bluuebunny/crossref_metadata_2025_split huggingface dataset:
Saccade vigor partly reflects the subjective economic value of the visual stimulus
Authors: Yoon Tehrim , Jaleel Afareen , Ahmed Alaa A. , Shadmehr Reza 
Published: September 2019

AbstractDecisions are made based on the subjective value that the brain assigns to options. However, subjective value is a mathematical construct that cannot be measured directly, but rather inferred from choices. Recent results have demonstrated that reaction time and velocity of movements are modulated by reward, raising the possibility that there is a link between how the brain evaluates an option, and how it controls movements toward that option. Here, we asked people to choose among risky options represented by abstract stimuli, some associated with gain, others with loss. From their choices in decision trials we estimated the subjective value that they assigned to each stimulus. In probe trials, they were presented with a single stimulus at center and made a saccade to a peripheral location. We found that the reaction time and peak velocity of that saccade varied roughly linearly from loss to gain with the subjective value of the stimulus. Naturally, participants differed in how much they valued a given stimulus. Remarkably, those who valued a stimulus more, as evidenced by their choices in decision trials, tended to move with greater vigor in response to that stimulus in probe trials. Thus, saccade vigor partly reflected the subjective value that the brain assigned the stimulus. However, the influence of subjective value on vigor was only a modest predictor of preference: vigor in probe trials allowed us to predict choice in decision trials with roughly 60% accuracy.New and NoteworthyWe found that saccade vigor tends to vary monotonically with subjective value: smallest for stimuli that predict a loss, and highest for stimuli that predict a gain. Notably, between-subject differences in valuation could be gleaned from the between-subject differences in their patterns of vigor. However, the influence of subjective value on vigor was modest, allowing partial ability to infer subjective value for the purpose of predicting choice in decision trials.
Increased cell size, structural complexity and migration of cancer cells acquiring fibroblast organelles by cell-projection pumping
Authors: Zoellner Hans , Chami Belal , Kelly Elizabeth , Moore Malcolm A.S. 
Published: September 2019

AbstractWe recently described a hydrodynamic mechanism for cytoplasmic transfer between cells, termed cell-projection pumping (CPP). Earlier image analysis related altered SAOS-2 osteosarcoma cell morphology, to what we now recognize as CPP uptake of fibroblast cytoplasm. We here examine SAOS-2 phenotype following co-culture with human dermal fibroblasts (HDF) in which organelles were pre-labelled with a fluorescent lipophilic marker. Fluorescence activated cell sorting (FACS) analysis was performed of HDF and SAOS-2, cultured either alone or together. FACS forward scatter is proportionate to cell size, and increased for SAOS-2 with high levels of HDF fluorescence uptake (p < 0.004). FACS side scatter is proportionate to internal cell complexity, and increased in SAOS-2 with increasing uptake of HDF fluorescence (p < 0.004), consistent with uptake of HDF organelles. Scratch migration assays revealed that HDF migrated more quickly than SAOS-2 in both isolated cell culture, and following co-culture (p < 0.004). Notably, SAOS-2 with high levels of HDF labelling migrated faster compared with SAOS-2 with low HDF labelling (p < 0.008). A slight and unconvincing reduction in SAOS-2 proliferation was seen (p < 0.02). Similar results were obtained in single additional experiments with A673 and H312 cancer cells. Forward and side scatter results suggest organellar transfer by CPP increases cancer cell morphological diversity. This may contribute to histological pleomorphism relevant to cancer diagnosis and prognosis. Also, increased migration of sub-populations of cancer cells with high CPP organellar uptake, may contribute to invasion and metastasis in-vivo. We thus suggest relevance of CPP to cancer diagnosis and progression.
A Functionally Conserved Mechanism of Modulation via a Vestibule Site in Pentameric Ligand-Gated Ion Channels
Authors: Brams Marijke , Govaerts Cedric , Kambara Kumiko , Price Kerry , Spurny Radovan , Gharpure Anant , Pardon Els , Evans Genevieve L. , Bertrand Daniel , Lummis Sarah C. R. , Hibbs Ryan E. , Steyaert Jan , Ulens Chris 
Published: September 2019

ABSTRACTPentameric ligand-gated ion channels (pLGICs) belong to a class of ion channels involved in fast synaptic signaling in the central and peripheral nervous systems. Molecules acting as allosteric modulators target binding sites that are remote from the neurotransmitter binding site, but functionally affect coupling of ligand binding to channel opening. Here, we investigated an allosteric binding site in the ion channel vestibule, which has converged from a series of studies on prokaryote and eukaryote channel homologs. We discovered single domain antibodies, called nanobodies, which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote channel ELIC bound either to a positive (PAM) or a negative (NAM) allosteric modulator. We extrapolate the functional importance of the vestibule binding site to eukaryote ion channels, suggesting a conserved mechanism of allosteric modulation. This work identifies key elements of allosteric binding sites and extends drug design possibilities in pLGICs using nanobodies.
Enhanced nutrient uptake is sufficient to drive emergent cross-feeding between bacteria in a synthetic community
Authors: Fritts Ryan K , Bird Jordan T , Behringer Megan G , Lipzen Anna , Martin Joel , Lynch Michael , McKinlay James B 
Published: September 2019

ABSTRACTInteractive microbial communities are ubiquitous, influencing biogeochemical cycles and host health. One widespread interaction is nutrient exchange, or cross-feeding, wherein metabolites are transferred between microbes. Some cross-fed metabolites, such as vitamins, amino acids, and ammonium (NH4+), are communally valuable and impose a cost on the producer. The mechanisms that enforce cross-feeding of communally valuable metabolites are not fully understood. Previously we engineered mutualistic cross-feeding between N2-fixingRhodopseudomonas palustrisand fermentativeEscherichia coli. EngineeredR. palustrisexcreted essential nitrogen as NH4+toE. coliwhileE. coliexcreted essential carbon as fermentation products toR. palustris. Here, we enriched for nascent cross-feeding in cocultures with wild-typeR. palustris, not known to excrete NH4+. Emergent NH4+cross-feeding was driven by adaptation ofE. colialone. A missense mutation inE. coliNtrC, a regulator of nitrogen scavenging, resulted in constitutive activation of an NH4+transporter. This activity likely allowedE. colito subsist on the small amount of leaked NH4+and better reciprocate through elevated excretion of organic acids from a largerE. colipopulation. Our results indicate that enhanced nutrient uptake by recipients, rather than increased excretion by producers, is an underappreciated yet possibly prevalent mechanism by which cross-feeding can emerge.
A natural variant of the sole pyruvate kinase of fission yeast lowers glycolytic flux triggering increased respiration and oxidative-stress resistance but decreased growth
Authors: Kamrad Stephan , Grossbach Jan , Rodríguez-López Maria , Townsend StJohn , Mülleder Michael , Cappelletti Valentina , Stojanovski Gorjan , Picotti Paola , Beyer Andreas , Ralser Markus , Bähler Jürg 
Published: September 2019

AbstractCells balance glycolysis with respiration to support their energetic and biosynthetic needs in different environmental or physiological contexts. With abundant glucose, many cells prefer to grow by aerobic glycolysis, or fermentation in yeast. Using 161 natural isolates of fission yeast, we investigated the genetic basis and phenotypic effects of the fermentation-respiration balance. The laboratory and a few other strains were more dependent on respiration. This trait was associated with a missense variant in a highly conserved region of Pyk1. Pyk1 is the single pyruvate kinase in fission yeast, while most organisms possess isoforms with different activity. This variant reduced Pyk1 activity and glycolytic flux. Replacing the ‘low-activity’pyk1allele in the laboratory strain with the common ‘high-activity’ allele was sufficient to increase fermentation and decrease respiration. This metabolic reprogramming triggered systems-level adaptations in the transcriptome and proteome, and in cellular phenotypes, including increased growth and chronological lifespan, but decreased resistance to oxidative stress. Thus, low Pyk1 activity provided no growth advantage but stress tolerance, despite increased respiration. The genetic tuning of glycolytic flux by a single-nucleotide change might reflect an adaptive trade-off in a species lacking pyruvate-kinase isoforms.
Effect of Changing Heart Rate on the Ocular Pulse and Dynamic Biomechanical Behavior of the Optic Nerve Head
Authors: Jin Yuejiao , Wang Xiaofei , Irnadiastputri Sylvi Febriana Rachmawati , Mohan Rosmin Elsa , Aung Tin , Perera Shamira A. , Boote Craig , Jonas Jost B. , Schmetterer Leopold , Girard Michaël J.A. 
Published: September 2019

ABSTRACTPurposeTo study the effect of changing heart rate on the ocular pulse and the dynamic biomechanical behaviour of the optic nerve head (ONH) using a comprehensive mathematical model.MethodsIn a finite element model of a healthy eye, a biphasic choroid consisted of a solid phase with connective tissues and a fluid phase with blood, and the lamina cribrosa (LC) was viscoelastic as characterized by a stress-relaxation test. We applied arterial pressures at 18 ocular entry sites (posterior ciliary arteries) and venous pressures at four exit sites (vortex veins). In the model, the heart rate was varied from 60 bpm to 120 bpm (increment: 20 bpm). We assessed the ocular pulse amplitude (OPA), pulse volume, ONH deformations and the dynamic modulus of the LC at different heart rates.ResultsWith an increasing heart rate, the OPA decreased by 0.04 mmHg for every 10 bpm increase in heart rate. The ocular pulse volume decreased linearly by 0.13 µL for every 10 bpm increase in heart rate. The storage modulus and the loss modulus of the LC increased by 0.014 MPa and 0.04 MPa, respectively, for every 10 bpm increase in heart rate.conclusionsIn our model, the OPA, pulse volume, and ONH deformations decreased with an increasing heart rate, while the LC became stiffer. The effects of blood pressure / heart rate changes on ONH stiffening may be of interest for glaucoma pathology.SupportSingapore Ministry of Education, Academic Research Fund, Tier 2 (R-397-000-280-112).Commercial relationshipNone
The social dynamics of collective problem-solving
Authors: Yahosseini Kyanoush Seyed , Moussaïd Mehdi 
Published: September 2019

AbstractWhen searching for solutions to a problem, people often rely on the observation of their peers. How does this process of social learning impact the individual and the group’s performance? On the one hand, research has shown that individuals benefit from social learning in numerous situations and across many domains. Through social learning, individuals can access good solutions found by others, improve them, and share them in turn. On the other hand, this individual benefit may come at a cost: An excessive tendency to copy others often decreases the overall exploration volume of the group, thus reducing the diversity of discovered solutions, and eventually impairing the collective performance.Here we investigate the conditions under which social learning can be beneficial or detrimental to individuals and to the group. For that, we model problem-solving as a search task and simulate various amounts of social learning. We avoid model specific considerations by relying on a simple framework whereby individuals gradually explore the search environment – a two-dimensional landscape of solutions – while being attracted to the best solution of the group.Our results highlight a collective search dilemma: When group members learn from one another, they tend to improve their own individual performance at the expense of the collective performance. How is this dilemma affected by the structure of the search environment? By varying two structural aspects of the search environment, our results reveal that the negative effect of the dilemma is mitigated in more difficult environments.Finally, we show that single individuals can profit from a high propensity of social learning, which in turn is damaging for the other group members. As a consequence, if individuals continually adapt their behavior to maximize their own payoff, groups converge to a sub-optimal level of social learning. Unraveling these intricate social dynamics helps to understand the complex picture of collective problem-solving.
Controlling septum thickness by a large protein ring
Authors: Wenzel Michaela , Celik Gulsoy Ilkay N. , Gao Yongqiang , Willemse Joost , van Rosmalen Mariska G. M. , Wuite Gijs J. L. , Roos Wouter H. , Hamoen Leendert W. 
Published: September 2019

AbstractGram-positive bacteria divide by forming a thick cross wall. How the thickness of this septal wall is controlled is unknown. In this type of bacteria, the key cell division protein FtsZ is anchored to the cell membrane by two proteins, FtsA and SepF. We have isolated SepF homologues from different bacterial species and found that they all polymerize into large protein rings with diameters varying from 19 to 41 nm. Importantly, these values correlated well with the thickness of their septa. To test whether ring diameter determines septal thickness, we tried to construct different SepF chimeras with the purpose to manipulate the diameter of the SepF protein ring. This was indeed possible and confirmed that the conserved core domain of SepF determines ring diameter. Importantly, when SepF chimeras with a smaller diameter were expressed in the bacterial host Bacillus subtilis, the thickness of its septa also became smaller. These results strongly support a model in which septal thickness is controlled by curved molecular clamps formed by SepF polymers attached to the leading edge of nascent septa. This also implies that the intrinsic shape of a protein polymer can function as a mould to shape the cell wall.Significance StatementMany bacteria form a thick cell wall and divide by forming a cross wall. How they control the thickness of their cell wall and cross wall is unknown. In this study we show that in these bacteria the cell division protein SepF forms very large protein rings with diameters that correspond to the diameter of their cross walls. Importantly, when we reduced the diameter of SepF rings in the bacterial host Bacillus subtilis the cross wall also became thinner. These results provide strong evidence that a large protein ring can function as a mould to control the thickness of the cell wall that divides these bacterial cells.
Seeing cells smell: Dynamic optical measurements of Ca2+and cAMP signaling from Olfactory Receptors transiently expressed in HEK293TN cells
Authors: Pietraszewska-Bogiel A , van Weeren L , Goedhart J 
Published: September 2019

ABSTRACTOlfactory receptors (ORs) constitute the largest family of G-protein coupled receptors. They are responsible for the perception of odor (olfaction) and also play important roles in other biological processes, including regulation of cell proliferation. Their increasing diagnostic and therapeutic potential, especially for cancer research, requests the ongoing development of methodologies that would allow their robust functional expression in non-olfactory cells, and dynamic analysis of their signaling pathways. To enable realtime detection of OR activity, we use single cell imaging with genetically encoded fluorescent biosensors, Yellow Cameleon or EPAC, which are routinely used for kinetic measurements of Ca2+or cAMP signaling downstream of various G-protein coupled receptors. We demonstrate that the co-expression of Lucy-Rho tagged variants of ORs together with an accessory protein, RTP1s, in HEK293TN cells is sufficient to detect the activity of a panel of ORs. Using this methodology, we were able to detect both Ca2+and cAMP signaling downstream of twelve ORs within 2 minutes from the application of odorant.
Multi-Region Brain Stimulation Optimization Using Transcranial Direct Current Stimulation
Authors: Xu Ziliang , Sun Jinbo , Chen Yao , Yu Yang , Yang Xuejuan , Liu Peng , Chen Badong , Qin Wei 
Published: September 2019

AbstractTranscranial direct current stimulation (tDCS) is a type of noninvasive transcranial electrical brain stimulation. By optimizing the current distribution of each electrode on the scalp, the stimulation can be guided to a target brain region using a tDCS dense electrode array system. However, previous studies have yielded simple results using optimization schemes in single target stimulation cases. The detailed parameter settings for each optimization scheme and the associated simulation results have not been comprehensively assessed. In this study, we investigated parameter settings of optimization schemes in detail in both single target and multi-target cases. Two optimization schemes, minimum least squares (MLS) and maximum electrical field strength (ME), were examined in this study. MLS minimizes the squared errors between the expected electrical field and the estimated electrical field, whereas ME maximizes the electrical field strength in the target region. We constructed a five layer finite-element head model with 64 electrodes placed on the scalp according to the EEG 10/10 system for simulation. We evaluated the effects of stimulation using these two schemes under three conditions, 1) single target stimulation, 2) multi-target stimulation, and 3) multi-target stimulation under specific task activation, which shown that directly using MLS and ME scheme in multi-target stimulation case may lead to a wrong result. We also reported the improved results fixed by our proposed weighted MLS and weighted ME schemes which take detailed parameter settings into consideration. Our results indicate that the parameter settings in each optimization scheme greatly affected the final stimulation results, especially in the case of multi-target stimulation, and thus, indicate that the parameter settings of each optimization scheme should be carefully considered according to the expected stimulation mode. Our results also suggest that, by calculating the parameters through our proposed methods, the weighted ME and weighted MLS scheme can precisely distribute energy into each target brain region.
Multiple-site diversification of regulatory sequences enables inter-species operability of genetic devices
Authors: Hueso-Gil Angeles , Nyerges Ákos , Pál Csaba , Calles Belén , de Lorenzo Víctor 
Published: September 2019

AbstractThe features of the light-responsive cyanobacterial CcaSR regulatory node that determine interoperability of this optogenetic device between Escherichia coli and Pseudomonas putida have been examined. For this, all structural parts (i.e. ho1 and pcyA genes for synthesis of phycobilin, the ccaS/ccaR system from Synechocystis and its cognate downstream promoter) were maintained but their expression levels and stoichiometry diversified by [i] reassembling them together in a single broad host range, standardized vector and [ii] subjecting the non-coding regulatory sequences to multiple cycles of directed evolution with random genomic mutations (DIvERGE), a recombineering method that intensifies mutation rates within discrete DNA segments. Once passed to P. putida, various clones displayed a wide dynamic range, insignificant leakiness and excellent capacity in response to green light. Inspection of the evolutionary intermediates pinpointed translational control as the main bottleneck for interoperability and suggested a general approach for easing the exchange of genetic cargoes between different species i.e. optimization of relative expression levels and upturning of subcomplex stoichiometry.
Microtubule binding of the kinesin-4 KIF7 and its regulation by autoinhibition
Authors: Blasius T. Lynne , Yue Yang , Verhey Kristen 
Published: September 2019

AbstractKIF7 is a member of the kinesin-4 family and plays critical roles in Hedgehog signaling in vertebrate cells. KIF7 is an atypical kinesin as it binds to microtubules but is immotile. We demonstrate that, like conventional kinesins, KIF7 is regulated by autoinhibition as the full-length motor cannot bind to microtubules whereas truncated versions bind statically to microtubules in cells. Previous work suggested that truncated KIF7 motors bind preferentially to the plus ends of microtubulesin vitro, however, we find that truncated KIF7 does not bind preferentially to or track the plus ends of growing microtubules in mammalian cells or in cell extracts. Although the truncated KIF7 did alter microtubule dynamics in cells, this property is not specific to KIF7 as expression of an active kinesin-1 motor also altered microtubule growth rates. The immotile behavior of KIF7 is not due to the extended neck linker domain as its deletion does not activate KIF7 for motility and its presence in a KIF5C/KIF7 chimeric motor does not prevent processive motility. Together this work indicates that the atypical kinesin KIF7 is regulated by autoinhibition to prevent binding to microtubules and alteration of microtubule dynamics in cells.
Transcriptional and Spatial Resolution of Cell Types in the Mammalian Habenula
Authors: Hashikawa Yoshiko , Hashikawa Koichi , Basiri Marcus L. , Liu Yuejia , Johnston Nathan L. , Ahmad Omar R. , Stuber Garret D. 
Published: September 2019

SummaryThe habenula complex is appreciated as a critical regulator of motivated and pathological behavioral states via its output to midbrain nuclei. Despite this, transcriptional definition of cell populations that comprise both the medial (MHb) and lateral habenular (LHb) subregions in mammals remain undefined. To resolve this, we performed single-cell transcriptional profiling and highly multiplexed in situ hybridization experiments of the mouse habenula complex in naïve mice and those exposed to an acute aversive stimulus. Transcriptionally distinct neuronal cell types identified within the MHb and LHb, were spatially defined, and differentially engaged by aversive stimuli. Cell types identified in mice, also displayed a high degree of transcriptional similarity to those previously described in zebrafish, highlighting the well conserved nature of habenular cell types across the phylum. These data identify key molecular targets within habenula cell types, and provide a critical resource for future studies.