bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neural inflammation alters synaptic plasticity probed by 10 Hz repetitive magnetic stimulation
Authors: Lenz Maximilian , Eichler Amelie , Kruse Pia , Strehl Andreas , Rodriguez-Rozada Silvia , Goren Itamar , Yogev Nir , Frank Stefan , Waisman Ari , Deller Thomas , Jung Steffen , Maggio Nicola , Vlachos Andreas 
Published: October 2020

ABSTRACTSystemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimulation (rMS) of organotypic entorhino-hippocampal tissue cultures induced a robust increase in excitatory neurotransmission onto CA1 pyramidal neurons. Furthermore, LPS-treated tissue cultures did not express rMS-induced synaptic plasticity. Live-cell microscopy in tissue cultures prepared from a novel transgenic reporter mouse line [C57BL6-Tg(TNFa-eGFP)] confirms thatex vivoLPS administration triggers microglial tumor necrosis factor alpha (TNFα) expression, which is ameliorated in the presence of IL10. Consistent with this observation, IL10 hampers the LPS-induced increase in TNFα, IL6, IL1β, and IFNγ and restores the ability of neurons to express rMS-induced synaptic plasticity in the presence of LPS. These findings establish organotypic tissue cultures as a suitable model for studying inflammation-induced alterations in synaptic plasticity, thus providing a biological basis for the diagnostic use of transcranial magnetic stimulation in the context of brain inflammation.
A new approach of dissecting genetic effects for complex traits
Authors: Luo Meng , Gu Shiliang 
Published: October 2020

AbstractDuring the past decades, genome-wide association studies (GWAS) have been used to successfully identify tens of thousands of genetic variants associated with complex traits included in humans, animals, and plants. All common genome-wide association (GWA) methods rely on population structure correction to avoid false genotype and phenotype associations. However, population structure correction is a stringent penalization, which also impedes the identification of real associations. Here, we used recent statistical advances and proposed iterative screen regression (ISR), which enables simultaneous multiple marker associations and shown to appropriately correction population stratification and cryptic relatedness in GWAS. Results from analyses of simulated suggest that the proposed ISR method performed well in terms of power (sensitivity) versus FDR (False Discovery Rate) and specificity, also less bias (higher accuracy) in effect (PVE) estimation than the existing multi-loci (mixed) model and the single-locus (mixed) model. We also show the practicality of our approach by applying it to rice, outbred mice, and A.thaliana datasets. It identified several new causal loci that other methods did not detect. Our ISR provides an alternative for multi-loci GWAS, and the implementation was computationally efficient, analyzing large datasets practicable (n>100,000).
A paired liver biopsy and plasma proteomics study reveals circulating biomarkers for alcohol-related liver disease
Authors: Niu Lili , Thiele Maja , Geyer Philipp E. , Rasmussen Ditlev Nytoft , Webel Henry Emanuel , Santos Alberto , Gupta Rajat , Meier Florian , Strauss Maximilian , Kjaergaard Maria , Lindvig Katrine , Jacobsen Suganya , Rasmussen Simon , Hansen Torben , Krag Aleksander , Mann Matthias 
Published: October 2020

AbstractExisting tests for detecting liver fibrosis, inflammation and steatosis, three stages of liver disease that are still reversible are severely hampered by limited accuracy or invasive nature. Here, we present a paired liver-plasma proteomics approach to infer molecular pathophysiology and to identify biomarkers in a cross-sectional alcohol-related liver disease cohort of nearly 600 individuals. Metabolic functions were downregulated whereas fibrosis-associated signaling and novel immune responses were upregulated, but only half of tissue proteome changes were transmitted to the circulation. Machine learning models based on our biomarker panels outperformed existing tests, laying the foundation for a generic proteomic liver health assessment.
Phosphorylation-dependent sub-functionalization of the calcium-dependent protein kinase CPK28
Authors: Bredow Melissa , Bender Kyle W. , Dingee Alexandra Johnson , Holmes Danalyn R. , Thomson Alysha , Ciren Danielle , Tanney Cailun A. S. , Dunning Katherine E. , Trujillo Marco , Huber Steven C. , Monaghan Jacqueline 
Published: October 2020

ABSTRACTCalcium (Ca2+)-dependent protein kinases (CDPKs or CPKs) are a unique family of Ca2+-sensor/kinase-effector proteins with diverse functions in plants. InArabidopsis thaliana, CPK28 contributes to immune homeostasis by promoting degradation of the key immune signaling receptor-like cytoplasmic kinase BOTRYTIS-INDUCED KINASE 1 (BIK1), and additionally functions in vegetative-to-reproductive stage transition. How CPK28 controls these seemingly disparate pathways is unknown. Here, we identify a single phosphorylation site in the kinase domain of CPK28 (Ser318) that is differentially required for its function in immune homeostasis and stem elongation. We show that CPK28 undergoes intra- and inter-molecular auto-phosphorylation on Ser318 and can additionally be trans-phosphorylated on this residue by BIK1. Analysis of several other phosphorylation sites demonstrates that Ser318 phosphorylation is uniquely required to prime CPK28 for Ca2+activation at physiological concentrations of Ca2+, possibly through stabilization of the Ca2+-bound active state as indicated by intrinsic fluorescence experiments. Together, our data indicate that phosphorylation of Ser318 is required for the activation of CPK28 at low intracellular [Ca2+] to prevent initiation of an immune response in the absence of infection. By comparison, phosphorylation of Ser318 is not required for stem-elongation, indicating pathway specific requirements for phosphorylation-based Ca2+-sensitivity priming. We additionally provide evidence for a conserved function for Ser318 phosphorylation in related group IV CDPKs which holds promise for biotechnological applications by generating CDPK alleles that enhance resistance to microbial pathogens without consequences to yield.
Malleability of the cortical hand map following a finger nerve block
Authors: Wesselink Daan B. , Sanders Zeena-Britt , Edmondson Laura R. , Dempsey-Jones Harriet , Kieliba Paulina , Kikkert Sanne , Themistocleous Andreas C. , Emir Uzay , Diedrichsen Jörn , Saal Hannes P. , Makin Tamar R. 
Published: October 2020

AbstractIndividual fingers in the primary somatosensory cortex (S1) are known to be represented separately and adjacently, forming a cortical hand map. Electrophysiological studies in monkeys show that finger amputation triggers increased selectivity to the neighbouring fingers within the deprived S1, causing local reorganisation. Neuroimaging research in humans, however, shows persistent S1 finger representation of the missing hand, even decades after amputation. We aimed to resolve these apparently contrasting evidence by examining finger representation in humans following pharmacological ‘amputation’ using single-finger nerve block and 7T neuroimaging. We hypothesised that beneath the apparent selectivity of individual fingers in the hand map, peripheral and central processing is distributed across fingers. If each finger contributes to the cortical representation of the others, then localised input loss will weaken finger representation across the hand map. For the same reason, the non-blocked fingers will stabilise the blocked finger’s representation, resulting in persistent representation of the blocked finger. Using univariate selectivity profiling, we replicated the electrophysiological findings of local S1 reorganisation. However, more comprehensive analyses confirmed that local blocking reduced representation of all fingers across the entire hand area. Importantly, multivariate analysis demonstrated that despite input loss, representation of the blocked finger remained persistent and distinct from the unblocked fingers. Computational modelling suggested that the observed findings are driven by distributed processing underlying the topographic map, combined with homeostatic mechanisms. Our findings suggest that the long-standing depiction of the somatosensory hand map is misleading. As such, accounts for map reorganisation, e.g. following amputation, need to be reconsidered.
Translation-dependent and independent mRNA decay occur through mutually exclusive pathways that are defined by ribosome density during T Cell activation
Authors: Mercier Blandine C. , Labaronne Emmanuel , Cluet David , Bicknell Alicia , Corbin Antoine , Guiguettaz Laura , Aube Fabien , Modolo Laurent , Auboeuf Didier , Moore Melissa J. , Ricci Emiliano P. 
Published: October 2020

AbstractmRNA translation and degradation are strongly interconnected processes that participate in the fine tuning of gene expression. Particularly, targeting mRNAs to translation-dependent degradation (TDD) could attenuate protein expression by making any increase in mRNA translation self-limiting. However, the extent to which TDD is a general mechanism for limiting protein expression is currently unknown. Here we describe a comprehensive analysis of basal and signal-induced TDD in mouse primary CD4 T cells. Our data indicate that most cellular transcripts are decayed to some extent in a translation-dependent manner, both in resting and activated cells. Our analysis further identifies the length of untranslated regions, the density of ribosomes and the GC content of the coding region as major determinants of TDD magnitude. Consistent with this, all transcripts that undergo changes in ribosome density upon T cell activation display a corresponding change in their TDD level. Surprisingly, the amplitude of translation-independent mRNA decay (TID) appears as a mirror image of TDD. Moreover, TID also responds to changes in ribosome density upon T cell activation but in the opposite direction from the one observed for TDD. Our data demonstrate a strong interconnection between mRNA translation and decay in mammalian cells. Furthermore, they indicate that ribosome density is a major determinant of the pathway by which transcripts are degraded within cells.
Histone modifications form a cell-type-specific chromosomal bar code that modulates and maintains patterns of gene expression through the cell cycle
Authors: Halsall John A. , Andrews Simon , Krueger Felix , Rutledge Charlotte E. , Ficz Gabriella , Reik Wolf , Turner Bryan M. 
Published: October 2020

ABSTRACTBackgroundChromatin configuration influences gene expression in eukaryotes at multiple levels, from individual nucleosomes to chromatin domains several Mb long. Post-translational modifications (PTM) of core histones seem to be involved in chromatin structural transitions, but how remains unclear.To explore this, we used ChIP-seq and two cell types, HeLa and lymphoblastoid (LCL) to define how changes in chromatin packaging through the cell cycle influence the distributions of three transcription-associated histone modifications, H3K9ac, H3K4me3 and H3K27me3.ResultsChromosome regions (bands) of 10-50Mb, detectable by immunofluorescence microscopy of metaphase (M) chromosomes, are also present in G1and G2. We show that they comprise 1-5Mb sub-bands that differ between HeLa and LCL but remain consistent through the cell cycle. The same sub-bands are defined by H3K9ac and H3K4me3, while H3K27me3 spreads more widely.We found little change between cell cycle phases, whether compared by 5Kb rolling windows or when analysis was restricted to functional elements such as transcription start sites and topologically associating domains.Only a small number of genes showed cell-cycle related changes: at genes encoding proteins involved in mitosis, H3K9 became highly acetylated in G2M, possibly because of ongoing transcription.ConclusionsModified histone isoforms H3K9ac, H3K4me3 and H3K27me3 exhibit a characteristic genomic distribution at resolutions of 1Mb and below that differs between HeLa and lymphoblastoid cells but remains remarkably consistent through the cell cycle. We suggest that this cell-type-specific chromosomal bar-code is part of a homeostatic mechanism by which cells retain their characteristic gene expression patterns, and hence their identity, through multiple mitoses.
Comparison of morphine, oxycodone and the biased MOR agonist SR-17018 for tolerance and efficacy in mouse models of pain
Authors: Pantouli Fani , Grim Travis W. , Schmid Cullen L. , Acevedo-Canabal Agnes , Kennedy Nicole M. , Bannister Thomas D. , Bohn Laura M. 
Published: October 2020

AbstractThe mu opioid receptor-selective agonist, SR-17018, preferentially activates GTPγS binding over βarrestin2 recruitment in cellular assays. In mice, SR-17018 stimulates GTPγS binding in brainstem and produces antinociception with potencies similar to morphine. However, it produces much less respiratory suppression and mice do not develop antinociceptive tolerance in the hot plate assay upon repeated dosing. Herein we evaluate the effects of acute and repeated dosing of SR-17018, oxycodone and morphine in additional models of pain-related behaviors. In the mouse warm water tail immersion assay, an assessment of spinal reflex to thermal nociception, repeated administration of SR-17018 produces tolerance as does morphine and oxycodone. SR-17018 retains efficacy in a formalin-induced inflammatory pain model upon repeated dosing, while oxycodone does not. In a chemotherapeutic-induced neuropathy pain model SR-17018 is more potent and efficacious than morphine or oxycodone, moreover, this efficacy is retained upon repeated dosing of SR-17018. These findings demonstrate that, with the exception of the tail flick test, SR-17018 retains efficacy upon chronic treatment across several pain models.
Mechanistic theory predicts the effects of temperature and humidity on inactivation of SARS-CoV-2 and other enveloped viruses
Authors: Morris Dylan H. , Yinda Kwe Claude , Gamble Amandine , Rossine Fernando W. , Huang Qishen , Bushmaker Trenton , Fischer Robert J. , Matson M. Jeremiah , Doremalen Neeltje van , Vikesland Peter J. , Marr Linsey C. , Munster Vincent J. , Lloyd-Smith James O. 
Published: October 2020

AbstractEnvironmental conditions affect virus inactivation rate and transmission potential. Understanding those effects is critical for anticipating and mitigating epidemic spread. Ambient temperature and humidity strongly affect the inactivation rate of enveloped viruses, but a mechanistic, quantitative theory of those effects has been elusive. We measure the stability of the enveloped respiratory virus SARS-CoV-2 on an inert surface at nine temperature and humidity conditions and develop a mechanistic model to explain and predict how temperature and humidity alter virus inactivation. We find SARS-CoV-2 survives longest at low temperatures and extreme relative humidities; median estimated virus half-life is over 24 hours at 10 °C and 40 % RH, but approximately 1.5 hours at 27 °C and 65 % RH. Our mechanistic model uses simple chemistry to explain the increase in virus inactivation rate with increased temperature and the U-shaped dependence of inactivation rate on relative humidity. The model accurately predicts quantitative measurements from existing studies of five different human coronaviruses (including SARS-CoV-2), suggesting that shared mechanisms may determine environmental stability for many enveloped viruses. Our results indicate scenarios of particular transmission risk, point to pandemic mitigation strategies, and open new frontiers in the mechanistic study of virus transmission.
Real-time luminescence assay for cytoplasmic cargo delivery of extracellular vesicles
Authors: Somiya Masaharu , Kuroda Shun’ichi 
Published: October 2020

AbstractExtracellular vesicles (EVs) have been considered to deliver biological cargos between cells and mediate intercellular communication. However, the mechanisms that underlie the biological process of EV uptake and cytoplasmic cargo release in recipient cells are largely unknown. Quantitative and real-time assays for assessment of the cargo delivery efficiency inside recipient cells have not been feasible. In this study, we developed an EV cargo delivery (EVCD) assay using a split luciferase called the NanoBiT system. Recipient cells expressing LgBiT, a large subunit of luciferase, emit luminescence when the EV cargo proteins fused with a small luminescence tag (HiBiT tag) that can complement LgBiT are delivered to the cytoplasm of recipient cells. Using the EVCD assay, the cargo delivery efficiency of EVs could be quantitatively measured in real time. This assay was highly sensitive in detecting a single event of cargo delivery per cell. We found that modification of EVs with a virus-derived fusogenic protein significantly enhanced the cytoplasmic cargo delivery; however, in the absence of a fusogenic protein, the cargo delivery efficiency of EVs was below the threshold of the assay. The EVCD assay could assess the effect of entry inhibitors on EV cargo delivery. Furthermore, using a luminescence microscope, the cytoplasmic cargo delivery of EVs was directly visualized in living cells. This assay could reveal the biological mechanism of the cargo delivery processes of EVs.
A comparison of Remdesivir versus Au22Glutathione18in COVID-19 golden hamsters: a better therapeutic outcome of gold compound
Authors: He Zhesheng , Ye Fei , Zhang Chunyu , Fan Jiadong , Du Zhongying , Zhao Wencong , Yuan Qing , Niu Wenchao , Gao Fuping , He Bo , Cao Peng , Zhao Lina , Gao Xuejiao , Gao Xingfa , Sun Bo , Dong Yuhui , Zhao Jincun , Qi Jianxun , Jiang Huaidong , Gong Yong , Tan Wenjie , Gao Xueyun 
Published: October 2020

AbstractWe firstly disclose single compound yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from Au22Glutathione18(GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication (EC50: ~0.24 μM) and intrinsically down-regulates NFκB pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The lung viral load and inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir while their lung viral load are decreased to same level. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 golden hamsters.One Sentence SummaryWe found that gold cluster molecule directly inhibits SARS-CoV-2 replication and intrinsically suppresses inflammatory cytokines expression in COVID-19 transgenic mouse and golden hamster model, gold cluster providing a better lung injury protection than Remdesivir in COVID-19 golden hamsters via intranasally dropping administration.
Neural correlates of hand-object congruency effects during action planning
Authors: Zhang Zuo , Nelissen Natalie , Zeidman Peter , Filippini Nicola , Diedrichsen Jörn , Bracci Stefania , Friston Karl , Rounis Elisabeth 
Published: October 2020

AbstractSelecting hand actions to manipulate an object is affected both by perceptual factors and by action goals. Affordances are associated with the automatic potentiation of motor representations to an object, independent of the goal of the actor. In previous studies, we have demonstrated an influence of the congruency between hand and object orientations on response times when reaching to turn an object, such as a cup. In this study, we investigated how the representation of hand postures triggered by planning to turn a cup were influenced by this congruency effect, in an fMRI scanning environment. Healthy participants were asked to reach and turn a real cup that was placed in front of them either in an upright orientation or upside down. They were instructed to use a hand orientation that was either congruent or incongruent with the cup orientation. As expected, the motor responses were faster when the hand and cup orientations were congruent. There was increased activity in a network of brain regions involving object-directed actions during action planning, which included bilateral primary and extrastriate visual, medial and superior temporal areas, as well as superior parietal, primary motor and premotor areas in the left hemisphere. Specific activation of the dorsal premotor cortex (PMd) was associated with hand-object orientation congruency during planning, and prior to any action taking place. Activity in that area and its connectivity with the lateral occipito-temporal cortex (LOTC) increased when planning incongruent actions. The increased activity in premotor areas in trials where the orientation of the hand was incongruent to that of the object suggests a role in eliciting competing representations specified by hand postures in LOTC.
A hyper-attenuated variant of Rift Valley fever virus (RVFV) generated by a mutagenic drug (favipiravir) unveils potential virulence markers
Authors: Borrego Belén , Brun Alejandro 
Published: October 2020

SUMMARY/ABSTRACTIn a previous work, we showed that favipiravir, a promising drug with antiviral activity against a number of RNA viruses, led to the extinction of RVFV from infected cell cultures. Nevertheless, certain drug concentrations allowed the recovery of a virus variant showing increased resistance to favipiravir. In this work, we characterized this novel resistant variant both at genomic and phenotypic levelin vitroandin vivo. Interestingly, the resistant virus displayed reduced growth rates in insect cells and was highly attenuated but still immunogenicin vivo. Some amino acid substitutions were identified in the viral RNA-dependent RNA-polymerase (RdRp) gene and in the encoded IFN antagonist NSs gene, in catalytic core motifs and nuclear localization associated positions respectively. These data may help to characterize novel potential virulence markers, offering additional strategies for further safety improvements of RVF live attenuated vaccine candidates.SIGNIFICANCE STATEMENTLive attenuated virus vaccines usually provide long lasting immune responses upon administration. These vaccines are not recommended for use in immune compromised hosts, due to the presence of uncontrolled residual virulence. Cell culture virus propagation in the presence of mutagenic drugs often results in weakened virus lacking virulence as well as limited spreading capabilities. Here, we have characterized a mutagen-induced RVFV variant (40F-p8) that is not virulent in a highly sensitive mouse strain lacking antiviral response. The observed lack of virulence correlates with the presence of specific mutations along key residues in the viral genome, unveiling potential virulence determinants. Thus, 40F-p8 constitutes the basis for a novel RVFV vaccine strain with additional safety features.