bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical and raphe GABAA, AMPA receptors and glial GLT-1 glutamate transporter contribute to the sustained antidepressant activity of ketamine
Authors: Pham Thu Ha , Defaix Céline , Loan Nguyen Thi Mai , Mendez-David Indira , Tritschler Laurent , David Denis J , Gardier Alain M. 
Published: March 2020

ABSTRACTAt sub-anaesthetic doses, ketamine, a non competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated remarkable and rapid antidepressant (AD) efficacy in patients with treatment-resistant depression (TRD). However, its mechanism of action of ketamine is not fully understood. Since comorbid depression and anxiety disorders often occur, GABAergic/inhibitory and glutamatergic/excitatory drug treatments may be co-administered in these patients. Information regarding this combination is critical to establish efficacy or treatment restrictions to maximize translation from animal models to TRD patients, effectiveness and safety. To assess the specific role of excitatory/inhibitory neurotransmission in the medial prefrontal cortex-raphe nuclei (mPFC-DRN) circuit in the sustained antidepressant-like activity (AD) of ketamine (at t24h post dose), AMPA-R antagonist (intra-DRN) and GABAA-R agonist (intra-mPFC) were co-administered with ketamine (intra-mPFC). Twenty-four hours later, responses in the forced swim test (FST) and neurochemical consequences on extracellular mPFC glutamate, GABA and 5-HT levels were measured in BALB/cJ mice. Intra-DRN NBQX prevented the sustained AD-like activity of ketamine evidenced by decreases in FST swimming duration and blunted cortical 5-HTextand Gluext.Intra-mPFC muscimol blocked ketamine AD-like activity and its effects on cortical 5-HText. Moreover, a selective glutamate transporter GLT-1 inhibitor, dihydrokainic acid (DHK) locally perfused into the mPFC produced an AD-like activity at t24h associated with robust increases in mPFC 5-HText, Gluextand GABAext. Thus, the sustained AD-like activity of ketamine is triggered by AMPA-R activation in the DRN and 5-HT - glutamate release in the mPFC, but limited by GABAA-R activation - GABA release in the mPFC. The local blockade of GLT-1 in the mPFC also mimics the rapid responses of ketamine, thus highlighting the role of neuronal-glial adaptation in these effects. These results also suggests the need to test for the concomitant prescription of ketamine and BZD to see whether its sustained antidepressant activity is maintained in TRD patients.
ThiL is a valid antibacterial target that is essential for both thiamine biosynthesis and salvage pathway inPseudomonas aeruginosa
Authors: Kim Hyung Jun , Lee Hyunjung , Lee Yunmi , Choi Inhee , Ko Yoonae , Lee Sangchul , Jang Soojin 
Published: March 2020

ABSTRACTThiamine pyrophosphate (TPP) is an essential cofactor for various pivotal cellular processes in all living organisms, including bacteria. As thiamine biosynthesis occurs in bacteria but not humans, bacterial thiamine biosynthesis is an attractive target for antibiotic development. Among enzymes in the thiamine biosynthetic pathway, thiamine monophosphate kinase (ThiL) catalyzes the final step of the pathway, phosphorylating thiamine monophosphate (TMP) to produce TPP. In this work, we extensively investigated ThiL inPseudomonas aeruginosa, a major pathogen of hospital-acquired infections. We demonstrated thatthiLdeletion abolishes not only thiamine biosynthesis but also thiamine salvage capability, showing growth defects of the ΔthiLmutant even in the presence of thiamine derivatives except TPP. Most importantly, the pathogenesis of the ΔthiLmutant was markedly attenuated compared to wild-type bacteria, with lower inflammatory cytokine induction and 103~104times decreased bacterial load in anin vivoinfection model where the intracellular TPP level is in the submicromolar range. In order to validateP. aeruginosaThiL (PaThiL) as a new drug target, we further characterized its biochemical properties determining a Vmax of 4.0±0.2 nomol·min−1and KMvalues of 111±8 and 8.0±3.5μM for ATP and TMP, respectively. A subsequentin vitrosmall molecule screening identified PaThiL inhibitors including WAY213613 that is a noncompetitive inhibitor with a Ki value of 13.4±2.3 μM and a potential antibacterial activity againstP. aeruginosa. This study proved that PaThiL is a new drug target againstP. aeruginosaproviding comprehensive biological and biochemical data that could facilitate to develop a new repertoire of antibiotics.
Sox2-dependent maintenance of mouse oligodendroglioma involves the Sox2-mediated downregulation of Cdkn2b, Ebf1, Zfp423 and Hey2
Authors: Barone Cristiana , Buccarelli Mariachiara , Alessandrini Francesco , Pagin Miriam , Rigoldi Laura , Sambruni Irene , Favaro Rebecca , Ottolenghi Sergio , Pallini Roberto , Ricci-Vitiani Lucia , Malatesta Paolo , Nicolis Silvia K. 
Published: March 2020

AbstractCancer stem cells (CSC) are essential for tumorigenesis. The transcription factor Sox2 is overexpressed in brain tumors. In gliomas, Sox2 is essential to maintain CSC. In mouse high-grade glioma pHGG, Sox2 deletion causes cell proliferation arrest and inability to reform tumorsin vivo;134 genes are significantly derepressed. To identify genes mediating the effects of Sox2 deletion, we overexpressed into pHGG cells nine among the most derepressed genes, and identified four genes, Cdkn2b, Ebf1, Zfp423 and Hey2, that strongly reduced cell proliferationin vitroand brain tumorigenesisin vivo. CRISPR/Cas9 mutagenesis, or pharmacological inactivation, of each of these genes, individually, showed that their activity is essential for the proliferation arrest caused by Sox2 deletion. These Sox2-inhibited antioncogenes also inhibited clonogenicity in primary human glioblastoma-derived cancer stem-like cell lines. These experiments identify critical anti-oncogenic factors whose inhibition by Sox2 is involved in CSC maintenance, defining new potential therapeutic targets for gliomas.Table of Contents ImageMain PointsSox2 maintains glioma tumorigenicity by repressing the antioncogenic activity of a regulatory network involving the Ebf1, Hey2, Cdkn2b and Zfp423 genes.Mutation of these genes prevents the cell proliferation arrest of Sox2-deleted glioma cells.
The m6A reader Ythdf restricts axonal growth inDrosophilathrough target selection modulation of the Fragile X mental retardation protein
Authors: Soldano Alessia , Worpenberg Lina , Paolantoni Chiara , Longhi Sara , Mulorz Miriam M. , Lence Tina , Wessels Hans-Hermann , Aiello Giuseppe , Notarangelo Michela , Sutandy FX Reymond , Scheibe Marion , Edupuganti Raghu R. , Busch Anke , Möckel Martin M. , Vermeulen Michiel , Butter Falk , König Julian , Ohler Uwe , Dieterich Christoph , Quattrone Alessandro , Roignant Jean-Yves 
Published: March 2020

AbstractN6-methyladenosine (m6A) regulates a variety of physiological processes through modulation of RNA metabolism. The modification is particularly enriched in the nervous system of several species, and its dysregulation has been associated with neurodevelopmental defects and neural dysfunctions. InDrosophila, loss of m6A alters fly behavior albeit the underlying mechanism and the role of m6A during nervous system development have remained elusive. Here we find that impairment of the m6A pathway leads to axonal overgrowth and misguidance at larval neuromuscular junctions as well as in the adult mushroom bodies. We identify Ythdf as the main m6A reader in the nervous system being required for limiting axonal growth. Mechanistically, we show that Ythdf directly interacts with Fragile X mental retardation protein to inhibit the translation of key transcripts involved in axonal growth regulation. Altogether, this study demonstrates that the m6A pathway controls development of the nervous system by modulating Fmr1 target selection.
Characterization of the Endometrial Transcriptome in Early Diestrus Influencing Pregnancy Establishment in Dairy Cattle after Transfer of In-Vitro Produced Embryos
Authors: Mazzoni Gianluca , Pedersen Hanne S , Rabaglino Maria B , Hyttel Poul , Callesen Henrik , Kadarmideen Haja N 
Published: March 2020

AbstractModifications of the endometrial transcriptome at day 7 of the estrus cycle are crucial to maintain gestation after transfer of in-vitro produced (IVP) embryos. The aim of this study was to identify genes, and their related biological mechanisms, in the endometria of recipient lactating dairy cows that become pregnant in the subsequent estrus cycle upon transfer of IVP embryos. Endometrial biopsies were taken from lactating Holstein Friesian cows on day 6-8 of the estrus cycle followed by embryo transfer in the following cycle. Animals were classified retrospectively as pregnant (PR, n=8) or non-pregnant (non-PR, n=11) cows, according to pregnancy status at 26-47 days. Extracted mRNAs from endometrial samples were sequenced with an Illumina platform to determine differentially expressed genes (DEG) between the endometrial transcriptome from PR and non-PR cows. There were 111 DEG (FDR<0.05), which were mainly related to extracellular matrix interaction, histotroph metabolic composition, prostaglandin synthesis, TGF-β signaling as well as inflammation and leukocyte activation. Comparison of these DEG with DEG identified in two public external datasets confirmed the more fertile endometrial molecular profile of PR cows. In conclusion, this study provides insights into the key early endometrial mechanisms for pregnancy establishment, after IVP embryo transfer in dairy cows.
Emergent behavioral organization in heterogeneous groups of a social insect
Authors: Ulrich Yuko , Kawakatsu Mari , Tokita Christopher K. , Saragosti Jonathan , Chandra Vikram , Tarnita Corina E. , Kronauer Daniel J. C. 
Published: March 2020

AbstractThe composition of social groups has profound effects on their function, from collective decision-making to foraging efficiency. But few social systems afford sufficient control over group composition to precisely quantify its effects on individual and collective behavior. Here we combine experimental and theoretical approaches to study the effect of group composition on individual behavior and division of labor (DOL) in a social insect. Experimentally, we use automated behavioral tracking to monitor 120 colonies of the clonal raider ant,Ooceraea biroi,with controlled variation in three key correlates of social insect behavior: genotype, age, and morphology. We find that each of these sources of heterogeneity generates a distinct pattern of behavioral organization, including the amplification or dampening of inherent behavioral differences in colonies with mixed types. Theoretically, we use a well-studied model of DOL to explore potential mechanisms underlying the experimental findings. We find that the simplest implementation of this model, which assumes that heterogeneous individuals differ only in response thresholds, could only partially recapitulate the empirically observed patterns of behavior. However, the full spectrum of observed phenomena was recapitulated by extending the model to incorporate two factors that are biologically meaningful but theoretically rarely considered: variation among workers in task performance efficiency and among larvae in task demand. Our results thus show that different sources of heterogeneity within social groups can generate different, sometimes non-intuitive, behavioral effects, but that relatively simple models can capture these dynamics and thereby begin to elucidate the basic organizational principles of DOL in social insects.Significance StatementWhen individuals interact in an aggregate, many factors that are not knowna prioriaffect group dynamics. A social group will therefore show emergent properties that cannot easily be predicted from how its members behave in isolation. This problem is exacerbated in mixed groups, where different individuals have different behavioral tendencies. Here we describe different facets of collective behavioral organization in mixed groups of the clonal raider ant, and show that a simple theoretical model can capture even non-intuitive aspects of the behavioral data. These results begin to reveal the principles underlying emergent behavioral organization in social insects. Importantly, our insights might apply to complex biological systems more generally and be used to help engineer collective behavior in artificial systems.
Rapid Epistatic Mixed Model Association Studies by Controlling Multiple Polygenic Effects
Authors: Wang Dan , Tang Hui , Liu Jian-Feng , Xu Shizhong , Zhang Qin , Ning Chao 
Published: March 2020

SummaryWe have developed a rapid mixed model algorithm for exhaustive genome-wide epistatic association analysis by controlling multiple polygenic effects. Our model can simultaneously handle additive by additive epistasis, dominance by dominance epistasis and additive by dominance epistasis, and account for intrasubject fluctuations due to individuals with repeated records. Furthermore, we suggest a simple but efficient approximate algorithm, which allows examination of all pairwise interactions in a remarkably fast manner of linear with population size. Application to publicly available yeast and human data has showed that our mixed model-based method has similar performance with simple linear model-based Plink on computational efficiency. It took less than 40 hours for the pairwise analysis of 5,000 individuals genotyped with roughly 350,000 SNPs with five threads on Intel Xeon E5 2.6GHz CPU.Availability and implementationSource codes are freely available athttps://github.com/chaoning/GMAT.
Frontotemporal Coordination Predicts Working Memory Performance and its Local Neural Signatures
Authors: Rezayat Ehsan , Dehaqani Mohmmad-Reza A. , Clark Kelsey , Bahmani Zahra , Moore Tirin , Noudoost Behrad 
Published: March 2020

AbstractNeurons in some sensory areas reflect the content of working memory (WM) in their spiking activity. However, this spiking activity is seldom related to behavioral performance. We studied the responses of inferotemporal (IT) neurons, which exhibit object-selective activity, along with Frontal Eye Field (FEF) neurons, which exhibit spatially-selective activity, during the delay period of an object WM task. Unlike the spiking activity and local field potentials (LFPs) within these areas, which were poor predictors of behavioral performance, the phase-locking of IT spikes and LFPs with the beta band of FEF LFPs robustly predicted successful WM maintenance. In addition, IT neurons exhibited greater object-selective persistent activity when their spikes were locked to the phase of FEF LFPs. These results demonstrate a key role of coordination between prefrontal and temporal cortex in the successful maintenance of visual information during WM.
Altering the bilayer motif in ERBB2 HER2 TMD and in ErbB HER TMD dimer causing in vitro and in vivo tumor suppression
Authors: Menyhert Laszlo David , Tejeda Miguel 
Published: March 2020

AbstractHuman ERBB2 is a transmembrane signaling tyrosine kinase receptor, which seems an ideal target of human WNT16B, the secreted growth factor possibly causes transmembrane domain (TMD) mutations. There is a strong relationship between the chemical nature of the TMD mutations and the potency with which they activate HER2.In silico, we modeled the possible docking conformation of human WNT16B and human ERBB2 TMD homodimer, resulted a mutant complex. The ribbon structure, the C-terminal and N-terminal and GG4-like motif structures are similar in HER2 TMD and HER TMD, we modeled WNTl6B’s possible docking conformation to the HER1 TMD (ErbB), also resulted a mutant complex. If there is a strong relationship between TMD mutations improving the active dimer interface or stabilizing an activated conformation and the potency with which they activate HER2 (and possibly also HER), than the TMD dimerization part seems ideal reagent-target. The agent we tested – the 4-(Furan-2-yl)hepta-1,6-dien-4-ol (AKOS004122375) – has very good connectivity attributes by its several rotatable bonds, and according to thein silicoinspection of close residues intermolecular bonds, and the ligand docking, it can straight connect to human ERBB2 TMD (HER2), and to the ErbB TMD (HER1) dimer bilayer motif as well.In silico, we also tested the agent ligand’s docking into the residues of human WNT16B and human ERBB2 TMD (HER2) mutant complex, and human WNT16B and human ErbB TMD (HER1) mutant complex. We tested the agent ligandin vitroandin vivoin several tumor models, highlighting that targeting the EGFR’s TMD with an agent not only reduces treatment-induced metastasis, but radically decreases the tumor growth as well. Because of the analogous structure of HER2 TMD and HER TMD, this dimerization motif-targeting can also be successful in HER and HER2 EGFR signaling.In vitro, we reached 80-94% proliferation percentage in different tumor models,in vivowe reached 35-61% tumor suppression in different tumor models, the metastasis inhibition effect of the compound was 82-87% in different tumor models.
Contrasted gene decay in subterranean vertebrates: insights from cavefishes and fossorial mammals
Authors: Policarpo Maxime , Fumey Julien , Lafargeas Philippe , Naquin Delphine , Thermes Claude , Naville Magali , Dechaud Corentin , Volff Jean-Nicolas , Cabau Cedric , Klopp Christophe , Møller Peter Rask , Bernatchez Louis , García-Machado Erik , Rétaux Sylvie , Casane Didier 
Published: March 2020

AbstractEvolution sometimes proceeds by loss, especially when structures and genes become dispensable after an environmental shift relaxing functional constraints. Gene decay can serve as a read-out of this evolutionary process. Animals living in the dark are outstanding models, in particular cavefishes as hundreds of species evolved independently during very different periods of time in absence of light. Here, we sought to understand some general principals on the extent and tempo of decay of several gene sets in cavefishes. The analysis of the genomes of two Cuban species belonging to the genusLucifugaprovides evidence for the most massive loss of eye genes reported so far in cavefishes. Comparisons with a recently-evolved cave population ofAstyanax mexicanusand three species belonging to the tetraploid Chinese genusSinocyclocheilusrevealed the combined effects of the level of eye regression, time and genome ploidy on the number of eye pseudogenes. In sharp contrast, most circadian clock and pigmentation genes appeared under strong selection. In cavefishes for which complete genomes are available, the limited extent of eye gene decay and the very small number of loss of function (LoF) mutations per pseudogene suggest that eye degeneration is never very ancient, ranging from early to late Pleistocene. This is in sharp contrast with the identification of several eye pseudogenes carrying many LoF mutations in ancient fossorial mammals. Our analyses support the hypothesis that blind fishes cannot thrive more than a few millions of years in cave ecosystems.
Death recognition by undertaker bees
Authors: Wen Ping 
Published: March 2020

AbstractDead conspecifics removal is important of being social to avoid pathogen transmission, which resulted in the evolution of a specific caste of undertaking workers in all hives bee species. However, it is mysterious that how the undertakers distinguish death and life instantly. Through integrative studies of behavioural tests and chemical analyses, a novel mechanism for dead conspecifics recognition is found in the Asian beeApis cerana ceranaFabricius. The bees detect quickly the death of conspecifics based on decreased cuticular hydrocarbon (CHC) emissions, caused by the cooling of the dead bee. Specifically, with the decline of body temperature in death, the CHC emission was reduced. Undertakers perceived the major CHCs. Addition of synthetic CHCs, followed by heating, inhibited undertaking behaviour. Among these CHCs, heptacosane and nonacosane are the major compounds in a natural bee hive, providing a continuous signal associated with life. Via changing the vapour pressure then the ratio of emitted compounds encoding the physiological status of signal sender, insect chemical communication can be finely tuned by body temperature. This straightforward death recognition mechanism requiring little cost can be universal in animal living in social groups, especially in the social insects. Body temperature affected behaviour can response to increasing frequency of extreme weathers in global climate change, which help explain the recent worldwide bee health problem.
Tracking the outbreak. An optimized delimiting survey strategy forXylella fastidiosa
Authors: Lázaro E. , Sesé M. , López-Quílez A. , Conesa D. , Dalmau V. , Ferrer-Matoses A. , Vicent A. 
Published: March 2020

SummaryCurrent legislation enforces the implementation of intensive surveillance programs for quarantine plant pathogens. After an outbreak, surveys are implemented to delimit the geographic extent of the pathogen and execute disease control. The feasibility of control programs is highly dependent on budget availability, thus it is necessary to target and optimize surveillance strategies.A sequential adaptive delimiting survey involving a three-phase and a two-phase design with increasing spatial resolution was developed and implemented for theXylella fastidiosaoutbreak in Alicante, Spain. Inspection and sampling intensities were optimized using simulation-based methods and results were validated using Bayesian spatial models.This strategy made it possible to sequence inspection and sampling considering different spatial resolutions, and to adapt the inspection and sampling intensity according to the information obtained in the previous, coarser, spatial resolution.The proposed strategy was able to delimit efficiently the extent ofXfimproving efficiency of the current in terms of survey efforts. From a methodological perspective, our approach provides new insights of alternative delimiting designs and new reference sampling intensity values.