bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic neural integration is greater downstream of recurrent information flow in organotypic cortical cultures
Authors: Sherrill Samantha P. , Timme Nicholas M. , Beggs John M. , Newman Ehren L. 
Published: May 2020

AbstractThe directionality of network information flow dictates how networks process information. A central component of information processing in both biological and artificial neural networks is their ability to perform synergistic integration–a type of computation. We established previously that synergistic integration varies directly with the strength of feedforward information flow. However, the relationships between both recurrent and feedback information flow and synergistic integration remain unknown. To address this, we analyzed the spiking activity of hundreds of neurons in organotypic cultures of mouse cortex. We asked how empirically observed synergistic integration varied with local functional network structure that was categorized into motifs with varying recurrent and feedback information flow. We found that synergistic integration was elevated in motifs with greater recurrent information flow beyond that expected from the local feedforward information flow. Feedback information flow was interrelated with feedforward information flow and was associated with decreased synergistic integration. Our results indicate that synergistic integration is distinctly influenced by the directionality of local information flow.Author SummaryNetworks compute information. That is, they modify inputs to generate distinct outputs. These computations are an important component of network information processing. Knowing how the routing of information in a network influences computation is therefore crucial. Here we asked how a key form of computation—synergistic integration—is related to the direction of local information flow in networks of spiking cortical neurons. Specifically, we asked how information flow between input neurons (i.e., recurrent information flow) and information flow from output neurons to input neurons (i.e., feedback information flow) was related to the amount of synergistic integration performed by output neurons. We found that greater synergistic integration occurred where there was more recurrent information flow. And, lesser synergistic integration occurred where there was more feedback information flow relative to feedforward information flow. These results show that computation, in the form of synergistic integration, is distinctly influenced by the directionality of local information flow. Such work is valuable for predicting where and how network computation occurs and for designing networks with desired computational abilities.
Combined pigment and metatranscriptomic analysis reveals synchronized diel patterns of phenotypic light response across domains in the open ocean
Authors: Becker Kevin W. , Harke Matthew J. , Mende Daniel R. , Muratore Daniel , Weitz Joshua S. , DeLong Edward F. , Dyhrman Sonya T. , Van Mooy Benjamin A.S. 
Published: May 2020

AbstractSunlight is the most important environmental control on diel fluctuations in phytoplankton activity, and understanding diel microbial processes is essential to the study of oceanic biogeochemical cycles. Yet, little is known about thein situfrequency of phytoplankton metabolic activities and their coordination across different populations. We investigated the diel orchestration of phytoplankton activity involved in photosynthesis, photoacclimation, and photoprotection by analyzing the pigment and quinone distribution in combination with metatranscriptomes in the surface waters of the North Pacific Subtropical Gyre (NPSG). We found diel cycles in pigment abundances resulting from the balance of their synthesis and consumption. The night represents a metabolic recovery phase to refill cellular pigment stores, while the photosystems are remodeled towards photoprotection during the day. Transcript levels of genes involved in photosynthesis and pigment metabolism had highly synchronized diel expression patterns among all taxa, suggesting that there are similar regulatory mechanisms for light and energy metabolism across domains, and that other environmental factors drive niche differentiation. Observed decoupling of diel oscillations in transcripts and related pigments in the NPSG indicates that pigment abundance is modulated by environmental factors extending beyond gene expression/regulation, showing that metatranscriptomes may provide only limited insights on real-time photophysiological metabolism.
Mu-opioids suppress GABAergic synaptic transmission onto orbitofrontal cortex pyramidal neurons with subregional selectivity
Authors: Lau Benjamin K. , Ambrose Brittany P. , Thomas Catherine S. , Qiao Min , Borgland Stephanie L. 
Published: May 2020

AbstractThe orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion specific manner. However, it is unknown how mu-opioid signalling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist, DAMGO produced a concentration-dependant inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long-lasting and not reversed upon washout of DAMGO, or by application of the mu-opioid receptor antagonist, CTAP, suggesting an inhibitory long-term depression (iLTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/PKA signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Taken together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.Significance StatementConsidering that both the OFC and the opioid system regulate reward, motivation, and food intake; understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Secondly, mu-opioids recruit PV+ inputs to suppress inhibitory synaptic transmission in the mOFC. Thirdly, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.
A deletion inGDF7is associated with a heritable forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts in cats
Authors: Yu Yoshihiko , Creighton Erica K. , Buckley Reuben M. , Lyons Leslie A. ,   99 Lives Consortium
Published: May 2020

AbstractAn inherited neurologic syndrome in a family of mixed-breed Oriental cats has been characterized as forebrain commissural malformation concurrent with ventriculomegaly and interhemispheric cysts. However, the genetic basis for this autosomal recessive syndrome in cats is unknown. Forty-three cats were genotyped on the Illumina Infinium Feline 63K iSelect DNA Array and used for analyses. Genome-wide association studies, including a sib-transmission disequilibrium test, a case-control association analysis, and homozygosity mapping, identified a critical region on cat chromosome A3. Short-read whole genome sequencing was completed for a cat trio segregating with the syndrome. A homozygous 7 bp deletion ingrowth differentiation factor 7(GDF7) (c.221_227delGCCGCGC [p.Arg74Profs]) was identified in affected cats by comparison to the 99 Lives Cat variant dataset, validated using Sanger sequencing, and genotyped by fragment analyses. This variant was not identified in 192 unaffected cats in the 99 Lives dataset. The variant segregated concordantly in an extended pedigree. Obligate carrier cats were heterozygous. In mice,GDF7mRNA is expressed within the roof plate when commissural axons initiate ventrally-directed growth. This finding emphasizes the importance ofGDF7in the neurodevelopmental process in the mammalian brain. A genetic test can be developed for use by cat breeders to eradicate this variant.
Multifractal signatures of perceptual processing on anatomical sleeves of the human body
Authors: Mangalam Madhur , Carver Nicole S. , Kelty-Stephen Damian G. 
Published: May 2020

AbstractResearch into haptic perception typically concentrates on mechanoreceptors and their supporting neuronal processes. This focus risks ignoring crucial aspects of active perception. For instance, bodily movements influence the information available to mechanoreceptors, entailing that movement facilitates haptic perception. Effortful manual wielding of an object prompts feedback loops at multiple spatiotemporal scales, rippling outwards from the wielding hand to the feet, maintaining an upright posture, and interweaving to produce a nonlinear web of fluctuations throughout the body. Here, we investigated whether and how this bodywide nonlinearity engenders a flow of multifractal fluctuations that could support perception of object properties via dynamic touch. Blindfolded participants manually wielded weighted dowels and reported judgments of heaviness and length. Mechanical fluctuations on the anatomical sleeves, from hand to the upper body, as well as to the postural center of pressure, showed evidence of multifractality arising from nonlinear temporal correlations across scales. The modeling of impulse-response functions obtained from vector autoregressive (VAR) analysis revealed that distinct sets of pairwise exchanges of multifractal fluctuations entailed accuracy in heaviness and length judgments. These results suggest that the accuracy of perception via dynamic touch hinges on specific flowing patterns of multifractal fluctuations that people wear on their anatomical sleeves.
Re-ranking of Computational Protein–Peptide Docking Solutions With Amino Acid Profiles of Rigid-Body Docking Results
Authors: Ohue Masahito 
Published: May 2020

AbstractProtein–peptide interactions, in which one partner is a globular protein and the other is a flexible linear peptide, are important for understanding cellular processes and regulatory pathways, and are therefore targets for drug discovery. In this study, I combined rigid-body protein-protein docking software (MEGADOCK) and global flexible protein–peptide docking software (CABS-dock) to establish a re-ranking method with amino acid contact profiles using rigid-body sampling decoys. I demonstrate that the correct complex structure cannot be predicted (< 10 Å peptide RMSD) using the current version of CABS-dock alone. However, my newly proposed re-ranking method based on the amino acid contact profile using rigid-body search results (designated the decoy profile) demonstrated the possibility of improvement of predictions. Adoption of my proposed method along with continuous efforts for effective computational modeling of protein–peptide interactions can provide useful information to understand complex biological processes in molecular detail and modulate protein-protein interactions in disease treatment.
Comparison of SARS-CoV-2 Indirect and Direct Detection Methods
Authors: Pearson Joel D. , Trcka Daniel , Hyduk Sharon J. , Aynaud Marie-Ming , Hernández J. Javier , Peidis Filippos , Lu Suying , Chan Kin , Woodgett Jim , Mazzulli Tony , Attisano Liliana , Pelletier Laurence , Cybulsky Myron I. , Wrana Jeffrey L. , Bremner Rod 
Published: May 2020

ABSTRACTThe COVID-19 pandemic caused by the SARS-CoV-2 virus has placed extensive strain on RNA isolation and RT-qPCR reagents. Rapid development of new test kits has helped to alleviate these shortages. However, comparisons of these new detection systems are largely lacking. Here, we compare indirect methods that require RNA extraction, and direct RT-qPCR on patient samples. For RNA isolation we compared four different companies (Qiagen, Invitrogen, BGI and Norgen Biotek). For detection we compared two recently developed Taqman-based modules (BGI and Norgen Biotek), a SYBR green-based approach (NEB Luna Universal One-Step Kit) with published and newly-developed primers, and clinical results (Seegene STARMag RNA extraction system and Allplex 2019-nCoV RT-qPCR assay). Most RNA isolation procedures performed similarly, and while all RT-qPCR modules effectively detected purified viral RNA, the BGI system proved most sensitive, generating comparable results to clinical diagnostic data, and identifying samples ranging from 65 copies – 2.1×105copies of viral Orf1ab/μl. However, the BGI detection system is ∼4x more expensive than other options tested here. With direct RT-qPCR we found that simply adding RNase inhibitor greatly improved sensitivity, without need for any other treatments (e.g. lysis buffers or boiling). The best direct methods were ∼10 fold less sensitive than indirect methods, but reduce sample handling, as well as assay time and cost. These studies will help guide the selection of COVID-19 detection systems and provide a framework for the comparison of additional systems.
Safety and Pharmacokinetics of a Novel Non-Steroidal Mineralocorticoid Receptor Antagonist, KBP-5074, in Hemodialysis and Non-Hemodialysis Patients with Severe Chronic Kidney Disease
Authors: Connaire Jeffrey , Bush Mark , Ruckle Jon , Yang Fred , Liu Jinrong , Tan Xiaojuan , Wang Ping , Zhou Tian , Zhang Min , Benn Vincent 
Published: May 2020

AbstractObjectiveKBP-5074 is a novel non-steroidal mineralocorticoid receptor antagonist for the potential treatment of hypertension. The purpose of this study was to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single dose of 0.5 mg KBP-5074 in subjects with end stage renal disease on and not on hemodialysis.ResultsSingle doses of 0.5 mg KBP-5074 were generally well tolerated in both hemodialysis (N=6) and non-hemodialysis (N=5) subjects with severe renal impairment. Of the 11 subjects in the study, there was a single report of hyperkalemia in a hemodialysis subject on Day 14 that was not considered drug-related and was resolved in 2 days. Mean plasma KBP-5074 concentrations peaked at 6 and 4 hours in non-dialysis and dialysis subjects, respectively, and slowly declined through 312 hours postdose. Overall, the KBP-5074 exposures were significantly lower and had a shorter half-life in hemodialysis subjects compared with the non-hemodialysis subjects. However, hemodialysis had minimal direct impact on drug concentrations with negligible drug levels in the dialysate samples. Plasma aldosterone and serum potassium concentrations were generally comparable between non-hemodialysis and hemodialysis subjects, most likely to due to high variability in the hemodialysis subjects.ConclusionThe overall plasma exposure of KBP-5074 was statistically significantly lower in hemodialysis subjects compared to subjects with renal impairment not on hemodialysis.
A Systems Approach Identifies Key Regulators of HPV-Positive Cervical Cancer
Authors: Sinkala Musalula , Zulu Mildred , Nkhoma Panji , Kafita Doris , Zulu Ephraim , Tembo Rabecca , Ngwira Zifa , Daka Victor , Munsaka Sody 
Published: May 2020

AbstractCervical cancer has remained the most prevalent and lethal malignancy among women worldwide and accounted for over 250,000 deaths in 2019. Nearly ninety-five per cent of cervical cancer cases are associated with persistent infection with high-risk Human Papillomavirus (HPV), and seventy per cent of these are associated with viral integration in the host genome. HPV-infection imparts specific changes in the regulatory network of infected cancer cells that are of diagnostic, prognostic and importance. Here, we conducted a systems-level analysis of the regulatory network changes, and the associated regulatory proteins thereof, in HPV-positive cervical cancer. We applied functional pathway analysis to show that HPV-positive cancers are characterised by perturbations of numerous cellular processes, predominantly in those linked to the cell cycle, mitosis, cytokine and immune cell signalling. Using computational predictions, we revealed that HPV-positive cervical cancers are regulated by transcription factors including, SOX2, E2F, NANOG, OCT4, and MYC, which control various processes such as the renewal of cancer stem cells, and the proliferation and differentiation of tumour cells. Through the analysis of upstream regulatory kinases, we identified the mitogen-activated protein kinases; among others, MAPK1, MAPK3 and MAPK8, and the cyclin-dependent kinases; among others, CDK1, CDK2 and CDK4, as the key kinases that control the biological processes in HPV-positive cervical cancers. Taken together, we uncover a landscape of the key regulatory pathways and proteins in HPV-positive cervical cancers, all of which may provide attractive drug targets for future therapeutics.
An adaptive pre-DNA-damage-response protects genome integrity
Authors: Ragu Sandrine , Matos-Rodrigues Gabriel , Droin Nathalie , Barascu Aurélia , Caillat Sylvain , Zarkovic Gabriella , Siberchicot Capucine , Dardillac Elodie , Gelot Camille , Radicella Juan Pablo , Ishchenko Alexander A. , Ravanat Jean-Luc , Solary Eric , Lopez Bernard S. 
Published: May 2020

AbstractThe DNA damage response (DDR) interrupts cell cycle progression to restore genome integrity. However, unchallenged proliferating cells are continually exposed to endogenous stress, raising the question of a stress-threshold for DDR activation. Here, we identified a stress threshold below which primary human fibroblasts, activate a cell-autonomous response that not activates full DDR and not arrests cell cycle progression,. We characterized this “pre-DDR” response showing that it triggers the production of reactive oxygen species (ROS) by the NADPH oxidases DUOX1 and DUOX2, under the control of NF-κB and PARP1. Then, replication stress-induced ROS (RIR) activates the FOXO1 detoxifying pathway, preventing the nuclear accumulation of the pre-mutagenic 8-oxoGuanine lesion, upon endogenous as well as exogenous pro-oxidant stress. Increasing the replication stress severity above the threshold triggers the canonical DDR, leading to cell cycle progression arrest, but also to RIR suppression. These data reveal that cells adapt their response to stress severity, unveiling a tightly regulated ”pre-DDR” adaptive response that protects genome integrity without arresting cell cycle progression.
PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis
Authors: Sladky Valentina , Knapp Katja , Szabo Tamas G. , Bongiovanni Laura , van den Bos Hilda , Spierings Diana C.J. , Westendorp Bart , Stojakovic Tatjana , Scharnagl Hubert , Timelthaler Gerald , Tsuchia Kaoru , Pinter Matthias , Foijer Floris , de Bruin Alain , Reiberger Thomas , Rohr-Udilova Nataliya , Villunger Andreas 
Published: May 2020

AbstractPolyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. The PIDDosome multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome-deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome-deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome-deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts of survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and tumor cell density serves as a novel prognostic marker for recurrence free survival in HCC patients.
Network Analysis and Transcriptome Profiling Identify Autophagic and Mitochondrial Dysfunctions in SARS-CoV-2 Infection
Authors: Singh Komudi , Chen Yun-Ching , Judy Jennifer T , Seifuddin Fayaz , Tunc Ilker , Pirooznia Mehdi 
Published: May 2020

AbstractAnalyzing host transcriptional changes in response to SARS-CoV-2 infection will help delineate biological processes underlying viral pathogenesis. Comparison of expression profiles of lung cell lines A549 (infected with either SARS-CoV-2 (with ACE2 expression)) or Influenza A virus (IAV)) and Calu3 (infected with SARS-CoV-2 or MERS-CoV) revealed upregulation of the antiviral interferon signaling in all three viral infections. However, perturbations in inflammatory, mitochondrial, and autophagy processes were specifically observed in SARS-CoV-2 infected cells. Validation of findings from cell line data revealed perturbations in autophagy and mitochondrial processes in the infected human nasopharyngeal samples. Specifically, downregulation of mTOR expression, mitochondrial ribosomal, mitochondrial complex I, and lysosome acidification genes were concurrently observed in both infected cell lines and human datasets. Furthermore, SARS-CoV-2 infection impedes autophagic flux by upregulating GSK3B in lung cell lines, or by downregulating autophagy genes, SNAP29 and lysosome acidification genes in human samples, contributing to increased viral replication. Therefore, drugs targeting lysosome acidification or autophagic flux could be tested as intervention strategies. Additionally, downregulation of MTFP1 (in cell lines) or SOCS6 (in human samples) results in hyperfused mitochondria and impede proper interferon response. Coexpression networks analysis identifies correlated clusters of genes annotated to inflammation and mitochondrial processes that are misregulated in SARS-CoV-2 infected cells. Finally, comparison of age stratified human gene expression data revealed impaired upregulation of chemokines, interferon stimulated and tripartite motif genes that are critical for antiviral signaling. Together, this analysis has revealed specific aspects of autophagic and mitochondrial function that are uniquely perturbed in SARS-CoV-2 infection.