bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cocaine-dependent acquisition of locomotor sensitization and conditioned place preference requires D1 dopaminergic signaling through a cyclic AMP, NCS-Rapgef2, ERK and Egr-1/Zif268 pathway
Authors: Jiang Sunny Zhihong , Sweat Sean , Dahlke Sam , Loane Kathleen , Drossel Gunner , Xu Wenqin , Tejeda Hugo A. , Gerfen Charles R. , Eiden Lee E. 
Published: July 2020

ABSTRACTElucidation of the underlying mechanism of dopamine signaling to ERK that underlies plasticity in dopamine D1 receptor expressingneurons leadingto acquired cocaine preference is incomplete. NCS-Rapgef2 is a novel cAMP effector, expressed in neuronal and endocrine cells in adult mammals, that is required for D1 dopamine receptor-dependent ERK phosphorylation in mouse brain. In this report, we studied the effects of abrogating NCS-Rapgef2 expression on cAMP-dependent ERK→Egr-1/zif268 signaling in cultured neuroendocrine cells; in D1 medium spiny neurons (MSNs) of nucleus accumbens slices; and in mouse brain in a region-specific manner. NCS-Rapgef2 gene deletion in the nucleus accumbens (NAc) in adult mice, using AAV-mediated expression of cre recombinase, eliminated cocaine-induced ERK phosphorylation and Egr-1/Zif268 upregulation in D1-MSNs and cocaine-induced behaviors including locomotor sensitization and conditioned place preference (CPP). Abrogation of NCS-Rapgef2 gene expression in medium prefrontal cortex and basolateral amygdala, by crossing mice bearing a floxed Rapgef2 allele with a cre mouse line driven by calcium/calmodulin-dependent kinase IIα promoter also eliminated cocaine-induced phospho-ERK activation and Egr-1/Zif268 induction, but without effect on the cocaine-induced behaviors. Our results indicate that NCS-Rapgef2 signaling to ERK in dopamine D1-receptor expressing neurons in the NAc, butnotin corticolimbic areas, contributes to cocaine-induced locomotor sensitization and CPP. Ablation of cocaine-dependent ERK activation by elimination of NCS-Rapgef2 occurred with no effect on phosphorylation of CREB in D1 dopaminoceptive neurons of NAc. This study reveals a new cAMP-dependent signaling pathway for cocaine-induced behavioral adaptations, mediated through NCS-Rapgef2/phospho-ERK activation, independently of PKA/CREB signaling.SIGNIFICANCE STATEMENTERK phosphorylation in dopamine D1 receptor expressing neurons exerts a pivotal role in psychostimulant-induced neuronal gene regulation and behavioraladaptation, including locomotor sensitization and drug preference in rodents. In this study, we examined the role of dopamine signaling through the D1 receptor via a novel pathway initiated through the cAMP-activated guanine nucleotide exchange factor NCS-Rapgef2 in mice. NCS-Rapgef2 in the nucleus accumbens is required for activation of ERK and Egr-1/Zif268 in D1 dopaminoceptive neurons after acute cocaine administration, and subsequentenhanced locomotor response anddrugseeking behavior after repeated cocaine administration. This novel component in dopamine signaling provides a potential new target for intervention in psychostimulant-shaped behaviors, and new understanding of how D1-MSNs encode the experience of psychomotor stimulant exposure.
Arabidopsis poly(ADP-ribose)-binding protein RCD1 interacts with Photoregulatory Protein Kinases in nuclear bodies
Authors: Vainonen Julia P. , Shapiguzov Alexey , Krasensky-Wrzaczek Julia , Gossens Richard , Masi Raffaella De , Danciu Iulia , Puukko Tuomas , Battchikova Natalia , Jonak Claudia , Wirthmueller Lennart , Wrzaczek Michael , Kangasjärvi Jaakko 
Published: July 2020

AbstractContinuous reprogramming of gene expression in response to environmental signals is required for plant survival in changing environment. One mechanism responsible for this is signaling through hub proteins that integrate external stimuli and transcriptional responses. RADICAL-INDUCED CELL DEATH1 (RCD1) functions as a nuclear hub protein, that interacts with a variety of transcription factors through its C-terminal RST domain and acts as a co-regulator of numerous stress responses in plants. Here, a previously unknown function for RCD1 as a novel plant poly(ADP-ribose) (PAR) reader protein is described. RCD1 localizes to specific locations inside the nucleus, in a PAR-dependent manner; its N-terminal WWE domain o binds PAR and together with the PARP-like domain determines its localization to nuclear bodies (NBs), which is prevented by inhibition of PAR synthesis. RCD1 also interacts with Photoregulatory Protein Kinases (PPKs) that co-localize with RCD1 in the NBs. The PPKs, that have been associated with circadian clock, abscisic acid, and light signaling pathways, phosphorylate RCD1 at multiple sites in the intrinsically disordered region between the WWE and PARP-like domains. This affects its stability and functions in the nucleus and1 provides a mechanism where the turnover of a PAR-binding transcriptional co-regulator is controlled by nuclear protein kinases.
Neural mechanisms underlying expectation-dependent inhibition of distracting information
Authors: van Moorselaar Dirk , Lampers Eline , Cordesius Elisa , Slagter Heleen A. 
Published: July 2020

AbstractPredictions based on learned statistical regularities in the visual world have been shown to facilitate attention and goal-directed behavior by sharpening the sensory representation of goal-relevant stimuli in advance. Yet, how the brain learns to ignore predictable goal-irrelevant or distracting information is unclear. Here, we used EEG and a visual search task in which the predictability of a distractor’s location and/or spatial frequency was manipulated to determine how spatial and feature distractor expectations are neurally implemented and reduce distractor interference. We find that expected distractor features could not only be decoded pre-stimulus, but their representation differed from the representation of that same feature when part of the target. Spatial distractor expectations did not induce changes in preparatory neural activity, but a strongly reduced Pd, an ERP index of inhibition. These results demonstrate that neural effects of statistical learning critically depend on the task relevance and dimension (spatial, feature) of predictions.
Modeling collaterally sensitive drug cycles: shaping heterogeneity to allow adaptive therapy
Authors: Yoon Nara , Krishnan Nikhil , Scott Jacob 
Published: July 2020

AbstractIn previous work, we focused on the optimal therapeutic strategy with a pair of drugs which are collaterally sensitive to each other, that is, a situation in which evolution of resistance to one drug induces sensitivity to the other, and vice versa. [1] Here, we have extended this exploration to the optimal strategy with a collaterally sensitive drug sequence of an arbitrary length,N(≥ 2). To explore this, we have developed a dynamical model of sequential drug therapies withNdrugs. In this model, tumor cells are classified as one ofNsubpopulations represented as {Ri|i= 1,2,…,N}. Each subpopulation,Ri, is resistant to ‘Drug i’ and each subpopulation,Ri–1(orRN, ifi= 1), is sensitive to it, so that Riincreases under ‘Drug i’ as it is resistant to it, and after drug-switching, decreases under ‘Drug i+ 1’ as it is sensitive to that drug(s).Similar to our previous work examining optimal therapy with two drugs, we found that there is an initial period of time in which the tumor is ‘shaped’ into a specific makeup of each subpopulation, at which time all the drugs are equally effective. After this shaping period, all the drugs are quickly switched with duration relative to their efficacy in order to maintain each subpopulation, consistent with the ideas underlying adaptive therapy. [2, 3]Additionally, we have developed methodologies to administer the optimal regimen under clinical or experimental situations in which no drug parameters and limited information of trackable populations data (all the subpopulations or only total population) are known. The therapy simulation based on these methodologies showed consistency with the theoretical effect of optimal therapy.
Vascular dimorphism ensured by regulated proteoglycan dynamics favors rapid umbilical artery closure at birth
Authors: Nandadasa Sumeda , Szafron Jason M. , Pathak Vai , Murtada Sae-Il , Kraft Caroline M. , O’Donnell Anna , Norvik Christian , Hughes Clare , Caterson Bruce , Domowicz Miriam S. , Schwartz Nancy B. , Tran-Lundmark Karin , Veigl Martina , Sedwick David , Philipson Elliot H. , Humphrey Jay D. , Apte Suneel S. 
Published: July 2020

AbstractThe umbilical artery lumen occludes rapidly at birth, preventing blood loss, whereas the umbilical vein remains patent, providing the newborn with a placental infusion. Here, we identify differential arterial-venous proteoglycan dynamics as a determinant of these contrasting vascular responses. We show that the umbilical artery, unlike the vein, has an inner layer enriched in the hydrated proteoglycan aggrecan, external to which lie contraction-primed smooth muscle cells (SMC). At birth, SMC contraction drives inner layer buckling and centripetal displacement to occlude the arterial lumen, a mechanism elicited by biomechanical and computational analysis. Vascular dimorphism arises from spatially regulated proteoglycan expression and breakdown in umbilical vessels. Mice lacking aggrecan or the metalloprotease ADAMTS1, which degrades proteoglycans, demonstrated their opposing roles in umbilical cord arterial-venous dimorphism and contrasting effects on SMC differentiation. Umbilical vessel dimorphism is conserved in mammals, suggesting that their differential proteoglycan dynamics were a positive selection step in mammalian evolution.
Primary human colonic mucosal barrier crosstalk with super oxygen-sensitiveFaecalibacterium prausnitziiin continuous culture
Authors: Zhang Jianbo , Huang Yu-Ja , Yoon Jun-Young , Kemmitt John , Wright Charles , Schneider Kirsten , Sphabmixay Pierre , Hernandez-Gordillo Victor , Holcomb Steven J. , Bhushan Brij , Rohatgi Gar , Benton Kyle , Carpenter David , Kester Jemila C. , Eng George , Breault David T. , Yilmaz Omer , Taketani Mao , Voigt Christopher A. , Carrier Rebecca L. , Trumper David L. , Griffith Linda G. 
Published: July 2020

AbstractThe gut microbiome plays an important role in human health and disease. Gnotobiotic animal andin vitrocell-based models provide some informative insights into mechanistic crosstalk. However, there is no existing system for a chronic co-culture of a human colonic mucosal barrier with super oxygen-sensitive commensal microbes, hindering the study of human-microbe interactions in a controlled manner. Here, we investigated the effects of an abundant super oxygen-sensitive commensal anaerobe,Faecalibacterium prausnitzii, on a primary human mucosal barrier using a Gut-MIcrobiome (GuMI) physiome platform that we designed and fabricated. Chronic continuous co-culture ofF. prausnitziifor two days with colon epithelia, enabled by continuous flow of completely anoxic apical media and aerobic basal media, resulted in a strictly anaerobic apical environment fostering growth of and butyrate production byF. prausnitzii, while maintaining a stable colon epithelial barrier. We identified elevated differentiation and hypoxia-responsive genes and pathways in the platform compared with conventional aerobic static culture of the colon epithelia, attributable to a combination of anaerobic environment and continuous medium replenishment. Furthermore, we demonstrated anti-inflammatory effects ofF. prausnitziithrough HDAC and the TLR-NFKB axis. Finally, we identified that butyrate largely contributes to the anti-inflammatory effects by downregulating TLR3 and TLR4. Our results are consistent with some clinical observations regardingF. prausnitzii, thus motivating further studies employing this platform with more complex engineered colon tissues for understanding the interaction between the human colonic mucosal barrier and microbiota, pathogens, or engineered bacteria.
Is structure based drug design ready for selectivity optimization?
Authors: Albanese Steven K. , Chodera John D. , Volkamer Andrea , Keng Simon , Abel Robert , Wang Lingle 
Published: July 2020

AbstractAlchemical free energy calculations are now widely used to drive or maintain potency in small molecule lead optimization with a roughly 1 kcal/mol accuracy. Despite this, the potential to use free energy calculations to drive optimization of compoundselectivityamong two similar targets has been relatively unexplored in published studies. In the most optimistic scenario, the similarity of binding sites might lead to a fortuitous cancellation of errors and allow selectivity to be predicted more accurately than affinity. Here, we assess the accuracy with which selectivity can be predicted in the context of small molecule kinase inhibitors, considering the very similar binding sites of human kinases CDK2 and CDK9, as well as another series of ligands attempting to achieve selectivity between the more distantly related kinases CDK2 and ERK2. Using a Bayesian analysis approach, we separate systematic from statistical error and quantify the correlation in systematic errors between selectivity targets. We find that, in the CDK2/CDK9 case, a high correlation in systematic errors suggests free energy calculations can have significant impact in aiding chemists in achieving selectivity, while in more distantly related kinases (CDK2/ERK2), the correlation in systematic error suggests fortuitous cancellation may even occur between systems that are not as closely related. In both cases, the correlation in systematic error suggests that longer simulations are beneficial to properly balance statistical error with systematic error to take full advantage of the increase in apparent free energy calculation accuracy in selectivity prediction.
Tolerogenic Nanoparticles Impacting B and T Lymphocyte Responses Delay Autoimmune Arthritis in K/BxN Mice
Authors: Srivastava Amrita , Arlian Britni M. , Pang Lijuan , Kishimoto Takashi K. , Paulson James C. 
Published: July 2020

AbstractCurrent treatments for unwanted antibody responses largely rely on immunosuppressive drugs compromising overall immunity. New approaches to achieve antigen-specific tolerance are desirable to avoid unwanted side effects. Several nanoparticle-based approaches designed to tolerize the B or T cell arms of the humoral immune response have shown promise for induction of antigen-specific tolerance, raising the possibility that they could work synergistically if combined. Earlier we showed that Siglec-engaging tolerance-inducing antigenic liposomes (STALs) that display both an antigen (Ag) and glycan ligands of the inhibitory co-receptor CD22 (CD22L) lead to robust antigen-specific B cell tolerance to protein antigens in naïve mice. In another approach, administration of free Ag with poly(lactic co-glycolic acid)-rapamycin nanoparticles (PLGA-R) induced robust antigen-specific tolerance through production of regulatory T cells. Here we illustrate that co-administration of STALs together with PLGA-R to naïve mice induced more robust tolerance to multiple antigen challenges than either nanoparticle alone. Moreover, in K/BxN mice that develop spontaneous autoimmune arthritis to the self-antigen glucose-6-phosphate-isomerase (GPI), co-delivery of GPI-LP-CD22L and PLGA-R delayed onset of disease, and in some mice prevented the disease indefinitely. The results show synergy between B cell-tolerizing STALs and T cell-tolerizing PLGA-R and the potential to induce tolerance in early stage autoimmune disease.
Perturbations in dynamical models of whole-brain activity dissociate between the level and stability of consciousness
Authors: Perl Yonatan Sanz , Pallavicini Carla , Pérez Ipiña Ignacio , Demertzi Athena , Bonhomme Vincent , Martial Charlotte , Panda Rajanikant , Annen Jitka , Ibañez Agustín , Kringelbach Morten , Deco Gustavo , Laufs Helmut , Sitt Jacobo , Laureys Steven , Tagliazucchi Enzo 
Published: July 2020

AbstractConsciousness transiently fades away during deep sleep, more stably under anesthesia, and sometimes permanently due to brain injury. The development of an index to quantify the level of consciousness across these different states is regarded as a key problem both in basic and clinical neuroscience. We argue that this problem is ill-defined since such an index would not exhaust all the relevant information about a given state of consciousness. While the level of consciousness can be taken to describe the actual brain state, a complete characterization should also include its potential behavior against external perturbations. We developed and analyzed whole-brain computational models to show that the stability of conscious states provides information complementary to their similarity to conscious wakefulness. Our work leads to a novel methodological framework to sort out different brain states by their stability and reversibility, and illustrates its usefulness to dissociate between physiological (sleep), pathological (brain-injured patients), and pharmacologically-induced (anesthesia) loss of consciousness.
A tyrosine kinase protein interaction map reveals targetable EGFR network oncogenesis in lung cancer
Authors: Kaushik Swati , Haderk Franziska , Zhao Xin , Hu Hsien-Ming , Shah Khyati N. , Jang Gwendolyn M. , Olivas Victor , Nanjo Shigeki , Jascur John , Masto Vincent B. , Ciznadija Daniel , Sloma Ido , Gross Emilie , Weinrich Scott L. , Johnson Jeffery R. , Bivona Trever G. , Krogan Nevan J. , Bandyopadhyay Sourav 
Published: July 2020

SUMMARYSignaling networks balance the activities of many physically interacting proteins and perturbations to this network influence downstream signaling, potentially leading to oncogenic states. Using affinity purification-mass spectrometry we defined this network for all 90 human tyrosine kinases revealing 1,463 mostly novel interactions between these key cancer proteins and diverse molecular complexes. Modulation of interactor levels altered growth phenotypes associated with corresponding tyrosine kinase partners suggesting that tumors may alter the stoichiometries of interactors to maximize oncogenic signaling. We show that the levels of EGFR interactors delineates this form of network oncogenesis in 19% of EGFR wild-type lung cancer patients which were mostly otherwise oncogene negative, predicting sensitivity to EGFR inhibitors in vitro and in vivo. EGFR network oncogenesis occurs through mechanistically distinct network alleles often in cooperation with weak oncogenes in the MAPK pathway. Network oncogenesis may be a common and targetable convergent mechanism of oncogenic pathway activation in cancer.HIGHLIGHTSA human tyrosine kinome protein interaction map reveals novel physical and functional associations.Dependence on oncogenic tyrosine kinases is modulated through perturbation of their interactors.EGFR network oncogenesis in up to 19% of EGFR wild-type lung cancers is targetable.EGFR network oncogenesis cooperates with weak oncogenes in the MAPK pathway.
Substitutions at Non-Conserved Rheostat Positions Modulate Function by Re-Wiring Long-Range, Dynamic Interactions
Authors: Campitelli Paul , Swint-Kruse Liskin , Ozkan S. Banu 
Published: July 2020

AbstractAmino acid substitutions at nonconserved protein positions can have non-canonical and “long-distance” outcomes on protein function. Such outcomes might arise from changes in the internal protein communication network, which is often accompanied by changes in structural flexibility. To test this, we calculated flexibilities (“DFI”) and dynamic coupling (“DCI”) for positions in the linker region of the lactose repressor protein (“LacI”). This region contains nonconserved positions for which substitutions alter DNA binding affinity. We first chose to study eleven substitutions at position 52. In computations, substitutions showed long-range effects on flexibilities of DNA binding positions, and the degree of flexibility change correlated with experimentally-measured changes in DNA binding. Substitutions also altered dynamic coupling to DNA binding positions in a manner that captured other experimentally-determined functional changes. Next, we broadened calculations to consider the dynamic coupling between 17 linker positions and the DNA binding domain. Experimentally, these linker positions exhibited a wide range of substitution outcomes: Four conserved positions tolerated almost no substitutions (“toggle”), ten nonconserved positions showed progressive changes from a range of substitutions (“rheostat”), and three nonconserved positions tolerated almost all substitutions (“neutral”). In computations with wild-type LacI, the dynamic couplings between the DNA binding domain and these linker positions showed varied degrees of asymmetry that correlated with the observed toggle/rheostat/neutral substitution outcomes. Thus, we propose that long-range and non-canonical substitutions outcomes at nonconserved positions arise from re-wiring long-range communication among functionally-important positions. Such calculations might enable predictions for substitution outcomes at a range of nonconserved positions.
Split-wrmScarlet and split-sfGFP: Tools for faster, easier fluorescent labeling of endogenous proteins inCaenorhabditis elegans
Authors: Goudeau Jérôme , Sharp Catherine S. , Paw Jonathan , Savy Laura , Leonetti Manuel D. , York Andrew G. , Updike Dustin L. , Kenyon Cynthia , Ingaramo Maria 
Published: July 2020

AbstractWe create and share a new red fluorophore, along with a set of strains, reagents and protocols, to make it faster and easier to label endogenousC. elegansproteins with fluorescent tags. CRISPR-mediated fluorescent labeling ofC. elegansproteins is an invaluable tool, but it is much more difficult to insert fluorophore-size DNA segments than it is to make small gene edits. In principle, high-affinity asymmetrically split fluorescent proteins solve this problem inC. elegans: the small fragment can quickly and easily be fused to almost any protein of interest, and can be detected wherever the large fragment is expressed and complemented. However, there is currently only one available strain stably expressing the large fragment of a split fluorescent protein, restricting this solution to a single tissue (the germline) in the highly autofluorescent green channel. No availableC. eleganslines express unbound large fragments of split red fluorescent proteins, and even state-of-the-art split red fluorescent proteins are dim compared to the canonical split-sfGFP protein. In this study, we engineer a bright, high-affinity new split red fluorophore, split-wrmScarlet. We generate transgenicC. eleganslines to allow easy single-color labeling in muscle or germline cells and dual-color labeling in somatic cells. We also describe ‘glonads’, a novel expression strategy for the germline, where traditional expression strategies struggle. We validate these strains by targeting split-wrmScarlet to several genes whose products label distinct organelles, and we provide a protocol for easy, cloning-free CRISPR/Cas9 editing. As the collection of split-FP strains for labeling in different tissues or organelles expands, we will post updates at doi.org/10.5281/zenodo.3993663