emerges remain unknown and require both broad evolutionary sampling and systematic examination of embryogenesis across species.
Evaluating the effect of subsidies for rural development on agri-food and forestry firms
Authors: Pérez-Méndez José A. , Pérez-Urdiales María , Roibas David 
Published: November 2019

PurposeThis paper aims to evaluate the impact of the subsidies established by Measure 123 of the Rural Development Policy on the productivity of a sample of agri-food and forestry companies in the region of Asturias over the period 2006-2009.Design/methodology/approachThe authors estimate a stochastic frontier function which allows subsidies to be considered as affecting both the level of technical efficiency and technical progress.FindingsThe results show that while subsidies have a positive effect on the technical progress of companies in the agri-food industry, for the forestry industry, the effect materializes as an improvement in technical efficiency. Additionally, other factors affecting either, technical progress and technical efficiency were identified.Originality/valueThis study adopts a model that allows the separate identification of the effect of subsidies on the level of efficiency, on the one hand, and on the technical progress, on the other.