bluuebunny/crossref_metadata_2025_split huggingface dataset:
Attenuated Dopamine Receptor Signaling in Nucleus Accumbens Core in a Rat Model of Chemically-Induced Neuropathy
Authors: Selley D.E. , Lazenka M.F. , Sim-Selley L.J. , Potter D. N. , Chartoff Elena H. , Carlezon W.A. , Negus S.S. 
Published: August 2019

ABSTRACTNeuropathy is major source of chronic pain that can be caused by mechanically or chemically induced nerve injury. Previous work in a rat model of neuropathic pain demonstrated that bilateral formalin injection into the hind paws produced mechanical hypersensitivity (allodynia) and depressed responding for intracranial self-stimulation (ICSS). To determine whether neuropathy alters dopamine receptor responsiveness in mesolimbic brain regions, we examined dopamine D1-like and D2-like receptor (D1/2R) signaling and expression in male rats 14 days after bilateral intraplantar formalin injections into both rear paws. D2R-mediated G-protein activation and expression of the D2R long, but not short, isoform were reduced in nucleus accumbens (NAc) core, but not in NAc shell, caudate-putamen (CPu) or ventral tegmental area (VTA) of formalin-compared to saline-treated rats. In addition, D1R-stimulated adenylyl cyclase (AC) activity was also reduced in NAc core, but not in NAc shell or prefrontal cortex, of formalin-treated rats, whereas D1R expression was unaffected. Expression of other proteins involved in dopamine neurotransmission, including dopamine uptake transporter (DAT) and tyrosine hydroxylase (TH), were unaffected by formalin treatment. In behavioral tests, the effects of D2R agonists on ICSS were attenuated in formalin-treated rats, whereas the effects of D1R agonists were unchanged. These results indicate that intraplantar formalin as a model of chemically induced neuropathy produces attenuation of highly specific DA receptor signaling processes in NAc core of male rats.
Identifying branch-specific positive selection throughout the regulatory genome using an appropriate neutral proxy
Authors: Berrio Alejandro , Haygood Ralph , Wray Gregory A 
Published: August 2019

AbstractAdaptive changes incis-regulatory elements are an essential component of evolution by natural selection. Identifying adaptive and functional noncoding DNA elements throughout the genome is therefore crucial for understanding the relationship between phenotype and genotype. Here, we introduce a method we calledadaptyPhy, which adds significant improvements to our earlier method that tests for branch-specific directional selection in noncoding sequences. The motivation for these improvements is to provide a more sensitive and better targeted characterization of directional selection and neutral evolution across the genome. We use ENCODE annotations to identify appropriate proxy neutral sequences and demonstrate that the conservativeness of the test can be modulated during the filtration of reference alignments. We apply the method to noncoding Human Accelerated Elements as well as open chromatin elements previously identified in 125 human tissues and cell lines to demonstrate its utility. We also simulate sequence alignments under different classes of evolution in order to validate the ability ofadaptiPhyto distinguish positive selection from relaxation of constraint and neutral evolution. Finally, we evaluate the impact of query region length, proxy neutral sequence length, and branch count on test sensitivity.
Facetto: Combining Unsupervised and Supervised Learning for Hierarchical Phenotype Analysis in Multi-Channel Image Data
Authors: Krueger Robert , Beyer Johanna , Jang Won-Dong , Kim Nam Wook , Sokolov Artem , Sorger Peter K. , Pfister Hanspeter 
Published: August 2019

AbstractFacetto is a scalable visual analytics application that is used to discover single-cell phenotypes in high-dimensional multi-channel microscopy images of human tumors and tissues. Such images represent the cutting edge of digital histology and promise to revolutionize how diseases such as cancer are studied, diagnosed, and treated. Highly multiplexed tissue images are complex, comprising 109or more pixels, 60-plus channels, and millions of individual cells. This makes manual analysis challenging and error-prone. Existing automated approaches are also inadequate, in large part, because they are unable to effectively exploit the deep knowledge of human tissue biology available to anatomic pathologists. To overcome these challenges, Facetto enables a semi-automated analysis of cell types and states. It integrates unsupervised and supervised learning into the image and feature exploration process and offers tools for analytical provenance. Experts can cluster the data to discover new types of cancer and immune cells and use clustering results to train a convolutional neural network that classifies new cells accordingly. Likewise, the output of classifiers can be clustered to discover aggregate patterns and phenotype subsets. We also introduce a new hierarchical approach to keep track of analysis steps and data subsets created by users; this assists in the identification of cell types. Users can build phenotype trees and interact with the resulting hierarchical structures of both high-dimensional feature and image spaces. We report on use-cases in which domain scientists explore various large-scale fluorescence imaging datasets. We demonstrate how Facetto assists users in steering the clustering and classification process, inspecting analysis results, and gaining new scientific insights into cancer biology.
A neural network for online spike classification that improves decoding accuracy
Authors: Issar Deepa , Williamson Ryan C. , Khanna Sanjeev B. , Smith Matthew A. 
Published: August 2019

AbstractSeparating neural signals from noise can improve brain-computer interface performance and stability. However, most algorithms for separating neural action potentials from noise are not suitable for use in real time and have shown mixed effects on decoding performance. With the goal of removing noise that impedes online decoding, we sought to automate the intuition of human spike-sorters to operate in real time with an easily tunable parameter governing the stringency with which spike waveforms are classified. We trained an artificial neural network with one hidden layer on neural waveforms that were hand-labeled as either spikes or noise. The network output was a likelihood metric for each waveform it classified, and we tuned the network’s stringency by varying the minimum likelihood value for a waveform to be considered a spike. Using the network’s labels to exclude noise waveforms, we decoded remembered target location during a memory-guided saccade task from electrode arrays implanted in prefrontal cortex of rhesus macaque monkeys. The network classified waveforms in real time, and its classifications were qualitatively similar to those of a human spike-sorter. Compared to decoding with threshold crossings, in most sessions we improved decoding performance by removing waveforms with low spike likelihood values. Furthermore, decoding with our network’s classifications became more beneficial as time since array implantation increased. Our classifier serves as a feasible preprocessing step, with little risk of harm, that could be applied to both offline neural data analyses and online decoding.New & NoteworthyWhile there are many spike-sorting methods that isolate well-defined single units, these methods typically involve human intervention and have inconsistent effects on decoding. We used human classified neural waveforms as training data to create an artificial neural network that could be tuned to separate spikes from noise that impaired decoding. We found that this network operated in real time and was suitable for both offline data processing and online decoding.
Experimental Determination of Evolutionary Barriers to Horizontal Gene Transfer
Authors: Kirit Hande Acar , Lagator Mato , Bollback Jonathan P. 
Published: August 2019

AbstractHorizontal gene transfer, the acquisition of genes across species boundaries, is a major source of novel phenotypes. Several barriers have been suggested to impede the likelihood of horizontal transmission; however experimental evidence is scarce. We measured the fitness effects of genes transferred fromSalmonella entericaserovar Typhimurium toEscherichia coli, and found that most result in strong fitness costs. Previously identified evolutionary barriers — gene function and the number of protein-protein interactions — did not predict the fitness effects of transferred genes. In contrast, dosage sensitivity, gene length, and the intrinsic protein disorder significantly impact the likelihood of a successful horizontal transfer. While computational approaches have been successful in describing long-term barriers to horizontal gene transfer, our experimental results identified previously underappreciated barriers that determine the fitness effects of newly transferred genes, and hence their short-term eco-evolutionary dynamics.
The Human Motor Cortex Contributes to Gravity Compensation to Maintain Posture and During Reaching
Authors: Hardesty R. L. , Ellaway P. H. , Gritsenko V. 
Published: August 2019

AbstractHow the neural motor system recruits muscles to support the arm against gravity is a matter of active debate. It is unknown how the neural motor system compensates for the changing gravity-related joint moments either when holding a steady-state posture or during movement between postural steady states, e.g., during reaching. Here we used single-pulse transcranial magnetic stimulation to compare the roles that the human primary motor cortex plays in the muscle recruitment to compensate for gravity. We hypothesized that the motor cortex contributes to muscle recruitment to both maintain posture and to compensate for changes in gravitational passive joint moments during movement. To test this hypothesis, we used visual targets in virtual reality to instruct five postures and three movements with or against gravity. We then measured the amplitude and gain of motor evoked potentials in multiple muscles of the arm at several phases of the reaching motion and during posture maintenance. Stimulation below the resting motor threshold, calibrated to the biceps muscle, caused motor evoked potentials in all muscles during all postural and reaching tasks. The amplitude of motor evoked potentials was proportional to the motoneuronal excitability measured as muscle activity. The coefficient of proportionality was positively correlated with the postural component of muscle moment during posture and movement. Altogether our results support the hypothesis. The observed contribution of the motor cortex to the recruitment of multiple antagonistic muscles suggests a whole-limb strategy for overcoming passive gravity-related moments with both active muscle moments and muscle co-activation that modulates limb impedance.New & NoteworthyMaintaining static posture and producing motion appear to be contradictory tasks for the nervous system. In contrast to this seeming dichotomy, our results show that the motorcortical control signals play the same role in both tasks when it is framed in biomechanical terms, i.e., muscle contractions needed to compensate for gravity.
An efficient method to clone TAL effector genes fromXanthomonas oryzaeusing Gibson assembly
Authors: Li Chenhao , Ji Chonghui , Huguet-Tapia José C. , White Frank F. , Dong Hansong , Yang Bing 
Published: August 2019

AbstractTALes (Transcription Activator-Like effectors) represent the largest family of type III effectors among pathogenic bacteria and play a critical role in the process of infection. Strains ofXanthomonas oryzaepv. oryzae (Xoo) and some strains of otherXanthomonaspathogens contain large numbers of TALe genes. Previous techniques to clone individual or a complement of TALe genes through conventional strategies are inefficient and time-consuming due to multiple genes (up to 29 copies) in a given genome and technically challenging due to the repetitive sequences (up to 33 nearly identical 102-nucleotide repeats) of individual TALe genes. Thus, only a limited number of TALe genes have been molecularly cloned and characterized, and the functions of most TALe genes remain unknown. Here, we present an easy and efficient cloning technique to clone TALe genes selectively throughin vitrohomologous recombination and single strand annealing and demonstrate the feasibility of this approach with four different Xoo strains. Based on the Gibson assembly strategy, two complementary vectors with scaffolds that can preferentially capture all TALe genes from a pool of genomic fragments were designed. Both vector systems enabled cloning of a full complement of TALe genes from each of four Xoo strains and functional analysis of individual TALes in rice in approximately one month compared to three months by previously used methods. The results demonstrate a robust tool to advance TALe biology and a potential for broad usage of this approach to clone multiple copies of highly competitive DNA elements in any genome of interest.
Humans can navigate complex graph structures acquired during latent learning
Authors: Rmus Milena , Ritz Harrison , Hunter Lindsay E , Bornstein Aaron M , Shenhav Amitai 
Published: August 2019

AbstractHumans appear to represent many forms of knowledge in associative networks whose nodes are multiply connected, including sensory, spatial, and semantic. Recent work has shown that explicitly augmenting artificial agents with such graph-structured representations endows them with more human-like capabilities of compositionality and transfer learning. An open question is how humans acquire these representations. Previously, it has been shown that humans can learn to navigate graph-structured conceptual spaces on the basis of direct experience with trajectories that intentionally draw the network contours (Schapiro et al., 2012;2016), or through direct experience with rewards that covary with the underlying associative distance (Wu et al., 2018). Here, we provide initial evidence that this capability is more general, extending to learning to reason about shortest-path distances across a graph structure acquired across disjoint experiences with randomized edges of the graph - a form of latent learning. In other words, we show that humans can infer graph structures, assembling them from disordered experiences. We further show that the degree to which individuals learn to reason correctly and with reference to the structure of the graph corresponds to their propensity, in a separate task, to use model-based reinforcement learning to achieve rewards. This connection suggests that the correct acquisition of graph-structured relationships is a central ability underlying forward planning and reasoning, and may be a core computation across the many domains in which graph-based reasoning is advantageous.
Pervasive differential splicing in Marek’s Disease Virus can discriminate CVI-988 vaccine strain from RB-1B virulent strain in chicken embryonic fibroblasts
Authors: Sadigh Yashar , Tahiri-Alaoui Abdessamad , Spatz Stephen , Nair Venugopal , Ribeca Paolo 
Published: August 2019

AbstractMarek’s disease is a major scourge challenging poultry health worldwide. It is caused by the highly contagious Marek’s disease virus (MDV), an alphaherpesvirus. Here we show that, similar to other members of itsHerpesviridaefamily, MDV also presents a complex landscape of splicing events, most of which are uncharacterised and/or not annotated. Quite strikingly, and although the biological relevance of this fact is unknown, we found that a number of viral splicing isoforms are strain-specific despite the close sequence similarity of the strains considered, virulent RB-1B and vaccine CVI-988. We validated our findings by devising an assay that discriminates infections caused by the two strains in chicken embryonic fibroblasts based on the presence of some RNA species. To our knowledge, this study is the first ever to accomplish such a result, emphasizing how important a comprehensive knowledge of the viral transcriptome can be to understand viral pathogenesis.ImportanceMarek’s disease virus (MDV) causes an agro-economically important disease of chickens worldwide. Although commercial poultry are vaccinated against MDV, it is not possible to achieve sterilising immunity, and available vaccines can only protect chickens against the symptoms of the disease. Vaccinated chicken often become superinfected with virulent strains, shedding virus into the environment. The most effective MDV vaccine strain, CVI-988, shares >99% sequence identity with the prototype virulent virus strain RB-1B. Interestingly, our work shows that despite their almost identical sequences MDV strains CVI-988 and RB-1B have significantly different splicing profiles, and hence transcriptomes. We independently validated this discovery by detecting with real-time PCR some splicing isoforms expressed by MDV strain CVI-988 and absent in the transcriptome of the RB-1B strain. These results indicate that the coding potential of MDV might be much larger than previously thought, and suggest a likely underestimation of the role of the viral transcriptome in the pathogenesis and prevention of MDV.
Tick-borne pathogens in ticks (Acari: Ixodidae) collected from various domestic and wild hosts in Corsica (France), a Mediterranean island environment
Authors: Grech-Angelini Sébastien , Stachurski Frédéric , Vayssier-Taussat Muriel , Devillers Elodie , Casabianca François , Lancelot Renaud , Uilenberg Gerrit , Moutailler Sara 
Published: August 2019

ABSTRACTCorsica is a touristic mountainous French island in the north-west of the Mediterranean Sea presenting a large diversity of natural environments where many interactions between humans, domestic animals and wild fauna occur. Despite this favourable context, tick-borne pathogens (TBPs) have not systematically been investigated. In this study, a large number of TBPs were screened in ticks collected during one year from domestic and wild hosts in Corsica. More than 1,500 ticks belonging to nine species and five genera (Rhipicephalus,Hyalomma,Dermacentor,IxodesandHaemaphysalis) were analysed individually or pooled (by species, gender, host and locality). A real-time microfluidic PCR was used for high-throughput screening of TBPs DNA. This advanced methodology permitted the simultaneous detection of 29 bacterial and 12 parasitic species (includingBorrelia,Anaplasma,Ehrlichia,Rickettsia,Bartonella,CandidatusNeoehrlichia,Coxiella,Francisella,BabesiaandTheileria). CCHF virus was investigated individually in tick species known to be vectors or carriers of this virus. In almost half of the tick pools (48%), DNA from at least one pathogen was detected and eleven species of TBPs from six genera were reported. TBPs were found in ticks from all collected hosts and were present in more than 80% of the investigated area. The detection of some pathogens DNA confirmed their previous identification in Corsica, such asRickettsia aeschlimannii(23% of pools),Rickettsia slovaca(5%),Anaplasma marginale(4%) andTheileria equi(0.4%), but most TBPs DNA was not reported before in Corsican ticks. This includedAnaplasma phagocytophilum(16%),Rickettsia helvetica(1%), Borrelia afzelii(0.7%), Borrelia miyamotoi(1%), Bartonella henselae(2%),Babesia bigemina(2%) andBabesia ovis(0.5%). The important tick infection rate and the diversity of TBPs reported in this study highlight the probable role of animal reservoir hosts for zoonotic pathogens and human exposure to TBPs on Corsica.
Loss of intermediate filament IFB-1 reduces mobility, density and physiological function of mitochondria in C. elegans sensory neurons
Authors: Barmaver Syed Nooruzuha , Shanmugam Muniesh Muthaiyan , Chang Yen , Bhan Prerana , Wu Gong-Her , Wagner Oliver I. 
Published: August 2019

ABSTRACTMitochondria and intermediate filament (IF) accumulations often occur during imbalanced axonal transport leading to various types of neurological diseases. It is still poorly understood whether a link between neuronal IFs and mitochondrial mobility exist. In C. elegans, among the 11 cytoplasmic IF family proteins, IFB-1 is of particular interest as it is expressed in a subset of sensory neurons. Depletion of IFB-1 leads to mild dye-filling and significant chemotaxis defects as well as reduced life span. Sensory neuron development is affected and mitochondria transport is slowed down leading to reduced densities of these organelles. Mitochondria tend to cluster in neurons of IFB-1 mutants likely dependent on fission but independent of fusion events. Oxygen consumption and mitochondrial membrane potential is measurably reduced in worms carrying mutations in the ifb-1 gene. Membrane potential also seems to play a role in transport such as FCCP treatment led to increased directional switching of mitochondria. Mitochondria colocalize with IFB-1 in worm neurons and appear in a complex with IFB-1 in pull-down assays. In summary, we propose a model in which neuronal intermediate filaments may serve as critical (transient) anchor points for mitochondria during their long-range transport in neurons for steady and balanced transport.Abstract FigureSynopsisVarious neurological diseases are both associated with abnormal accumulations of neuronal intermediate filaments as well as mitochondria. Here, we report a link between these two phenomena employing the model organisms C. elegans. Depletion of neuronal intermediate filament IFB-1 impairs the transport of mitochondria in sensory neurons leading to clustered and accumulated mitochondria affecting neuronal growth and oxygen consumption in nematodes.
Structural Basis for CAL1-Mediated Centromere Maintenance
Authors: Medina-Pritchard Bethan , Lazou Vasiliki , Zou Juan , Byron Olwyn , Rappsilber Juri , Heun Patrick , Jeyaprakash A. Arockia 
Published: August 2019

SummaryCentromeres are microtubule attachment sites on chromosomes defined by the enrichment of CENP-A-containing nucleosomes. To preserve centromere identity, CENP-A must be escorted to centromeres by a CENP-A-specific chaperone for deposition. Despite this essential requirement, many eukaryotes differ in the composition of players involved in centromere maintenance highlighting the plasticity of this process. In humans, CENP-A recognition and centromere targeting is achieved by HJURP and the Mis18 complex, respectively. Here, using crystal structures, we show how Drosophila CAL1, an evolutionarily distinct CENP-A chaperone, targets CENP-A to the centromere receptor CENP-C without the requirement of the Mis18 complex: while the N-terminal CAL1 fragment (CAL11-160) wraps around CENP-A/H4 through multiple physical contacts, the C-terminal CAL1 fragment (CAL1893-914) directly binds CENP-C cupin dimer. Our work shows CAL1, though divergent at the primary structure, employs evolutionarily conserved and adaptive structural principles to recognise CENP-A/H4 and CENP-C providing insights into the minimalistic principles underlying centromere maintenance.