bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of the MEK1/2 inhibitor trametinib in combination with clinically-investigated γ-secretase inhibitors in rhabdomyosarcoma
Authors: Cleary Megan M. , Hawkins Douglas S. , Keller Charles 
Published: April 2019

AbstractThe childhood muscle cancer rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. In the last 40 years, outcomes for low and intermediate risk patients have improved; however, high risk patients with metastatic disease still have poor overall survival. Differentiation therapy for RMS has been considered a potential clinical approach to halting tumor progression by inducing the terminal myogenic differentiation program, and thus reducing the need for cytotoxic chemotherapy. Both the NOTCH and MEK pathway have been shown to play varying roles in inducing differentiation in RMS cells. Here, we tested several different RMS cell lines harboring varying genetic abnormalities with the MEK inhibitor trametinib alone, and in combination with γ-secretase inhibitors and found no significant effect on cell viability when used together.
The fungal sesquiterpenoid pyrenophoric acid B uses the plant ABA biosynthetic pathway to inhibit seed germination
Authors: Lozano-Juste Jorge , Masi Marco , Cimmino Alessio , Clement Suzette , Fernández Maria A. , Antoni Regina , Meyer Susan , Rodriguez Pedro L. , Evidente Antonio 
Published: April 2019

HighlightThe fungusPyrenophora semeniperdaproduces pyrenophoric acid B, a small molecule that exploits the plant ABA biosynthetic pathway to reduce seed germination, increasing its reproductive success.AbstractPyrenophoric acid (P-Acid), P-Acid B and P-Acid C are three phytotoxic sesquiterpenoids produced by the ascomycete seed pathogenPyrenophora semeniperda,a fungus proposed as a mycoherbicide for biocontrol of cheatgrass, an extremely invasive weed. When tested in cheatgrass bioassays these metabolites were able to delay seed germination, with P-Acid B being the most active compound. Here, we have investigated the cross-kingdom activity of P-Acid B and its mode of action and found that it activates the ABA signaling pathway in order to inhibit seedling establishment. P-Acid B inhibits seedling establishment in wild-typeArabidopsis thalianawhile several mutants affected in the early perception as well as in downstream ABA signaling components were insensitive to the fungal compound. However, in spite of structural similarities between ABA and P-Acid B, the latter is not able to activate the PYR/PYL family of ABA receptors. Instead, we have found that P-Acid B uses the ABA biosynthesis pathway at the level of alcohol dehydrogenase ABA2 to reduce seedling establishment. We propose that the fungusPyrenophora semeniperdamanipulates plant ABA biosynthesis as a strategy to reduce seed germination, increasing its ability to cause seed mortality and thereby increase its fitness through higher reproductive success.
Previously reward-associated stimuli capture spatial attention in the absence of changes in the corresponding sensory representations as measured with MEG
Authors: Tankelevitch L , Spaak E , Rushworth MFS , Stokes MG 
Published: April 2019

AbstractStudies of selective attention typically consider the role of task goals or physical salience, but recent work has shown that attention can also be captured by previously reward-associated stimuli, even if they are currently task-irrelevant. One theory underlying this value-driven attentional capture (VDAC) is that reward-associated stimulus representations may undergo plasticity in sensory cortex, thereby automatically capturing attention during early processing. To test this, we used magnetoencephalography to probe whether stimulus location and identity representations in sensory cortex are modulated by reward learning. We furthermore investigated the time-course of these neural effects, and their relationship to behavioural VDAC. Male and female human participants first learned stimulus-reward associations. Next, we measured VDAC in a separate task by presenting these stimuli in the absence of reward contingency, and probing their effects on the processing of separate target stimuli presented at different time lags. Using time-resolved multivariate pattern analysis, we found that learned value modulated the spatial selection of previously rewarded stimuli in posterior visual and parietal cortex from ∼260ms after stimulus onset. This value modulation was related to the strength of participants’ behavioural VDAC effect and persisted into subsequent target processing. Furthermore, we found a spatially invariant value signal from ∼340ms. Importantly, learned value did not influence cortical signatures of early processing (i.e., earlier than ∼200ms), nor did it influence the decodability of the identity of previously rewarded stimuli. Our results suggest that VDAC is underpinned by learned value signals which modulate spatial selection throughout posterior visual and parietal cortex. We further suggest that VDAC can occur in the absence of changes in early visual processing in cortex.Significance statementAttention is our ability to focus on relevant information at the expense of irrelevant information. It can be affected by previously learned but currently irrelevant stimulus-reward associations, a phenomenon termed “value-driven attentional capture” (VDAC). The neural mechanisms underlying VDAC remain unclear. It has been speculated that reward learning induces visual cortical plasticity which modulates early visual processing to capture attention. Although we find that learned value modulates spatial signals in visual cortical areas, an effect which correlates with VDAC, we find no relevant signatures of changes in early visual processing in cortex.
Dedicated setup for the photoconversion of fluorescent dyes for functional electron microscopy
Authors: Dobson Katharine L. , Howe Carmel L. , Nishimura Yuri , Marra Vincenzo 
Published: April 2019

AbstractHere, we describe a cost-effective setup for targeted photoconversion of fluorescent signals into electron dense ones. This approach has offered invaluable insights in the morphology and function of fine neuronal structures. The technique relies on the localized oxidation of diaminobenzidine (DAB) mediated by excited fluorophores. This paper includes a detailed description of how to build a simple photoconversion setup that can increase reliability and throughput of this well-established technique. The system described here, is particularly well-suited for thick neuronal tissue, where light penetration and oxygen diffusion may be limiting DAB oxidation. To demonstrate the system, we use Correlative Light and Electron Microscopy (CLEM) to visualize functionally-labelled individual synaptic vesicles released onto an identified layer 5 neuron in an acute cortical slice. The setup significantly simplifies the photoconversion workflow, increasing the depth of photoillumination, improving the targeting of the region of interest and reducing the time required to process each individual samples. We have tested this setup extensively for the photoconversion of FM 1-43FX and Lucifer Yellow both excited at 473 nm. In principle, the system can be adapted to any dye or nanoparticle able to oxidize DAB when excited by a specific light wavelength.
Mechanically Resolved Imaging of Bacteria using Expansion Microscopy
Authors: Lim Youngbin , Khariton Margarita , Lane Keara M. , Shiver Anthony L. , Ng Katharine M. , Bray Samuel R. , Qin Jian , Huang Kerwyn Casey , Wang Bo 
Published: April 2019

AbstractImaging dense and diverse microbial communities has broad applications in basic microbiology and medicine, but remains a grand challenge due to the fact that many species adopt similar morphologies. While prior studies have relied on techniques involving spectral labeling, we have developed an expansion microscopy method (μExM) in which cells are physically expanded prior imaging and their expansion patterns depend on the structural and mechanical properties of their cell walls, which vary across species and conditions. We use this phenomenon as a quantitative and sensitive phenotypic imaging contrast orthogonal to spectral separation in order to resolve bacterial cells of different species or in distinct physiological states. Focusing on host-microbe interactions that are difficult to quantify through fluorescence alone, we demonstrate the ability of μExM to distinguish species within a dense community throughin vivoimaging of a model gut microbiota, and to sensitively detect cell-envelope damage caused by antibiotics or previously unrecognized cell-to-cell phenotypic heterogeneity among pathogenic bacteria as they infect macrophages.
Morphogenesis and dynamics of slime molds in various environments
Authors: Patino-Ramirez Fernando , Boussard Aurèle , Arson Chloé , Dussutour Audrey 
Published: April 2019

AbstractCells, including unicellulars, are highly sensitive to external constraints from their environment. Amoeboid cells change their cell shape during locomotion and in response to external stimuli. Physarum polycephalum is a large multinucleated amoeboid cell that extends and develops pseudopods. In this paper, changes in cell behavior and shape were measured during the exploration of homogenous and non-homogenous environments that presented neutral, and nutritive and/or adverse substances. In the first place, we developed a fully automated image analysis method to measure quantitatively changes in both migration and shape. Then we measured various metrics that describe the area covered, the exploration dynamics, the migration rate and the slime mold shape. Our results show that: 1) Not only the nature, but also the spatial distribution of chemical substances affect the exploration behavior of slime molds; 2) Nutritive and adverse substances both slow down the exploration and prevent the formation of pseudopods; and 3) Slime mold placed in an adverse environment preferentially occupies previously explored areas rather than unexplored areas using mucus secretion as a buffer. Our results also show that slime molds migrate at a rate governed by the substrate up until they get within a critical distance to chemical substances.Author summaryPhysarum polycephalum, also called slime mold, is a giant single-celled organism that can grow to cover several square meters, forming search fronts that are connected to a system of intersecting veins. An original experimental protocol allowed tracking the shape of slime mold placed in homogenous substrates containing an attractant (glucose) or a repellent (salt), or inhomogeneous substrates that contained an attractive spot (glucose), an eccentric slime mold and a repulsive spot (salt) in between. For the first time, the rate of exploration of unexplored areas (primary growth) and the rate of extension in previously explored areas (secondary growth) were rigorously measured, by means of a sophisticated image analysis program. This paper shows that the chemical composition of the substrate has more influence on the morphology and growth dynamics of slime mold than that of concentrated spots of chemicals. It was also found that on a repulsive substrate, slime mold exhibits a bias towards secondary growth, which suggests that the mucus produced during slime mold migration acts as a protective shell in adverse environments.
Artifact-free, high-temporal-resolutionin vivoopto-electrophysiology with microLED optoelectrodes
Authors: Kim Kanghwan , Vöröslakos Mihály , Seymour John P. , Wise Kensall D. , Buzsáki György , Yoon Euisik 
Published: April 2019

AbstractThe combination ofin vivoextracellular recording and genetic-engineering-assisted optical stimulation is a powerful tool for the study of neuronal circuits. Precise analysis of complex neural circuits requires high-density integration of multiple cellular-size light sources and recording electrodes. However, high-density integration inevitably introduces stimulation artifact. We present minimal-stimulation-artifact (miniSTAR) µLED optoelectrodes that enable effective elimination of stimulation artifact. A multi-metal-layer structure with a shielding layer effectively suppresses capacitive coupling of stimulation signals. A heavily-boron-doped silicon substrate silences the photovoltaic effect induced from LED illumination. With transient stimulation pulse shaping, we reduced stimulation artifact on miniSTAR µLED optoelectrodes to below 50 µVpp, much smaller than a typical spike detection threshold, at optical stimulation of > 50 mW mm-2irradiance. We demonstrated high-temporal resolution (< 1 ms) opto-electrophysiology without any artifact-induced signal quality degradation duringin vivoexperiments. MiniSTAR µLED optoelectrodes will facilitate functional mapping of local circuits and discoveries in the brain.
Phase-specific microstimulation in brain machine interface setting differentially modulates beta oscillations and affects behavior
Authors: Peles Oren , Werner-Reiss Uri , Bergman Hagai , Israel Zvi , Vaadia Eilon 
Published: April 2019

SummaryIt is widely accepted that beta-band oscillations play a role in sensorimotor behavior. To further explore this role, we developed a novel hybrid platform to combine operant conditioning and phase-specific intracortical microstimulation (ICMS). We trained monkeys, implanted with 96 electrodes arrays in motor cortex, to volitionally enhance local field potential (LFP) beta-band (20-30Hz) activity at selected sites using a brain-machine interface (BMI). We demonstrate that beta oscillations of LFP and single-unit spiking activity increased dramatically with BMI training, and that pre-movement Beta-power was anti-correlated with task performance. We also show that phase-specific ICMS modulated the power and phase of oscillations, shifting local networks between oscillatory and non-oscillatory states. Furthermore, ICMS induced phase-dependent effects in animal reaction times and success rates. These findings contribute to unraveling of the functional role of cortical oscillations, and to future development of clinical tools for ameliorating abnormal neuronal activities in brain diseases.
Acquisition of Temporal Order Involves a Reverberating Network in Hippocampal Field CA3
Authors: Gunn B.G. , Cox B.M. , Cox C.D. , Le A.A. , Inshishian V.C. , Gall C.M. , Lynch G. 
Published: April 2019

AbstractHere we report that hippocampal field CA3 maintains self-sustained activity for remarkable periods following a brief input and that this effect is extremely sensitive to minor perturbations. Using novel behavioral tests, that as with human episodic learning do not involve training or explicit rewards, we show that partial silencing of the network in mice blocks acquisition of temporal order, but not the identity or location, of odors. These results suggest a solution to the question of how hippocampus adds time to episodic memories.
Structural and Functional Characterization of G Protein-Coupled Receptors with Deep Mutational Scanning
Authors: Jones Eric M. , Lubock Nathan B. , Venkatakrishnan AJ , Wang Jeffrey , Tseng Alex M. , Paggi Joseph M. , Latorraca Naomi R. , Cancilla Daniel , Satyadi Megan , Davis Jessica E. , Babu M. Madan , Dror Ron O. , Kosuri Sriram 
Published: April 2019

AbstractIn humans, the 813 G protein-coupled receptors (GPCRs) are responsible for transducing diverse chemical stimuli to alter cell state, and are the largest class of drug targets. Their myriad structural conformations and various modes of signaling make it challenging to understand their structure and function. Here we developed a platform to characterize large libraries of GPCR variants in human cell lines with a barcoded transcriptional reporter of G-protein signal transduction. We tested 7,800 of 7,828 possible single amino acid substitutions to the beta-2 adrenergic receptor (β2AR) at four concentrations of the agonist isoproterenol. We identified residues specifically important for β2AR signaling, mutations in the human population that are potentially loss of function, and residues that modulate basal activity. Using unsupervised learning, we resolve residues critical for signaling, including all major structural motifs and molecular interfaces. We also find a previously uncharacterized structural latch spanning the first two extracellular loops that is highly conserved across Class A GPCRs and is conformationally rigid in both the inactive and active states of the receptor. More broadly, by linking deep mutational scanning with engineered transcriptional reporters, we establish a generalizable method for exploring pharmacogenomics, structure and function across broad classes of drug receptors.
Long noncoding RNAAVANpromotes antiviral innate immunity by interacting with TRIM25 and enhancing the transcription of FOXO3a
Authors: Lai Chengcai , Liu Lihui , Liu Qinghua , Cheng Sijie , Wang Keyu , Zhao Lingna , Xia Min , Wang Cheng , Gu Hongjing , Duan Yueqiang , Zhao Zhongpeng , Zhang Lili , Liu Ziyang , Luo Jianjun , Song Jianxun , Yang Penghui , Chen Runsheng , Wang Xiliang 
Published: April 2019

AbstractAccumulating evidence has shown that long noncoding RNAs (lncRNAs) are involved in several biological processes, including immune responses. However, the role of lncRNAs in antiviral innate immune responses remains largely unexplored. Here, we identify an uncharacterized human lncRNA from influenza A virus (IAV) patients, antivirus and activate neutrophil (AVAN), that is significantly up-regulated upon virus infection. Mechanistically, nuclear lncRNA-AVANpositively regulates the transcription of forkhead box O3A (FOXO3a) by associating with its promoter and inducing chromatin remodeling to promote neutrophil chemotaxis. Furthermore, we also found that cytoplasmic lncRNA-AVANdirectly binds tripartite motif containing 25 (TRIM25) and enhances the association of TRIM25 and Retinoic acid inducible gene-1 proteins (RIG-I) and the ubiquitylation of RIG-I, thereby promoting TRIM25- and RIG-I-mediated antiviral innate immune signaling. More importantly, we enforced the expression of AVAN in transgenic mice and found that it significantly alleviated IAV virulence and virus production. Collectively, these findings highlight the potential clinical implications of lncRNA-AVANas a key positive regulator of the antiviral innate immune response and a promising target for developing broad antiviral therapeutics.
Hierarchical Network Exploration using Gaussian Mixture Models
Authors: Mathews James , Nadeem Saad , Pouryahya Maryam , Belkhatir Zehor , Deasy Joseph O. , Tannenbaum Allen 
Published: April 2019

AbstractWe present a framework based on optimal mass transport to construct, for a given network, a reduction hierarchy which can be used for interactive data exploration and community detection. Given a network and a set of numerical data samples for each node, we calculate a new computationally-efficient comparison metric between Gaussian Mixture Models, the Gaussian Mixture Transport distance, to determine a series of merge simplifications of the network. If only a network is given, numerical samples are synthesized from the network topology. The method has its basis in the local connection structure of the network, as well as the joint distribution of the data associated with neighboring nodes.The analysis is benchmarked on networks with known community structures. We also analyze gene regulatory networks, including the PANTHER curated database and networks inferred from the GTEx lung and breast tissue RNA profiles. Gene Ontology annotations from the EBI GOA database are ranked and superimposed to explain the salient gene modules. We find that several gene modules related to highly specific biological processes are well-coordinated in such tissues. We also find that 18 of the 50 genes of the PAM50 breast-tumor prognostic signature appear among the highly coordinated genes in a single gene module, in both the breast and lung samples. Moreover these 18 are precisely the subset of the PAM50 recently identified as the basal-like markers.
Acquired loss of cardiac vagal activity is associated with myocardial injury in patients undergoing non-cardiac surgery: prospective observational mechanistic cohort study
Authors: May Shaun M. , Reyes Anna , Martir Gladys , Reynolds Joseph , Paredes Laura Gallego , Karmali Shamir , Stephens Robert CM , Brealey David , Ackland Gareth L. 
Published: April 2019

AbstractBackgroundMyocardial injury is more frequent after non-cardiac surgery in patients with preoperative cardiac vagal dysfunction as quantified by delayed heart rate recovery after cessation of cardiopulmonary exercise testing. Here, we hypothesised that serial and dynamic measures of perioperative cardiac vagal activity should also be associated with myocardial injury after non-cardiac surgery.MethodsSerial measures in cardiac vagal activity were quantified preoperatively and daily using heart rate variability and a standardised orthostatic challenge in patients undergoing elective non-cardiac surgery. The primary outcome was myocardial injury (high-sensitivity troponin (hsTnT) ≥15ng.L−1) within 48h of surgery. Clinicians, patients and investigators were blinded to hsTnT. The exposure of interest was cardiac vagal activity (high-frequency power spectral analysis [HFlog]) and heart rate recovery after a standardised orthostatic challenge.ResultshsTnT≥15ng.L−1 occurred in 48/189 [25%] patients, of whom 41/48 [85%] had a revised cardiac risk index score <2. Patients with a post surgery troponin HsTnT ≥15ng.L−1 were associated with an early loss (within 24h) of cardiac vagal activity (HFLog) post surgery compared to day of surgery (4.19 [95%CI:3.62-4.75] vs 5.22 [95%CI:4.64-5.81]; p<0.001). Heart rate recovery after a standardised orthostatic challenge after surgery was slower in patients with hsTnT≥15ng.L−1 (5 beats minute−1 (95% CI: 3 −7), compared to heart rate recovery in patients who remained free of myocardial injury (10 beats minute−1 (95%CI:7 to 12]; p = 0.02).ConclusionsReal-time, serial heart rate measures indicating loss of cardiac vagal activity are associated with perioperative myocardial injury in lower-risk patients undergoing non-cardiac surgery.
The neural basis for response latency in a sensory-motor behavior
Authors: Lee Joonyeol , Darlington Timothy R. , Lisberger Stephen G. 
Published: April 2019

AbstractWe seek a neural circuit explanation for sensory-motor reaction times. We have found evidence that two of three possible mechanisms could contribute to reaction times in smooth pursuit eye movements. In the smooth eye movement region of the frontal eye fields (FEFSEM), an area that causally affects the initiation of smooth pursuit eye movement, neural and behavioral latencies have significant trial-by-trial correlations that can account for 40% to 100% of the variation in behavioral latency. The amplitude of preparatory activity, which represents the motor system’s expectations for target motion, shows negative trial-by-trial correlations with behavioral latency and could contribute to the neural computation of reaction time. In contrast, the traditional “ramp-to-threshold” model is contradicted by the responses of many, but not all FEFSEM neurons. As evidence of neural processing that determines reaction time, the local field potential in FEFSEM includes a brief wave in the 5-15 Hz frequency range that precedes pursuit initiation and whose phase is correlated with the latency of pursuit in individual trials. We suggest that the latency of the incoming visual motion signals combines with the state of preparatory activity to determine the latency of the transient response that drives eye movement.