bluuebunny/crossref_metadata_2025_split huggingface dataset:
ADP is the dominant controller of AMP-activated protein kinase activity dynamics in skeletal muscle during exercise
Authors: Coccimiglio Ian F. , Clarke David C. 
Published: December 2019

AbstractExercise training elicits profound metabolic adaptations in skeletal muscle cells. A key molecule in coordinating these adaptations is AMP-activated protein kinase (AMPK), whose activity increases in response to cellular energy demand. AMPK activity dynamics are primarily controlled by the adenine nucleotides ADP and AMP, but how each contributes to its control in skeletal muscle during exercise is unclear. We developed and validated a mathematical model of AMPK signaling dynamics, and then applied global parameter sensitivity analyses with data-informed constraints to predict that AMPK activity dynamics are determined principally by ADP and not AMP. We then used the model to predict the effects of two additional direct-binding activators of AMPK, ZMP and Compound 991, further validating the model and demonstrating its applicability to understanding AMPK pharmacology. The relative effects of direct-binding activators can be understood in terms of four properties, namely their concentrations, binding affinities for AMPK, abilities to enhance AMPK phosphorylation, and the magnitudes of their allosteric activation of AMPK. Despite AMP’s favorable values in three of these four properties, ADP is the dominant controller of AMPK activity dynamics in skeletal muscle during exercise by virtue of its higher concentration.Author SummaryDuring exercise, the enzyme “AMP-activated protein kinase” (AMPK) detects the disrupted cellular energy state by binding to the adenine nucleotides ATP, ADP, and AMP, which are the major chemical energy carriers of the cell. How the adenine nucleotides interact to control AMPK activity is poorly understood. In this study, we used mathematical modeling to investigate the control of AMPK activity by the adenine nucleotides in skeletal muscle during exercise. We simulated the model many times with randomly generated parameter sets. Ultimately the parameters affect four key properties of an AMPK activator, namely its concentration, the tightness with which it binds to AMPK, its ability to activate AMPK by promoting its phosphorylation, and its ability to activate AMPK through allostery. We found that ADP is the dominant controller of AMPK activity, instead of AMP, due to its high concentration relative to that of AMP. We also modeled AMPK activity in response to drugs that activate it, which further demonstrated the validity and applicability of the model. Overall, our research enhances understanding of AMPK action during exercise and could inform the development of drugs that target AMPK.
Simultaneous MRI-EEG during a motor imagery neurofeedback task: an open access brain imaging dataset for multi-modal data integration
Authors: Lioi Giulia , Cury Claire , Perronnet Lorraine , Mano Marsel , Bannier Elise , Lécuyer Anatole , Barillot Christian 
Published: December 2019

AbstractCombining EEG and fMRI allows for integration of fine spatial and accurate temporal resolution yet presents numerous challenges, noticeably if performed in real-time to implement a Neurofeedback (NF) loop. Here we describe a multimodal dataset of EEG and fMRI acquired simultaneously during a motor imagery NF task, supplemented with MRI structural data. The study involved 30 healthy volunteers undergoing five training sessions. We showed the potential and merit of simultaneous EEG-fMRI NF in previous work. Here we illustrate the type of information that can be extracted from this dataset and show its potential use. Our group is the second in the world to have integrated EEG and fMRI for NF, therefore this dataset is unique of its kind. We believe that it will be a valuable tool toAdvance and test methodologies to integrate complementary neuroimaging techniques (design and validation of methods of multi-modal data integration at various scales)Improve the quality of Neurofeedback providedImprove methodologies for de-noising EEG acquired under MRIInvestigate the neuromarkers of motor-imagery using multi-modal information
Neuropsychiatric mutations delineate functional brain connectivity dimensions contributing to autism and schizophrenia
Authors: Moreau Clara , Urchs Sebastian , Kuldeep Kumar , Orban Pierre , Schramm Catherine , Dumas Guillaume , Labbe Aurélie , Huguet Guillaume , Douard Elise , Quirion Pierre-Olivier , Lin Amy , Kushan Leila , Grot Stephanie , Luck David , Mendrek Adrianna , Potvin Stephane , Stip Emmanuel , Bourgeron Thomas , Evans Alan C. , Bearden Carrie E. , Bellec Pierre , Jacquemont Sebastien ,   Simons Variation in Individuals Project Consortium
Published: December 2019

Abstract16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear.We analyzed resting-state functional magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We used CNV FC-signatures to identify dimensions contributing to complex idiopathic conditions.CNVs had large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions played a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibited worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.
Base-pair resolution analysis of the effect of supercoiling on DNA flexibility and major groove recognition by triplex-forming oligonucleotides
Authors: Pyne Alice L. B. , Noy Agnes , Main Kavit , Velasco-Berrelleza Victor , Piperakis Michael M. , Mitchenall Lesley A. , Cugliandolo Fiorella M. , Beton Joseph G. , Stevenson Clare E.M. , Hoogenboom Bart W. , Bates Andrew D. , Maxwell Anthony , Harris Sarah A. 
Published: December 2019

AbstractIn the cell, DNA is arranged into highly-organised and topologically-constrained (supercoiled) structures. It remains unclear how this supercoiling affects the detailed double-helical structure of DNA, largely because of limitations in spatial resolution of the available biophysical tools. Here, we overcome these limitations, by a combination of atomic force microscopy (AFM) and atomistic molecular dynamics (MD) simulations, to resolve structures of negatively-supercoiled DNA minicircles at base-pair resolution. We observe that negative superhelical stress induces local variation in the canonical B-form DNA structure by introducing kinks and defects that affect global minicircle structure and flexibility. We probe how these local and global conformational changes affect DNA interactions through the binding of triplex-forming oligonucleotides to DNA minicircles. We show that the energetics of triplex formation is governed by a delicate balance between electrostatics and bonding interactions. Our results provide mechanistic insight into how DNA supercoiling can affect molecular recognition, that may have broader implications for DNA interactions with other molecular species.
Linear alkylbenzenes (LABs) as sewage pollution indicators in the aquatic ecosystem of Peninsular Malaysia
Authors: Alkhadher Sadeq. A. A. , Kadir Aeslina Abdul , Zakaria Mohamad Pauzi 
Published: December 2019

AbstractLinear alkylbenzenes (LABs) as sewerage indicators were investigated in the sediments of the West and South Peninsular Malaysia. Surface sediment samples were analyzed using gas chromatography–mass spectrometry. Results showed that LAB concentration in the samples of Port Dickson and the Kim Kim River varied from 111.6 to 255.8 and from 88.2 to 119.0 ng·g−1 dry weight, respectively. The ratios of internal isomer, in which the benzene ring was close to the center of the linear alkyl chain, to external isomer, in which the benzene ring was near the end of the linear alkyl chain (I/E ratios), of LABs in Port Dickson coast sediments ranged from 2.6 to 4.1. By contrast, the ratios for sediment from the Kim Kim River varied from 1.7 to 1.9. I/E, long-chained LABs over short-chained LABs (L/S), and C13/C12 ratios indicated that the aquatic environment received primary and secondary sewage effluents. These findings emphasized the necessity of continued water treatment system development in Malaysia.
Decay and damage of therapeutic phage OMKO1 by environmental stressors
Authors: Blazanin Michael , Lam Wai Tin , Vasen Emma , Chan Benjamin K. , Turner Paul E. 
Published: December 2019

AbstractAntibiotic resistant bacterial pathogens are increasingly prevalent, driving the need for alternative approaches to chemical antibiotics when treating infections. One such approach is bacteriophage therapy: the use of bacteria-specific viruses that lyse (kill) their host cells. Just as the effect of environmental conditions (e.g. elevated temperature) on antibiotic efficacy is well-studied, the effect of environmental stressors on the potency of phage therapy candidates demands examination. Therapeutic phage OMKO1 infects and kills the opportunistic human pathogen Pseudomonas aeruginosa. Here, we used phage OMKO1 as a model to test how different environments affect the decay rate of a therapeutic virus, and whether exposure to an environmental stressor can damage surviving viral particles. We assessed the effects of elevated temperatures, saline concentrations, and urea concentrations. We observed that OMKO1 particles were highly tolerant to different saline concentrations, but decayed more rapidly at elevated temperatures and under high concentrations of urea. Additionally, we found that exposure to elevated temperature reduced the ability of surviving phage particles to suppress the growth of P. aeruginosa, suggesting a temperature-induced damage. Our findings demonstrate that OMKO1 is highly tolerant to a range of conditions that could be experienced inside and outside the human body, while also showing the need for careful characterization of therapeutic phages to ensure that environmental exposure does not compromise their expected potency, dosing, and pharmacokinetics.
Chemogenetic actuator drugs impair prefrontal cortex-dependent working memory in rhesus monkeys
Authors: Upright Nicholas A. , Baxter Mark G. 
Published: December 2019

AbstractThe most common chemogenetic neuromodulatory system, Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), uses a non-endogenous actuator ligand to activate a modified muscarinic acetylcholine receptor that is no longer sensitive to acetylcholine. It is crucial in studies using these systems to test the potential effects of DREADD actuators prior to any DREADD transduction, so that effects of DREADDs can be attributed to the chemogenetic system rather than the actuator drug. We investigated working memory performance after injections of three DREADD agonists, clozapine, olanzapine, and deschloroclozapine, in male rhesus monkeys tested in a spatial delayed response task. Performance at 0.1 mg/kg clozapine and 0.1 mg/kg deschloroclozapine did not differ from mean performance after vehicle in any of the four subjects. Administration of 0.2 mg/kg clozapine impaired working memory function in three of the four monkeys. Two monkeys were impaired after administration of 0.1 mg/kg olanzapine and two monkeys were impaired after the 0.3 mg/kg dose of deschloroclozapine. We speculate that the unique neuropharmacology of prefrontal cortex function makes the primate prefrontal cortex especially vulnerable to off-target effects of DREADD actuator drugs with affinity for endogenous monoaminergic receptor systems. These findings underscore the importance of within-subject controls for DREADD actuator drugs to confirm that effects following DREADD receptor transduction are not due to the actuator drug itself, as well as validating the behavioral pharmacology of DREADD actuator drugs in the specific tasks under study.Significance StatementChemogenetic technologies, such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), allow for precise and remote manipulation of neuronal circuits. In the present study, we tested monkeys in a spatial delayed response task after injections of three actuator drugs – clozapine, olanzapine, and deschloroclozapine. We found that monkeys showed significant working memory impairments after 0.2 mg/kg clozapine, 0.1 mg/kg olanzapine, and 0.3 mg/kg deschloroclozapine compared to vehicle performance. In monkeys that showed impairments, these deficits were particularly apparent at longer delay periods. It is imperative to validate the drugs and dosages in the particular behavioral test to ensure any behavior after DREADD transduction can be attributed to activation of the receptors and not administration of the actuator drug itself.
NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronicToxoplasma gondiiinfection
Authors: Ivanova Daria L. , Krempels Ryan , Denton Stephen L. , Fettel Kevin D. , Saltz Giandor M. , Rach David , Fatima Rida , Mundhenke Tiffany , Materi Joshua , Dunay Ildiko R. , Gigley Jason P. 
Published: December 2019

AbstractNK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronicToxoplasma gondii(T. gondii) infection resulting in parasite reactivation and death. How chronicT. gondiiinfection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronicT. gondiiinfected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and reduces parasite reactivation. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis. ChronicT. gondiiinfection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell behavior. This splenic CD49a-CD49b+NKp46+ NK cell population develops during the early chronic phase of infection and increases through the late chronic phase of infection. They are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. They are also absent from brain. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced. Blockade of NKp46 also rescued the chronically infected mice from death. Immunization with a single dose non-persistent 100% protectiveT. gondiivaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronicT. gondiiinfection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.
Flanker task-elicited Event Related Potential sources reflect human recombinant Erythropoietin differential effects on Parkinson’s patients
Authors: Vega Maria L Bringas , Liu Shengnan , Zhang Min , Ibañez Ivonne Pedroso , Chacon Lilia M. Morales , Garcia Lidice Galan , Bocourt Vanessa Perez , Jahanshahi Marjan , Valdes-Sosa Pedro A 
Published: December 2019

AbstractWe used EEG source analysis to identify which cortical areas were involved in the automatic and controlled processes of inhibitory control on a flanker task and compared the potential efficacy of recombinant-human erythropoietin (rHuEPO) on the performance of Parkinson’ s Disease patients.The samples were 18 medicated PD patients (nine of them received rHuEPO in addition to their usual anti-PD medication through random allocation and the other nine patients were on their regular anti-PD medication only) and 9 age and education-matched healthy controls (HCs) who completed the flanker task with simultaneous EEG recordings. N1 and N2 event-related potential (ERP) components were identified and a low-resolution tomography (LORETA) inverse solution was employed to localize the neural generators.Reaction times and errors were increased for the incongruent flankers for PD patients compared to controls. EEG source analysis identified an effect of rHuEPO on the lingual gyri for the early N1 component. N2-related sources in middle cingulate and precuneus were associated with the inhibition of automatic responses evoked by incongruent stimuli differentiated PD and HCs.From our results rHuEPO, seems to mediate an effect on N1 sources in lingual gyri but not on behavioural performance. N2-related sources in middle cingulate and precuneus evoked by incongruent stimuli differentiated PD and HCs.
3dSpAn: An interactive software for 3D segmentation and analysis of dendritic spines
Authors: Das Nirmal , Baczynska Ewa , Bijata Monika , Ruszczycki Blazej , Zeug Andre , Plewczynski Dariusz , Saha Punam Kumar , Ponimaskin Evgeni , Wlodarczyk Jakub , Basu Subhadip 
Published: December 2019

AbstractThree dimensional segmentation and analysis of dendritic spines involve two major challenges: 1) how to segment individual spines from the dendrites and 2) how to quantitatively assess the morphology of individual spines. We developed a software named 3dSpAn to address these two issues by implementing our previously published 3D multiscale opening algorithm in shared intensity space and using effective morphological features for individual dendritic spine plasticity analysis. 3dSpAn consists of four modules: Preprocessing and ROI selection, Intensity thresholding and seed selection, Multiscale segmentation and Quantitative morphological feature extraction. We show the results of segmentation and morphological analysis for different observation methods, includingin vitroandex vivoimaging with confocal microscopy, andin vivosamples, using high-resolution two-photon microscopy. The software is freely available, the source code, windows installer, the software manual and video tutorial can be obtained from:https://sites.google.com/view/3dSpAn/.
RePAIR: a power solution to animal experimentation
Authors: Bonapersona V. , Hoijtink H. ,   RELACS, Sarabdjitsingh R.A. , Joëls M. 
Published: December 2019

AbstractLow statistical power challenges the reliability of animal research; yet, increasing sample sizes to the required level raises important ethical and practical issues. We present an alternative solution, RePAIR, which capitalizes on the observation that control groups in general are expected to be similar to each other. As shown in a simulation study, including information of previous control experiments in the statistical analysis using RePAIR reduced the required sample size by 49% or increased power up to 100%. We validated the potential of RePAIR in a unique dataset based on 7 independent experiments across the world, studying cognitive effects of early life adversity in mice. RePAIR comes with an open-source web-based tool and can be widely used to largely improve quality of animal experimentation.One Sentence SummaryPrior studies’ information can reduce use of animals or increase statistical power, improving animal research reliability
Tracking selective rehearsal and active inhibition of memory traces in directed forgetting
Authors: Fellner Marie-Christin , Waldhauser Gerd T. , Axmacher Nikolai 
Published: December 2019

SummarySelectively remembering or forgetting newly encountered information is essential for goal-directed behavior. It is still an open question, however, whether intentional forgetting is an active process based on the inhibition of unwanted memory traces or whether it occurs passively through reduced recruitment of selective rehearsal [1,2]. Here we show that intentional control of memory encoding relies on both, enhanced active inhibition and decreased selective rehearsal, and that these two processes can be separated in time and space. We applied representational similarity analysis (RSA [3]) and timefrequency analysis to EEG data during an item-method directed forgetting experiment [4]. We identified neural signatures of both the intentional suppression and the voluntary upregulation of item-specific representations. Successful active forgetting was associated with a downregulation of item-specific representations in an early time window, 500ms after the instruction. This process was initiated by an increase in oscillatory alpha (8-13 Hz) power, a well-established signature of neural inhibition [5,6], in occipital brain areas. During a later time window, 1500ms after the cue, intentional forgetting was associated with reduced employment of active rehearsal processes, as reflected by an attenuated upregulation of item-specific representations as compared to intentionally encoded items. Our data show that active inhibition and selective rehearsal are two separate mechanisms whose consecutive employment allows for a voluntary control of memory formation.
Transcription factor motifs associated with anterior insula gene-expression underlying mood disorder phenotypes
Authors: Arasappan Dhivya , Eickhoff Simon B. , Nemeroff Charles B , Hofmann Hans A. , Jabbi Mbemba 
Published: December 2019

ABSTRACTBackgroundMood disorders represent a major cause of morbidity and mortality worldwide but the brain-related molecular pathophysiology in mood disorders remains largely undefined.MethodsBecause the anterior insula is reduced in volume in patients with mood disorders, RNA was extracted from postmortem mood disorder samples and compared with unaffected control samples for RNA-sequencing identification of differentially expressed genes (DEGs) ina) bipolar disorder (BD; n=37) versus (vs.) controls (n=33), andb) major depressive disorder (MDD n=30) vs controls, andc) low vs. high Axis-I comorbidity (a measure of cumulative psychiatric disease burden). Given the regulatory role of transcription factors (TFs) in gene expression via specific-DNA-binding domains (motifs), we used JASPAR TF binding database to identify TF-motifs.ResultsWe found that DEGs in BD vs. controls, MDD vs. controls, and high vs. low Axis-I comorbidity were associated with TF-motifs that are known to regulate expression of toll-like receptor genes, cellular homeostatic-control genes, and genes involved in embryonic, cellular/organ and brain development.DiscussionRobust imaging-guided transcriptomics(i.e., using meta-analytic imaging results to guide independent post-mortem dissection for RNA-sequencing) was applied by targeting the gray matter volume reduction in the anterior insula in mood disorders, to guide independent postmortem identification of TF motifs regulating DEG. TF motifs were identified for immune, cellular, embryonic and neurodevelopmental processes.ConclusionOur findings of TF-motifs that regulate the expression of immune, cellular homeostatic-control, and developmental genes provides novel information about the hierarchical relationship between gene regulatory networks, the TFs that control them, and proximate underlying neuroanatomical phenotypes in mood disorders.