bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rational Design of a Protein Kinase A Nuclear-cytosol Translocation Reporter
Authors: Kim Allen K. , Wu Helen D. , Inoue Takanari 
Published: July 2019

AbstractProtein Kinase A (PKA) exists as a tetrameric holoenzyme which activates with increase of cAMP and plays an important role in many physiological processes including cardiac physiology, neuronal development, and adipocyte function. Although this kinase has been the subject of numerous biosensor designs, a single-fluorophore reporter that performs comparably to Förster resonance energy transfer (FRET) has not yet been reported. Here, we have used basic observations of electrostatic interactions in PKA substrate recognition mechanism and nucleus localization sequence motif to design a phosphorylation switch that shuttles between the cytosol and the nucleus, a strategy that should be generalizable to all basophilic kinases. The resulting reporter yielded comparable kinetics and dynamic range to the PKA FRET reporter, AKAR3EV. We also performed basic characterization and demonstrated its potential use in monitoring multiple signaling molecules inside cells using basic fluorescence microscopy. Due to the single-fluorophore nature of this reporter, we envision that this could find broad applications in studies involving single cell analysis of PKA activity.
An Optimally Weighted Combination Method to Detect Novel Disease Associated Genes Using Publicly Available GWAS Summary Data
Authors: Zhang Jianjun , Gonzales Samantha , Liu Jianguo , Gao Xiaoyi Raymond , Wang Xuexia 
Published: July 2019

AbstractGene-based analyses offer a useful alternative and complement to the usual single nucleotide polymorphism (SNP) based analysis for genome-wide association studies (GWASs). Using appropriate weights (pre-specified or eQTL-derived) can boost statistical power, especially for detecting weak associations between a gene and a trait. Because the sparsity level or association directions of the underlying association patterns in real data are often unknown and access to individual-level data is limited, we propose an optimal weighted combination (OWC) test applicable to summary statistics from GWAS. This method includes burden tests, weighted sum of squared score (SSU), weighted sum statistic (WSS), and the score test as its special cases. We analytically prove that aggregating the variants in one gene is the same as using the weighted combination of Z-scores for each variant based on the score test method. We also numerically illustrate that our proposed test outperforms several existing comparable methods via simulation studies. Lastly, we utilize schizophrenia GWAS data and a fasting glucose GWAS meta-analysis data to demonstrate that our method outperforms the existing methods in real data analyses. Our proposed test is implemented in the R program OWC, which is freely and publicly available.
Comparative analysis of the CDR loops of antigen receptors
Authors: Wong Wing Ki , Leem Jinwoo , Deane Charlotte M. 
Published: July 2019

AbstractThe adaptive immune system uses two main types of antigen receptors: T-cell receptors (TCRs) and antibodies. While both proteins share a globally similar β-sandwich architecture, TCRs are specialised to recognise peptide antigens in the binding groove of the major histocompatibility complex, while antibodies can bind an almost infinite range of molecules. For both proteins, the main determinants of target recognition are the complementarity-determining region (CDR) loops. Five of the six CDRs adopt a limited number of backbone conformations, known as the ‘canonical classes’; the remaining CDR (β3 in TCRs and H3 in antibodies) is more structurally diverse. In this paper, we first update the definition of canonical forms in TCRs, build an auto-updating sequence-based prediction tool (available at http://opig.stats.ox.ac.uk/resources) and demonstrate its application on large scale sequencing studies. Given the global similarity of TCRs and antibodies, we then examine the structural similarity of their CDRs. We find that TCR and antibody CDRs tend to have different length distributions, and where they have similar lengths, they mostly occupy distinct structural spaces. In the rare cases where we found structural similarity, the underlying sequence patterns for the TCR and antibody version are different. Finally, where multiple structures have been solved for the same CDR sequence, the structural variability in TCR loops is higher than that in antibodies, suggesting TCR CDRs are more flexible. These structural differences between TCR and antibody CDRs may be important to their different biological functions.
Representational organization of novel task sets during proactive encoding
Authors: Palenciano Ana F. , González-García Carlos , Arco Juan E. , Pessoa Luiz , Ruz María 
Published: July 2019

AbstractRecent multivariate analyses of brain data have boosted our understanding of the organizational principles that shape neural coding. However, most of this progress has focused on perceptual visual regions (Connolly et al., 2012), whereas far less is known about the organization of more abstract, action-oriented representations. In this study, we focused on humans’ remarkable ability to turn novel instructions into actions. While previous research shows that instruction encoding is tightly linked to proactive activations in fronto-parietal brain regions, little is known about the structure that orchestrates such anticipatory representation. We collected fMRI data while participants (both males and females) followed novel complex verbal rules that varied across control-related variables (integrating within/across stimuli dimensions, response complexity, target category) and reward expectations. Using Representational Similarity Analysis (Kriegeskorte et al., 2008) we explored where in the brain these variables explained the organization of novel task encoding, and whether motivation modulated these representational spaces. Instruction representations in the lateral prefrontal cortex were structured by the three control-related variables, while intraparietal sulcus encoded response complexity and the fusiform gyrus and precuneus organized its activity according to the relevant stimulus category. Reward exerted a general effect, increasing the representational similarity among different instructions, which was robustly correlated with behavioral improvements. Overall, our results highlight the flexibility of proactive task encoding, governed by distinct representational organizations in specific brain regions. They also stress the variability of motivation-control interactions, which appear to be highly dependent on task attributes such as complexity or novelty.Significance StatementIn comparison with other primates, humans display a remarkable success in novel task contexts thanks to our ability to transform instructions into effective actions. This skill is associated with proactive task-set reconfigurations in fronto-parietal cortices. It remains yet unknown, however, how the brain encodes in anticipation the flexible, rich repertoire of novel tasks that we can achieve. Here we explored cognitive control and motivation-related variables that might orchestrate the representational space for novel instructions. Our results showed that different dimensions become relevant for task prospective encoding depending on the brain region, and that the lateral prefrontal cortex simultaneously organized task representations following different control-related variables. Motivation exerted a general modulation upon this process, diminishing rather than increasing distances among instruction representations.
Chloride dynamics alter the input-output properties of neurons
Authors: Currin Christopher B. , Trevelyan Andrew J. , Akerman Colin J. , Raimondo Joseph V. 
Published: July 2019

AbstractFast synaptic inhibition is a critical determinant of neuronal output, with subcellular targeting of synaptic inhibition able to exert different transformations of the neuronal input-output function. At the receptor level, synaptic inhibition is primarily mediated by chloride-permeable Type A GABA receptors. Consequently, dynamics in the neuronal chloride concentration can alter the functional properties of inhibitory synapses. How differences in the spatial targeting of inhibitory synapses interact with intracellular chloride dynamics to modulate the input-output function of neurons is not well understood. To address this, we developed computational models of multi-compartment neurons that incorporate experimentally parametrised mechanisms to account for neuronal chloride influx, diffusion, and extrusion. We found that synaptic input (either excitatory, inhibitory, or both) can lead to subcellular variations in chloride concentration, despite a uniform distribution of chloride extrusion mechanisms. Accounting for chloride changes resulted in substantial alterations in the neuronal input-output function. This was particularly the case for peripherally targeted dendritic inhibition where dynamic chloride compromised the ability of inhibition to offset neuronal input-output curves. Our simulations revealed that progressive changes in chloride concentration mean that the neuronal input-output function is not static but varies significantly as a function of the duration of synaptic drive. Finally, we found that the observed effects of dynamic chloride on neuronal output were entirely mediated by changes in the dendritic reversal potential for GABA. Our findings provide a framework for understanding the computational effects of chloride dynamics on dendritically targeted synaptic inhibition.Author SummaryThe fundamental unit of computation in the brain is the neuron, whose output reflects information within the brain. A determining factor in the transfer and processing of information in the brain is the modulation of activity by inhibitory synaptic inputs. Fast synaptic inhibition is mediated by the neurotransmitter GABA binding to GABAA receptors, which are permeable to chloride ions. How changes in chloride ion concentration affect neuronal output is an important consideration for information flow in the brain that is currently not being thoroughly investigated. In this research, we used multi-compartmental models of neurons to link the deleterious effects that accumulation of chloride ions can have on inhibitory signalling with changes in neuronal ouput. Together, our results highlight the importance of accounting for changes in chloride concentration in theoretical and computer-based models that seek to explore the computational properties of inhibition.
Laminar differences in responses to naturalistic texture in macaque V1 and V2
Authors: Ziemba Corey M , Perez Richard K , Pai Julia , Hallum Luke E , Shooner Christopher , Kelly Jenna G , Movshon J Anthony 
Published: July 2019

AbstractMost single units recorded from macaque V2 respond with higher firing rates to synthetic texture images containing “naturalistic” higher-order statistics than to spectrally matched “noise” images lacking these statistics. In contrast, few single units in V1 show this property. We explored how the strength and dynamics of response vary across the different layers of visual cortex by recording multiunit and gamma band activity evoked by brief presentations of naturalistic and noise images in V1 and V2 of anesthetized macaque monkeys. As previously reported, recordings in V2 showed consistently stronger responses to naturalistic texture than to spectrally matched noise. In contrast to single unit recordings, V1 multiunit activity showed some preference for images with naturalistic statistics, and in gamma band activity this preference was comparable across V1 and V2. Sensitivity to naturalistic image structure was strongest in the supragranular and infragranular layers of V1, but weak in granular layers, suggesting that it might reflect feedback from V2. Response timing was consistent with this idea. Visual responses appeared first in V1, followed by V2. Sensitivity to naturalistic texture emerged first in V2, followed by the supragranular and infragranular layers of V1, and finally in the granular layers of V1. Our results demonstrate laminar differences in the encoding of higher-order statistics of natural texture, and suggest that this sensitivity first arises in V2 and is fed back to modulate activity in V1.Significance StatementThe circuit mechanisms responsible for visual representations of intermediate complexity are largely unknown. We used a well-validated set of synthetic texture stimuli to probe the temporal and laminar profile of sensitivity to the higher-order statistical structure of natural images. We found that this sensitivity emerges first and most strongly in V2 but soon after in V1. However, sensitivity in V1 is higher in the laminae (extragranular) and recording modalities (local field potential) most likely affected by V2 connections, suggesting a feedback origin. Our results show how sensitivity to naturalistic image structure emerges across time and circuitry in the early visual cortex.
Globally elevating the AGE clearance receptor, OST48, does not protect against the development of diabetic kidney disease, despite improving insulin secretion
Authors: Zhuang Aowen , Yap Felicia YT , McCarthy Domenica , Leung Sherman S. , Penfold Sally A. , Leung Chris , Sourris Karly C. , Harcourt Brooke E. , Thallas-Bonke Vicki , Coughlan Melinda T , Schulz Benjamin L , Forbes Josephine M 
Published: July 2019

AbstractThe accumulation of advanced glycation end products (AGEs) have been implicated in the development and progression of diabetic kidney disease (DKD). There has been interest in investigating the potential of AGE clearance receptors, such as oligosaccharyltransferase-48kDa subunit (OST48) to prevent the detrimental effects of excess AGE accumulation seen in the diabetic kidney. Here the objective of the study was to increase the expression of OST48 to examine if this slowed the development of DKD by facilitating the clearance of AGEs. Groups of 8-week-old heterozygous knock-in male mice (n=9-12/group) over-expressing the gene encoding for OST48, dolichyl-diphosphooligosaccharide-protein glycosyltransferase (DDOST+/-) and litter mate controls were randomised to either (i) no diabetes or (ii) diabetes induced via multiple low-dose streptozotocin and followed for 24 weeks. By the study end, global over expression of OST48 increased glomerular OST48. This facilitated greater renal excretion of AGEs but did not affect circulating or renal AGE concentrations. Diabetes resulted in kidney damage including lower glomerular filtration rate, albuminuria, glomerulosclerosis and tubulointerstitial fibrosis. In diabetic mice, tubulointerstitial fibrosis was further exacerbated by global increases in OST48. There was significantly insulin effectiveness, increased acute insulin secretion, fasting insulin concentrations and AUCinsulin observed during glucose tolerance testing in diabetic mice with global elevations in OST48 when compared to diabetic wild-type littermates. Overall, this study suggested that despite facilitating urinaryrenal AGE clearance, there were no benefits observed on kidney functional and structural parameters in diabetes afforded by globally increasing OST48 expression. However, the improvements in insulin secretion seen in diabetic mice with global over-expression of OST48 and their dissociation from effects on kidney function warrant future investigation.
A neuromechanical model of multiple network rhythmic pattern generators for forward locomotion inC. elegans
Authors: Olivares Erick , Izquierdo Eduardo J. , Beer Randall D. 
Published: July 2019

AbstractMultiple mechanisms contribute to the generation, propagation, and coordination of the rhythmic patterns necessary for locomotion inCaenorhabditis elegans. Current experiments have focused on two possibilities: pacemaker neurons and stretch-receptor feedback. Here, we focus on whether it is possible that a chain of multiple network rhythmic pattern generators in the ventral nerve cord also contribute to locomotion. We use a simulation model to search for parameters of the anatomically constrained ventral nerve cord circuit that, when embodied and situated, can drive forward locomotion on agar, in the absence of pacemaker neurons or stretch-receptor feedback. Systematic exploration of the space of possible solutions reveals that there are multiple configurations that result in locomotion that is consistent with certain aspects of the kinematics of worm locomotion on agar. Analysis of the best solutions reveals that gap junctions between different classes of motorneurons in the ventral nerve cord can play key roles in coordinating the multiple rhythmic pattern generators.
Lessons in genome engineering: opportunities, tools and pitfalls
Authors: Poernbacher Ingrid , Crossman Sam , Kurth Joachim , Nojima Hisashi , Baena-Lopez Alberto , Alexandre Cyrille , Vincent Jean-Paul 
Published: July 2019

ABSTRACTCRISPR/Cas technology allows the creation of double strand breaks and hence loss of function mutations at any location in the genome. This technology is now routine for many organisms and cell lines. Here we describe how CRISPR/Cas can be combined with other DNA manipulation techniques (e.g. homology-based repair, site-specific integration and Cre or FLP-mediated recombination) to create sophisticated tools to measure and manipulate gene activity. In one class of applications, a single site-specific insertion generates a transcriptional reporter, a loss-of function allele, and a tagged allele. In a second class of modifications, essential sequences are deleted and replaced with an integrase site, which serves as a platform for the creation of custom reporters, transcriptional drivers, conditional alleles and regulatory mutations. We describe how these tools and protocols can be implemented easily and efficiently. Importantly, we also highlight unanticipated failures, which serve as cautionary tales, and suggest mitigating measures. Our tools are designed for use inDrosophilabut the lessons we draw are likely to be widely relevant.AUTHOR SUMMARYThe genome contains all the information that an organism needs to develop and function throughout its life. One of the goal of genetics is to decipher the role of all the genes (typically several thousands for an animal) present in the genome. One approach is to delete each gene and assay the consequences. Deletion of individual genes is now readily achieved with a technique called CRISPR/Cas9. However, simple genetic deletion provides limited information. Here we describe strains and DNA vectors that streamline the generation of more sophisticated genetic tools. We describe general means of creating alleles (genetic variants) that enable gene activity to be measured and experimentally modulated in space and time. Although the tools we describe are universally applicable, each gene requires special consideration. Based on our experience of successes and failures, we suggest measures to maximise the chances that engineered alleles serve their intended purpose. Although our methods are designed for use in Drosophila, they could be adapted to any organism that is amenable to CRISPR/Cas9 genome modification.
Unilateral neglect is associated with poor proprioception after stroke – a systematic review
Authors: Fisher Georgia , de Oliveira Camila Quel , Gandevia Simon , Kennedy David 
Published: July 2019

AbstractBackgroundProprioceptive impairment is a potential contributing factor to the clinical presentation of Unilateral Neglect (UN), a common and debilitating condition that can occur after stroke. To date there has not been a comprehensive review of studies examining the various aspects of proprioception in UN after stroke.AimTo determine if the presence of UN is associated with more severe proprioceptive deficit in stroke affected populations.MethodsThe MEDLINE, Embase, Scopus, CINAHL and Web of Science databases were searched from inception to January 2019 using an a priori search strategy. Two independent reviewers screened abstracts and full texts. Two reviewers then independently extracted data from each full text. A third reviewer resolved disagreements at each step. Risk of bias was assessed using the AXIS Quality Assessment tool. For full protocol see PROSPERO, registration number CRD42018086070. One-hundred and sixty-seven abstracts were identified, of which fifty-four were eligible for full text screening. A total of 18 papers were included in the review.ConclusionsMore severe proprioceptive deficit is associated with the presence of UN after stroke. However, the available evidence is limited by the large heterogeneity of assessment of both UN and proprioception, and level of study quality. UN and proprioception are seldom completely assessed in research, and it is likely this is true in everyday clinical practice.
Exploring the basis of 2-propenyl and 3-butenyl glucosinolate synthesis by QTL mapping and RNA-sequencing in Brassica juncea
Authors: Khattak Aimal Nawaz , Wang Tianya , Yu Kunjiang , Yang Renqin , Wan Wei , Ye Botao , Tian Entang 
Published: July 2019

AbstractBrassica juncea is used as a condiment, as vegetables and as an oilseed crop, especially in semiarid areas. In the present study, we constructed a genetic map using one recombinant inbred line (RIL) of B. juncea. A total of 304 ILP (intron length polymorphism) markers were mapped to 18 linkage groups designated LG01-LG18 in B. juncea. The constructed map covered a total genetic length of 1671.13 cM with an average marker interval of 5.50 cM. The QTLs for 2-propenyl glucosinolates (GSLs) colocalized with the QTLs for 3-butenyl GSLs between At1g26180 and BnapPIP1580 on LG08 in the field experiments of 2016 and 2017. These QTLs accounted for an average of 42.3% and 42.6% phenotypic variation for 2-propenyl and 3-butenyl GSLs, respectively. Furthermore, the Illumina RNA-sequencing technique was used to excavate the genes responsible for the synthesis of GSLs in the siliques of the parental lines of the RIL mapping population, because the bulk of the seed GSLs might originate from the siliques. Comparative analysis and annotation by gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) revealed that 324 genes were involved in GSL metabolism, among which only 24 transcripts were differentially expressed genes (DEGs). Among those DEGs, 15 genes were involved in the biosynthesis and transport of aliphatic GSLs, and their expression patterns were further validated by qRT-PCR analysis. These RNA-Seq results will be helpful for further fine mapping, gene cloning and genetic mechanisms of 2-propenyl and 3-butenyl GSLs in B. juncea.
Heating of the cathode with a conical tip by atmospheric-pressure arc plasma
Authors: Liao Meng-Ran , Chen Tang , Lv Wei-Jian 
Published: July 2019

Purpose
In this study, the authors performed a numerical investigation on the heating of a hot cathode with a conical tip by atmospheric arc, taking into account of the two temperature sheath effect for the first time.

Design/methodology/approach
The Schottky effect at cathode surface is considered, which is based on the analytic solution of a one-dimensional sheath model. The unified model allows one to predict the cathode-plasma heat transfer.

Findings
The total heat flux to cathode surface is smaller than its components’ heat flux due to electron back diffusion is as large as that due to ion flux with the increase of cathode length the total heat transported to the cathode body has an obvious decrease.

Originality/value
It is found that two kinds of solution exist for the cathode with a 140° conical tip; however, only one stable solution exists when the conical angle is reduced to 130°.