bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADEP1 activated ClpP1P2 macromolecule ofLeptospira, an ideal Achilles’ heel to deregulate proteostasis and hamper the cell survival
Authors: Dhara Anusua , Hussain Md Saddam , Kanaujia Shankar Prasad , Kumar Manish 
Published: August 2020

ABSTRACTThe caseinolytic protease (ClpP) complex inLeptospira interrogansis unusual in its functional activation. The genusLeptospirahas two ClpPs, ClpP1 and ClpP2, which transcribes independently, regardless it couples to form the active tetradecamer. Acyldepsipeptide (ADEP) antibiotic hampers the growth of numerous bacterial species by activating the target protein ClpP and dysregulating the physiological proteostasis within the cell.In vitroculture of theL. interrogansfortified with the ADEP impeded the spirochete growth accompanied by a more elongated morphology. The chemoactivation of the ClpP is conditional on the duration of the self-compartmentalization of each of the ClpP isoforms. The small extent (10 min) self-assembled ClpP1P2 revealed inhibition in the peptidase activity (7-fold) in the presence of the ADEP due to the self-cleavage of the ClpP subunits. On supplementation of the β-casein or bovine serum albumin, the peptidase activity of the ClpP1P2 (short-incubated) got enhanced by the ADEP, while the ClpP1P2 (long-incubated) activity was retained to the same level. ADEP can also switch on the ClpP1P2 from a strict peptidase into proteolytic machinery that discerns and degrades the unfolded protein substrates autonomous of the cognate chaperone ClpX. In consensus to the most prokaryotes with the multi ClpP variants, the computational prototype of the ClpP1P2 tertiary structure infers that the hydrophobic pocket wherein the ADEPs predominantly docks are present in the ClpP2 heptamer. Additionally, the dynamic light scattering and the site-directed mutagenesis of a catalytic serine residue in either of the ClpP isoforms proposes a second interaction site for the ADEP.
3D imaging and morphometry of the heart capillary system in spontaneously hypertensive rats and normotensive controls
Authors: Olianti Camilla , Costantini Irene , Giardini Francesco , Lazzeri Erica , Crocini Claudia , Ferrantini Cecilia , Pavone Francesco Saverio , Camici Paolo Guido , Sacconi Leonardo 
Published: August 2020

ABSTRACTSystemic arterial hypertension is a highly prevalent chronic disease associated with hypertensive cardiomyopathy. One important feature of this condition is remodelling of intramural small coronary arteries and arterioles. Here, we investigated the implications of this remodelling in the downstream vascular organization, in particular at the capillary level. We used Spontaneously Hypertensive Rats (SHR) exhibiting many features of the human hypertensive cardiomyopathy. We generated 3D high-resolution mesoscopic reconstructions of the entire network of SHR hearts combining gel-based fluorescent labelling of coronaries with a CLARITY-based tissue clearing protocol. We performed morphometric quantification of the capillary network over time to assess capillary diameter, linear density, and angular dispersion. In SHRs, we found significant remodelling of the capillary network density and dispersion. SHR capillary density is increased in both ventricles and at all ages, including before the onset of systemic hypertension. This result suggests that remodelling occurs independently from the onset of systemic hypertension and left ventricular hypertrophy. On the contrary, capillary angular dispersion increases with time in SHR. Consistently, our multi-modal imaging underlined a strong correlation between vascular dispersion and cellular disarray. Together our data show that 3D high-resolution reconstruction of the capillary network can unveil anatomic signatures in both physiological and pathological cardiac conditions, thus offering a reliable method for integrated quantitative analyses.
Failure to modulate reward prediction errors in declarative learning with theta (6 Hz) frequency transcranial alternating current stimulation
Authors: Ergo Kate , De Loof Esther , Debra Gillian , Pastötter Bernhard , Verguts Tom 
Published: August 2020

AbstractRecent evidence suggests that reward prediction errors (RPEs) play an important role in declarative learning, but its neurophysiological mechanism remains unclear. Here, we tested the hypothesis that RPEs modulate declarative learning via theta-frequency oscillations, which have been related to memory encoding in prior work. For that purpose, we examined the interaction between RPE and transcranial Alternating Current Stimulation (tACS) in declarative learning. Using a between-subject (real versus sham stimulation group), single-blind stimulation design, 76 participants learned 60 Dutch-Swahili word pairs, while theta-frequency (6 Hz) tACS was administered over the medial frontal cortex (MFC). Previous studies have implied MFC in memory encoding. We replicated our previous finding of signed RPEs (SRPEs) boosting declarative learning; with larger and more positive RPEs enhancing memory performance. However, tACS failed to modulate the SRPE effect in declarative learning and did not affect memory performance. Bayesian statistics supported evidence for an absence of effect. Our study confirms a role of RPE in declarative learning, but also calls for standardized procedures in transcranial electrical stimulation.
Friendly-rivalry solution to the iteratedn-person public-goods game
Authors: Murase Yohsuke , Baek Seung Ki 
Published: August 2020

AbstractRepeated interaction promotes cooperation among rational individuals under the shadow of future, but it is hard to maintain cooperation when a large number of error-prone individuals are involved. One way to construct a cooperative Nash equilibrium is to find a ‘friendly rivalry’ strategy, which aims at full cooperation but never allows the co-players to be better off. Recently it has been shown that for the iterated Prisoner’s Dilemma in the presence of error, a friendly rival can be designed with the following five rules: Cooperate if everyone did, accept punishment for your own mistake, punish defection, recover cooperation if you find a chance, and defect in all the other circumstances. In this work, we construct such a friendly-rivalry strategy for the iteratedn-person public-goods game by generalizing those five rules. The resulting strategy makes a decision with referring to the previousm= 2n− 1 rounds. A friendly-rivalry strategy inherently has evolutionary robustness in the sense that no mutant strategy has higher fixation probability in this population than that of neutral drift, and our evolutionary simulation indeed shows excellent performance of the proposed strategy in a broad range of environmental conditions.Author summaryHow to maintain cooperation among a number of self-interested individuals is a difficult problem, especially if they can sometimes commit error. In this work, we propose a strategy for the iteratedn-person public-goods game based on the following five rules: Cooperate if everyone did, accept punishment for your own mistake, punish others’ defection, recover cooperation if you find a chance, and defect in all the other circumstances. These rules are not far from actual human behavior, and the resulting strategy guarantees three advantages: First, if everyone uses it, full cooperation is recovered even if error occurs with small probability. Second, the player of this strategy always never obtains a lower long-term payoff than any of the co-players. Third, if the co-players are unconditional cooperators, it obtains a strictly higher long-term payoff than theirs. Therefore, if everyone uses this strategy, no one has a reason to change it. Furthermore, our simulation shows that this strategy will become highly abundant over long time scales due to its robustness against the invasion of other strategies. In this sense, the repeated social dilemma is solved for an arbitrary number of players.
A unique neurogenomic state emerges after aggressive confrontations in males of the fishBetta splendens
Authors: Vu Trieu-Duc , Iwasaki Yuki , Oshima Kenshiro , Nikaido Masato , Chiu Ming-Tzu , Okada Norihiro 
Published: August 2020

AbstractTerritorial defense involves frequent aggressive confrontations with competitors, but little is known about how brain-transcriptomic profiles change between individuals competing for territory establishment. Our previous study elucidated that brain-transcriptomic synchronization occurs in a pair-specific manner between two males of the fishBetta splendensduring fighting, reflecting a mutual assessment process between them at the level of gene expression. Here we evaluated how the brain-transcriptomic profiles of opponents change immediately after shifting their social status (i.e., the winner/loser has emerged) and 30 min after this shift. We showed that unique and carryover hypotheses can be adapted to this system, in which changes in the expression of certain genes are unique to different fighting stages and in which the expression patterns of certain genes are transiently or persistently changed across all fighting stages. Interestingly, the specificity of the brain-transcriptomic synchronization of a pair during fighting was gradually lost after fighting ceased, because of the decrease in the variance in gene expression across all individuals, leading to the emergence of a basal neurogenomic state. Strikingly, this unique state was more basal than the state that existed in the before-fighting group and resulted in the reduced and consistent expression of genes across all individuals. In spite of the consistent and basal overall gene expression in each individual in this state, expression changes for genes related to metabolism, learning and memory, and autism still differentiated losers from winners. The fighting system using maleB. splendensthus provides a promising platform for investigating neurogenomic states of aggression in vertebrates.Author summaryCompetitive interactions involve complex decision-making tasks that are shaped by mutual feedback between participants. When two animals interact, transcriptomes across their brains synchronize in a way that reflects how they assess and predict the other’s fighting ability and react to each other’s decisions. Here, we elucidated the gradual loss of brain-transcriptomic synchrony between interacting opponents after their interaction ceased, leading to the emergence of a basal neurogenomic state, in which the variations in gene expression were reduced to a minimum among all individuals. This basal neurogenomic state shares common characteristics with the hibernation state, which animals adopt to minimize their metabolic rates to cope with harsh environmental conditions. We demonstrated that this unique neurogenomic state, which is newly characterized in the present study, is composed of the expression of a unique set of genes, each of which was presumably minimally required for survival, providing a hypothesis that this state represents the smallest unit of neurogenomic activity for sustaining an active life.
Epistasis and physico-chemical constraints contribute to spatial clustering of amino acid substitutions in protein evolution
Authors: Taverner Andrew M. , Blaine Logan J. , Andolfatto Peter 
Published: August 2020

AbstractThe causes of rate variation among sites within proteins are as yet poorly understood. Here, we compare the spatial autocorrelation of non-synonymous substitutions among species within diverse phylogenetic groups:Saccharomyces, Drosophila, Arabidopsis, and primates. Across these taxa, we find that amino acid substitutions exhibit excess clustering that extends over a 20-30 codon length (10-20 Angstrom distance) scale. We show that these substitutions cluster more strongly and exhibit compensatory dynamics within species lineages but exhibit patterns of convergent evolution between lineages. We evaluate a simple model of thermodynamic constraints on protein folding and conclude that it is unable to recapitulate the observed spatial clustering of substitutions. While pairs of substitutions with the strongest epistasis tend to spatially cluster in these simulations, the magnitude and length scale are smaller than that observed in real data. Additionally, we show that the pattern of convergent substitution is also not expected under this model, suggesting it is likely caused by factors other than these simple thermodynamic constraints. Our results support a prevalent role for epistasis and convergent evolution in shaping protein evolution across the tree of life.
CRISPR/Cas9 technology abolishes theBCR/ABL1oncogene in chronic myeloid leukemia and restores normal hematopoiesis
Authors: Vuelta Elena , Ordoñez José Luis , Alonso-Pérez Verónica , Méndez Lucía , Hernández-Carabias Patricia , Saldaña Raquel , Sevilla Julián , Sebastian Elena , Muntión Sandra , Sánchez-Guijo Fermín , Hernadez-Rivas Jesús María , García-Tuñón Ignacio , Sánchez-Martín Manuel 
Published: August 2020

ABSTRACTChronic myeloid leukemia (CML) is a hematopoietic stem cell disease produced by a unique oncogenic event involving the constitutively active tyrosine kinase (TK)BCR/ABL1. TK activity explains most features of CML, such as tumor development and maintenance. TK-inhibitory (TKI) drugs have changed its prognosis and natural history. Unfortunately, theABL1gene persists unaffected by TKIs, leukemic stem cells (LSCs) remains, resistant mutations arise and adverse effects may occur during treatment. To address this problem, we have designed a potential therapeutic alternative with CRISPR/Cas9 genome editing nucleases that target LSCs. The strategy was successfully developed in murine and human cell lines and finally was evaluated in primary LSCs isolated from CML transgenic mice and from CML patients. Mouse CML-LSCs edited were orthotopic transplanted in immunodeficient NSG niches where restored the normal hematopoiesis. Importantly, patient-derived xenografts with CD34+-LSCs edited, repopulated and restored the normal hematopoiesis in immunodeficient NSG niches. We show, for the first time, how CRISPR technology efficiently interrupts theBCR/ABL1oncogene in murine and human LSCs to provide a significant therapeutic benefit. We propose human CML as a potential candidate for CRISPR therapy, providing proof-of-principle for genome editing in CML patients, and open new avenues for the application of this technique in other fusion genes.Key pointsCRISPR system destroys BCR/ABL oncogene and induces a therapeutic benefit in a CML mouse model and CML patient derived xenografts.
Oak regeneration at the arid boundary of the temperate deciduous forest biome: insights from a seeding and watering experiment
Authors: Erdős László , Szitár Katalin , Öllerer Kinga , Ónodi Gábor , Kertész Miklós , Török Péter , Baráth Kornél , Tölgyesi Csaba , Bátori Zoltán , Somay László , Orbán Ildikó , Kröel-Dulay György 
Published: August 2020

AbstractTemperate deciduous forests dominated by oaks cover extensive areas in European lowlands. These ecosystems have been under intense anthropogenic use for millennia, thus their natural dynamics, and their regeneration in particular, is still not well understood. Previous studies found that pedunculate oak (Quercus robur), one of the most widespread and abundant species in European deciduous forests, regenerates in open habitats and forest edges, but not in closed forest interiors. However, these observations usually come from the core areas of the biome, and much less is known about such processes at its arid boundary, where limiting factors may be different, and climate change may first exert its effects.In a full factorial field experiment, we tested the effects of different habitats and increased growing season precipitation on the early regeneration of pedunculate oak in a forest-steppe ecosystem in Central Hungary, at the arid boundary of temperate deciduous forests. We planted acorns into three neighbouring habitats (grassland, forest edge, forest interior) and studied seedling emergence and plant performance under ambient weather and additional watering for four years.In the grassland habitat, seedling emergence was very low, and no seedlings survived by the fourth year. In contrast, seedling emergence was high and similar at forest edges and forest interiors, and was not affected by water addition. Most seedlings survived until the fourth year, with no difference between forest edge and forest interior habitats in numbers, and only minor or transient differences in size (leaf number, height).The lack of oak regeneration in the grassland contradicts previous reports on successful oak regeneration in open habitats, and may be related to a shift from light limitation to other limiting factors, such as moisture or microclimatic extremes, when moving away from the core of the deciduous forest biome towards its arid boundary. The similar number and performance of seedlings in forest edges and forest interiors may also be related to the decreasing importance of light limitation. The above-average precipitation in the year of seedling emergence (2016) might be a reason why watering had no effect on oak regeneration.Overall, our results highlight that oak regeneration and thus forest dynamics may be limited by different factors at a biome boundary compared to its core areas. Indeed, this very simple mechanism (inability of oak regeneration in grassland habitats) may contribute to the opening up of the closed forest biome, and the emergence of a biome transition zone.
Auditory cortex supports verbal working memory capacity
Authors: Bidelman Gavin M. , Brown Jane A. , Bashivan Pouya 
Published: August 2020

AbstractWorking memory (WM) is a fundamental construct of human cognition. The neural basis of auditory WM is thought to reflect a distributed brain network consisting of canonical memory and central executive brain regions including frontal lobe, prefrontal areas, and hippocampus. Yet, the role of auditory (sensory) cortex in supporting active memory representations remains controversial. Here, we recorded neuroelectric activity via EEG as listeners actively performed an auditory version of the Sternberg memory task. Memory load was taxed by parametrically manipulating the number of auditory tokens (letter sounds) held in memory. Source analysis of scalp potentials showed that sustained neural activity maintained in auditory cortex (AC) prior to memory retrieval closely scaled with behavioral performance. Brain-behavior correlations revealed lateralized modulations in left (but not right) AC predicted individual differences in auditory WM capacity. Our findings confirm a prominent role of auditory cortex, traditionally viewed as a sensory-perceptual processor, in actively maintaining memory traces and dictating individual differences in behavioral WM limits.
A comprehensive macaque fMRI pipeline and hierarchical atlas
Authors: Jung Benjamin , Taylor Paul A. , Seidlitz Jakob , Sponheim Caleb , Perkins Pierce , Ungerleider Leslie G. , Glen Daniel , Messinger Adam 
Published: August 2020

AbstractFunctional neuroimaging research in the non-human primate (NHP) has been advancing at a remarkable rate. The increase in available data establishes a need for robust analysis pipelines designed for NHP neuroimaging and accompanying template spaces to standardize the localization of neuroimaging results. Our group recently developed the NIMH Macaque Template (NMT), a high-resolution population average anatomical template and associated neuroimaging resources, providing researchers with a standard space for macaque neuroimaging (Seidlitz, Sponheim et al., 2018). Here, we release NMT v2, which includes both symmetric and asymmetric templates in stereotaxic orientation, with improvements in spatial contrast, processing efficiency, and segmentation. We also introduce the Cortical Hierarchy Atlas of the Rhesus Macaque (CHARM), a hierarchical parcellation of the macaque cerebral cortex with varying degrees of detail. These tools have been integrated into the neuroimaging analysis software AFNI (Cox, 1996) to provide a comprehensive and robust pipeline for fMRI processing, visualization and analysis of NHP data. AFNI’s new @animal_warper program can be used to efficiently align anatomical scans to the NMT v2 space, and afni_proc.py integrates these results with full fMRI processing using macaque-specific parameters: from motion correction through regression modeling. Taken together, the NMT v2 and AFNI represent an all-in-one package for macaque functional neuroimaging analysis, as demonstrated with available demos for both task and resting state fMRI.HighlightsThe NMT v2, a stereotaxically aligned symmetric macaque template, is introduced.A new atlas (CHARM), defined on NMT v2, parcellates the cortex at six spatial scales.AFNI’s @animal_warper aligns and maps data between monkey anatomicals and templates.AFNI’s afni_proc.py facilitates monkey fMRI analysis with automated scripting and QC.Demos of macaque task and resting state fMRI analysis with these tools are provided.
ThermoBRET: a ligand-engagement nanoscale thermostability assay applied to GPCRs
Authors: Hoare Bradley L. , Tippett David N. , Kaur Amandeep , Cullum Sean A. , Miljuš Tamara , Koers Eline J. , Harwood Clare R. , Dijon Nicola , Holliday Nicholas D. , Sykes David A. , Veprintsev Dmitry B. 
Published: August 2020

AbstractMeasurements of membrane protein thermostability allows indirect detection of ligand binding. Current thermostability assays require protein purification or rely on pre-existing radiolabelled or fluorescent ligands, limiting their application to established target proteins. Alternative methods detect protein aggregation which requires sufficiently high level of protein expression.Here, we present a ThermoBRET method to quantify the relative thermostability of G protein coupled receptors (GPCRs), using cannabinoid receptors (CB1and CB2) and the β2-adrenoceptor (β2AR) as model systems. ThermoBRET reports receptor unfolding, does not need labelled ligands and can be used with non-purified proteins. It uses Bioluminescence Resonance Energy Transfer (BRET) between Nanoluciferase (Nluc) and a thiol-reactive fluorescent dye that binds cysteines exposed by unfolding. We demonstrate that the melting point (Tm) of Nluc-fused GPCRs can be determined in non-purified detergent solubilised membrane preparations or solubilised whole cells, revealing differences in thermostability for different solubilising conditions and in the presence of stabilising ligands. We extended the range of the assay by developing the thermostable tsNLuc by incorporating mutations from the fragments of split-Nluc (Tmof 87 ⁰C vs 59 ⁰C). ThermoBRET allows determination of GPCR thermostability, which is useful for protein purification optimisation and as part of drug discovery screening strategies.