bluuebunny/crossref_metadata_2025_split huggingface dataset:
Motor cortical output for skilled forelimb movement is selectively distributed across projection neuron classes
Authors: Park Junchol , Phillips James W. , Guo Jian-Zhong , Martin Kathleen A. , Hantman Adam W. , Dudman Joshua T. 
Published: September 2019

AbstractThe interaction of descending neocortical outputs and subcortical premotor circuits is critical for shaping the skilled movements. Two broad classes of motor cortical output projection neurons provide input to many subcortical motor areas: pyramidal tract neurons (PT), which project throughout the neuraxis; and intratelencephalic neurons (IT), which project within cortex and subcortical striatum. It is unclear whether these classes are functionally in series or whether separable components of descending motor control signals are distributed across these distinct classes of projection neurons. Here we combine large-scale neural recordings across all layers of motor cortex with cell-type specific perturbations to study cortically-dependent mouse motor behaviors: kinematically-variable manipulation of a joystick and a kinematically-precise reach-to-grasp. We find that striatum-projecting IT neuron activity preferentially represents amplitude whereas pons-projecting PT neurons preferentially represent the variable direction of forelimb movements. Thus, separable components of descending motor cortical commands are distributed across motor cortical projection cell classes.One-sentence summary:Separable components of cortical motor commands are distributed across distinct glutamatergic projection neuron cell-types.
Operant self-stimulation of thalamic terminals in the dorsomedial striatum is constrained by metabotropic glutamate receptor 2
Authors: Johnson Kari A. , Voyvodic Lucas , Mateo Yolanda , Lovinger David M. 
Published: September 2019

ABSTRACTDorsal striatal manipulations including stimulation of dopamine release and activation of medium spiny neurons (MSNs) are sufficient to drive reinforcement-based learning. Glutamatergic innervation of the dorsal striatum by both the cortex and thalamus is a critical determinant of both MSN activity and local regulation of dopamine release. However, the relationship between glutamatergic inputs to the striatum and behavioral reinforcement is not well understood. We sought to evaluate the reinforcing properties of optogenetic stimulation of thalamostriatal terminals, which are associated with vesicular glutamate transporter 2 (Vglut2) expression, in the dorsomedial striatum (DMS), a region implicated in goal-directed operant behaviors. In mice expressing channelrhodopsin-2 (ChR2) under control of the Vglut2 promoter, brief optical stimulation of the DMS reinforces operant lever-pressing behavior. Mice also acquire operant self-stimulation of thalamic terminals in the DMS when ChR2 expression is virally targeted to the intralaminar thalamus. Because the presynaptic G protein-coupled receptor metabotropic glutamate receptor 2 (mGlu2) robustly inhibits glutamate and dopamine release induced by activation of thalamostriatal afferents, we examined the regulation of thalamostriatal self-stimulation by mGlu2. We find that administration of an mGlu2/3 agonist or an mGlu2-selective positive allosteric modulator reduces self-stimulation. In contrast, blockade of these receptors increases thalamostriatal self-stimulation, suggesting that endogenous activation of these receptors negatively modulates the reinforcing properties of thalamostriatal activity. These findings demonstrate that stimulation of thalamic terminals in the DMS is sufficient to reinforce a self-initiated action, and that thalamostriatal reinforcement is constrained by mGlu2 activation.
Polyunsaturated fatty acid analogues differentially affect cardiac Nav, Cav, and Kv channels through unique mechanisms
Authors: Bohannon Briana M. , Wu Xiaoan , Perez Marta E. , Liin Sara I. , Peter Larsson H. 
Published: September 2019

AbstractThe cardiac ventricular action potential depends on several voltage-gated ion channels, including Nav, Cav, and Kv channels. Mutations in these channels can cause Long QT Syndrome (LQTS) which increases the risk for ventricular fibrillation and sudden cardiac death. Polyunsaturated fatty acids (PUFAs) have emerged as potential therapeutics for LQTS because they are modulators of voltage-gated ion channels. Here we demonstrate that PUFA analogues vary in their selectivity for human voltage-gated ion channels involved in the ventricular action potential. The effects of specific PUFA analogues range from selective for a specific ion channel to broadly modulating all three cardiac ion channels (NaV, CaL, and IKs). In addition, PUFA analogues do not modulate these channels through a shared mechanism. Our data suggest that different PUFA analogues could be tailored towards specific forms of LQTS, which are caused by mutations in distinct cardiac ion channels, and thus restore a normal ventricular action potential.
Reproducibility test of radiomics using network analysis and Wasserstein K-means algorithm
Authors: Oh Jung Hun , Apte Aditya P. , Katsoulakis Evangelia , Riaz Nadeem , Hatzoglou Vaios , Yu Yao , Leeman Jonathan E. , Mahmood Usman , Pouryahya Maryam , Iyer Aditi , Shukla-Dave Amita , Tannenbaum Allen R. , Lee Nancy Y. , Deasy Joseph O. 
Published: September 2019

ABSTRACTPurposeTo construct robust and validated radiomic predictive models, the development of a reliable method that can identify reproducible radiomic features robust to varying image acquisition methods and other scanner parameters should be preceded with rigorous validation. Due to the property of high correlation present between radiomic features, we hypothesize that reproducible radiomic features across different datasets that are obtained from different image acquisition settings preserve some level of connectivity between features in the form of a network.MethodsWe propose a regularized partial correlation network to identify robust and reproducible radiomic features. This approach was tested on two radiomic feature sets generated with two different reconstruction methods from a cohort of 47 lung cancer patients. The commonality of the resulting two networks was assessed. A largest common network component from the two networks was tested on phantom data consisting of 5 cancer samples. We further propose a novel K-means algorithm coupled with the optimal mass transport (OMT) theory to cluster samples. This approach following the regularized partial correlation analysis was tested on computed tomography (CT) scans from 77 head and neck cancer patients that were downloaded from The Cancer Imaging Archive (TCIA) and validated on CT scans from 83 head and neck cancer patients treated at our institution.ResultsCommon radiomic features were found in relatively large network components between the resulting two partial correlation networks from a cohort of 47 lung cancer patients. The similarity of network components in terms of the common number of radiomic features was statistically significant. For phantom data, the Wasserstein distance on a largest common network component from the lung cancer data was much smaller than the Wasserstein distance on the same network using random radiomic features, implying the reliability of those radiomic features present in the network. Further analysis using the proposed Wasserstein K-means algorithm on TCIA head and neck cancer data showed that the resulting clusters separate tumor subsites and this was validated on our institution data.ConclusionsWe showed that a network-based analysis enables identifying reproducible radiomic features. This was validated using phantom data and external data via the Wasserstein distance metric and the proposed Wasserstein K-means method.
Exercise and angiotensin receptor blockade enhance recovery after orthopaedic trauma in mice by decreasing pain and improving muscle regeneration
Authors: Tawfik Vivianne L. , Quarta Marco , Paine Patrick , Forman Thomas E. , Pajarinen Jukka , Takemura Yoshinori , Goodman Stuart B. , Rando Thomas A. , Clark J. David 
Published: September 2019

ABSTRACTChronic pain and disability after limb injury are major public health problems. One key obstacle to addressing these adverse outcomes is that we do not know when exercise should be initiated or whether the beneficial effects of exercise can be reproduced using pharmacological tools. In these studies, we developed and used a murine model of orthopaedic trauma combining tibia fracture and pin fixation with tibialis anterior muscle damage. Behavioral measures included mechanical nociceptive thresholds and distances run on exercise wheels. Bone healing was quantified using microCT scanning, and muscle fiber size distribution as well as fibrosis were followed using immunohistochemistry. We found that the model provided robust mechanical allodynia, fibrosis and a shift to smaller average muscle fiber size lasting up to 5 weeks from injury. We also observed that allowing “late” (weeks 1-2) rather than “early” (weeks 0-1) wheel running after injury resulted in greater overall running activity and greater reversal of allodynia. In parallel, the late running paradigm was also associated with lower levels of muscle fibrosis and a return towards normal muscle fiber diameters. Providing the anti-fibrotic angiotensin receptor blocker losartan to mice in drinking water blocked TGFbeta production while reducing both allodynia and muscle fibrosis. Combining losartan and late exercise provided no additional benefit. We conclude that early healing after orthopaedic trauma must be allowed prior to the initiation of exercise to achieve optimal pain, functional and physiological outcomes. Losartan may provide many of the same pain, functional and physiological outcomes by its regulation of TGFbeta signaling and is a viable candidate for translational studies.Key points summaryOur tibial fracture orthopaedic injury model in mice recapitulates the major manifestations of complex trauma including nociceptive sensitization, bone fracture, muscle fibrosis and muscle fiber loss.Delayed exercise after complex orthopaedic trauma results in decreased muscle fibrosis and improved painLosartan, an angiotensin-receptor blocker with antifibrotic abilities, recapitulates the effect of exercise on post-injury recovery
ER stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress
Authors: Ho Nurulain , Wu Haoxi , Xu Jiaming , Koh Jhee Hong , Yap Wei Sheng , Goh Wilson Wen Bin , Chong Shu Chen , Taubert Stefan , Thibault Guillaume 
Published: September 2019

SUMMARYMembrane integrity at the endoplasmic reticulum (ER) is tightly regulated and is implicated in metabolic diseases when compromised. Using an engineered sensor that exclusively activates the unfolded protein response (UPR) during aberrant ER membrane lipid composition, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and are conserved in C. elegans. To systematically validate yeast mutants disrupting ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensing switch in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation (ChIP) analyses pinpoint the UPR as a broad-spectrum compensatory pathway in which LBS and proteotoxic stress-induced UPR deploy divergent transcriptional programs. Together, these findings reveal the UPR program as the sum of two independent stress events and could be exploited for future therapeutic intervention.
Position-dependent effects of cytosine methylation onFWAexpression inArabidopsis thaliana
Authors: Srikant Thanvi , Wibowo Anjar , Schwab Rebecca , Weigel Detlef 
Published: September 2019

ABSTRACTGene expression can be modulated by epigenetic modifications to chromatin, and variants of the same locus distinguished by fixed, heritable epigenetic differences are known as epialleles. DNA methylation at cytosines is a prominent epigenetic modification, particularly in plant genomes, that can modulate gene expression. There are several examples where epialleles are associated with differentially methylated regions that affect the expression of overlapping or close-by genes. However, there are also many differentially methylated regions that have not been assigned a biological function despite their proximity to genes. We investigated the positional importance of DNA methylation at theFWA (FLOWERING WAGENINGEN)locus inArabidopsis thaliana, a paradigm for stable epialleles. We show that cytosine methylation can be established not only over the well-characterizedSINE-derived repeat elements that overlap with the transcription start site, but also in more distal promoter regions.FWAsilencing, however, is most effective when methylation covers the transcription start site.
Information-based taste maps in insular cortex are shaped by stimulus concentration
Authors: Porcu E , Benz KM , Ball F , Tempelmann C , Hanke M , Noesselt T 
Published: September 2019

AbstractTaste processing is an essential ability in all animals signaling potential harm or benefit of ingestive behavior. Although the peripheral taste coding is well understood, current evidence for central taste processing remains contradictory. To address this issue, human participants judged pleasantness and intensity of low and high-concentration tastes (salty, sweet, sour, bitter) in two fMRI-experiments. High-resolution fMRI and multivariate pattern analysis were used to characterize taste-related informational content in human gustatory cortex (GC). Clusters within GC were narrowly tuned to specific tastants consistently across tasks. Importantly, taste concentrations completely altered the spatial layout of putative taste-specific maps with distinct, non-overlapping patterns for each taste category at different concentration levels. Together, our results point at population-level representations in human GC as a complex function of taste category and concentration.
Reconstruction of Average Subtracted Tubular Regions (RASTR) Enables Structure Determination of Tubular Filaments by Cryo-EM
Authors: Randolph Peter S. , Stagg Scott M. 
Published: September 2019

AbstractAs the field of electron microscopy moves forward, the increasing complexity of samples being produced demand more involved processing methods. In this study, we have developed a new processing method for generating 3D reconstructions of tubular structures. Tubular biomolecules are common throughout many cellular processes and are appealing targets for a variety of biophysical research. Processing of tubules with helical symmetry is relatively straightforward for electron microscopy if the helical parameters are known, but tubular structures that deviate from helical symmetry (asymmetrical components, local but no global order, etc) present myriad issues. Here we present a new processing technique called Reconstruction of Average Subtracted Tubular Regions (RASTR), which was developed to reconstruct tubular structures without applying symmetry. We explain the RASTR approach and quantify its performance using three examples: a simulated symmetrical tubular filament, a symmetrical tubular filament from cryo-EM data, and a membrane tubule coated with locally ordered but not globally ordered proteins.
Photon-statistics in sensitized emission FRET and FLIM: a comparative theoretical analysis
Authors: Esposito Alessandro 
Published: September 2019

AbstractFRET imaging is an essential analytical method in biomedical research. The limited photon-budget experimentally available, however, imposes compromises between spatiotemporal and biochemical resolutions, photodamage and phototoxicity. The study of photon-statistics in biochemical imaging is thus important in guiding the efficient design of instrumentation and assays. Here, we show a comparative analysis of photon-statistics in FRET imaging demonstrating how the precision of FRET imaging varies vastly with imaging parameters. Therefore, we provide analytical and numerical tools for assay optimization. FLIM is a very robust technique with excellent photon-efficiencies but also intensity-based FRET imaging can reach very high precision by utilizing also information within acceptor fluorescence.
Identification of Chikungunya virus nucleocapsid core assembly modulators
Authors: Jones-Burrage Sara E. , Tan Zhenning , Li Lichun , Zlotnick Adam , Mukhopadhyay Suchetana 
Published: September 2019

Abstract:The alphavirus Chikungunya virus is transmitted to humans via infected mosquitos. Most infected humans experience symptoms which can range from short-term fatigue and fever to debilitating arthritis that can last for months or years. Some patients relapse and experience symptoms months or years after the initial bout of disease. The capsid protein of Chikungunya virus forms a shell around the viral RNA genome; this structure is called the nucleocapsid core. The core protects the genome during virus transmission and with the correct environmental trigger, this proteinaceous shell dissociates and releases the viral genome to initiate infection. We hypothesized that targeting compounds to interfere with the nucleocapsid core’s function would constrain virus spread either by inhibiting the release of viral genomes during entry or by reducing the number of infectious virus particles assembled. We implemented a high throughput,in vitro,FRET-based assay to monitor nucleic acid packaging by purified Chikungunya capsid protein as a proxy for nucleocapsid core assembly and disassembly. We screened 10,000 compounds and found 45 that substantially modulated the assembly of core-like particles. A subset of compounds was selected to study their effects in virus-infected vertebrate cells. Our results show that four compounds inhibit infectious virus production by at least 90% in a dose-dependent manner. The most promising inhibitor was tested and found to reduce the amount of nucleocapsid cores inside the cell during Chikungunya virus infection. These compounds could be the foundation for anti-viral therapeutics.HighlightsA FRET-based assay to detect nucleic acid packaging by Chikungunya virus capsid proteinIdentification of small molecules that modulate core-like particle assemblyA subset of compounds that interfere with in vitro assembly also inhibit Chikungunya virus production in cell cultureIdentification of antiviral molecules that may not be identified by assays using reporter virusesPotential starting compounds for developing direct-acting antivirals
Epigenetic adaptation prolongs photoreceptor survival during retinal degeneration
Authors: Dharmat Rachayata , Kim Sangbae , Liu Hehe , Fu Shangyi , Li Yumei , Chen Rui 
Published: September 2019

AbstractNeural degenerative diseases often display a progressive loss of cells as a stretched exponential distribution. The mechanisms underlying the survival of a subset of genetically identical cells in a population beyond what is expected by chance alone remains unknown. To gain mechanistic insights underlying prolonged cellular survival, we used Spata7 mutant mice as a model and performed single-cell transcriptomic profiling of retinal tissue along the time course of photoreceptor degeneration. Intriguingly, rod cells that survive beyond the initial rapid cell apoptosis phase progressively acquire a distinct transcriptome profile. In these rod cells, expression of photoreceptor-specific phototransduction pathway genes is downregulated while expression of other retinal cell type-specific marker genes is upregulated. These transcriptomic changes are achieved by modulation of the epigenome and changes of the chromatin state at these loci, as indicated by immunofluorescence staining and single-cell ATAC-seq. Consistent with this model, when induction of the repressive epigenetic state is blocked by in vivo histone deacetylase inhibition, all photoreceptors in the mutant retina undergo rapid degeneration, strongly curtailing the stretched exponential distribution. Our study reveals an intrinsic mechanism by which neural cells progressively adapt to genetic stress to achieve prolonged survival through epigenomic regulation and chromatin state modulation.
A post-processing algorithm for building longitudinal medication dose data from extracted medication information using natural language processing from electronic health records
Authors: McNeer Elizabeth , Beck Cole , Weeks Hannah L. , Williams Michael L. , James Nathan T. , Choi Leena 
Published: September 2019

ABSTRACTObjectiveWe developed a post-processing algorithm to convert raw natural language processing (NLP) output from electronic health records (EHRs) into a usable format for analysis. This algorithm was specifically developed for creating datasets for use in medication-based studies.Materials and MethodsThe algorithm was developed using output from two NLP systems, MedXN and medExtractR. We extracted medication information from deidentified clinical notes from Vanderbilt’s EHR system for two medications, tacrolimus and lamotrigine. The algorithm consists of two parts. Part I parses the raw NLP output and connects entities together. Part II removes redundancies and calculates dose intake and daily dose. We evaluated each part by comparing to human-determined gold standards that were generated using approximately 300 records from 10 subjects for each medication and each NLP system.ResultsThe algorithm performed well. For MedXN, the F-measures were at or above 0.99 for Part I and at or above 0.97 for Part II. For medExtractR, the F-measures for Part I were 1.00 and for Part II they were at or above 0.98.DiscussionOur post-processing algorithm was developed separately from an NLP system, making it easier to modify and generalize to other systems. It performed well to convert NLP output to analyzable data, but it cannot perform well in certain cases, such as when incorrect information is extracted by the NLP system.ConclusionOur post-processing algorithm provides a way to convert raw NLP output to a form that is useful for medication-based studies, leading to more opportunities to use EHR data for diverse studies.
Increasing demand for plasma membrane contributes to the energetic cost of early zebrafish embryogenesis
Authors: Rodenfels Jonathan , Sartori Pablo , Golfier Stefan , Nagendra Kartikeya , Neugebauer Karla , Howard Jonathon 
Published: September 2019

AbstractHow do early embryos apportion the resources stored in the sperm and egg? Recently, we established isothermal calorimetry (ITC) to measure heat dissipation by living zebrafish embryos and to estimate the energetics of specific developmental events. During the reductive cleavage divisions, the rate of heat dissipation increases from ∼60 nJ·s−1at the 2-cell stage to ∼90 nJ·s−1at the 1024-cell stage. Here we ask, which cellular process(es) drive these increasing energetic costs? We present evidence that the cost is due to the increase in the total surface area of all of the cells of the embryo. First, embryo volume stays constant during the cleavage stage, indicating that the increase is not due to growth. Second, the heat increase is blocked by nocodazole, which inhibits DNA replication, mitosis and cell division; this implicates some aspect of cell proliferation contributing to these costs. Third, the heat increase scales with total cell surface area rather than total cell number. Finally, the calculated costs of maintaining and assembling plasma membranes and associated proteins probably accounts for a significant proportion of the heat increase. Thus, the cell’s membrane is likely to contribute significantly to the total energy budget of the embryo.Highlight summary for TOCRodenfels et al. measure the energetic costs of early zebrafish development, using calorimetry. Embryonic heat dissipation increases, but, more slowly than the number of cells during early cleavage stage development. Instead, the heat dissipation scales with the energetic cost associated with maintaining and producing new plasma membrane.