bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dimensionality, information and learning in prefrontal cortex
Authors: Bartolo Ramon , Saunders Richard C. , Mitz Andrew , Averbeck Bruno B. 
Published: October 2019

AbstractLearning leads to changes in population patterns of neural activity. In this study we wanted to examine how these changes in patterns of activity affect the dimensionality of neural responses and information about choices. We addressed these questions by carrying out high channel count recordings in dorsal-lateral prefrontal cortex (dlPFC; 768 electrodes) while monkeys performed a two-armed bandit reinforcement learning task. The high channel count recordings allowed us to study population coding while monkeys learned choices between actions or objects. We found that the dimensionality of neural population activity was higher across blocks in which animals learned the values of novel pairs of objects, than across blocks in which they learned the values of actions. The increase in dimensionality with learning in object blocks was related to less shared information across blocks, and therefore patterns of neural activity that were less similar, when compared to learning in action blocks. Furthermore, these differences emerged with learning, and were not a simple function of the choice of a visual image or action. Therefore, learning the values of novel objects increases the dimensionality of neural representations in dlPFC.
Monkeys and Humans Implement Causal Inference to Simultaneously Localize Auditory and Visual Stimuli
Authors: Mohl Jeff T. , Pearson John M. , Groh Jennifer M. 
Published: October 2019

AbstractThe environment is sampled by multiple senses, which are woven together to produce a unified perceptual state. However, optimally unifying such signals requires assigning particular signals to the same or different underlying objects or events. Many prior studies (especially in animals) have assumed fusion of cross-modal information, whereas recent work in humans has begun to probe the appropriateness of this assumption. Here we present results from a novel behavioral task in which both monkeys and humans localized visual and auditory stimuli and reported their perceived sources through saccadic eye movements. When the locations of visual and auditory stimuli were widely separated, subjects made two saccades, while when the two stimuli were presented at the same location they made only a single saccade. Intermediate levels of separation produced mixed response patterns: a single saccade to an intermediate position on some trials or separate saccades to both locations on others. The distribution of responses was well described by a hierarchical causal inference model that accurately predicted both the explicit “same vs. different” source judgements as well as biases in localization of the source(s) under each of these conditions. The results from this task are broadly consistent with prior work in humans across a wide variety of analogous tasks, extending the study of multisensory causal inference to non-human primates and to a natural behavioral task with both a categorical assay of the number of perceived sources and a continuous report of the perceived position of the stimuli.Author SummaryWe experience the world through multiple sensory systems, which interact to shape perception. To do so, the brain must first determine which pieces of sensory input arise from the same source and which have nothing to do with one another. To probe how the brain accomplishes this causal inference, we developed a naturalistic paradigm that provides a behavioral report both of the number of perceived stimuli and their locations. We tested performance on this task in both humans and monkeys, and we found that both species perform causal inference in a similar manner. By providing this cross-species comparison at the behavioral level, our paradigm lays the groundwork for future experiments using neuronal recording techniques that may be impractical or impossible in human subjects.
Replacing murine insulin 1 with human insulin protects NOD mice from diabetes
Authors: Elso Colleen M. , Scott Nicholas A. , Mariana Lina , Masterman Emma I. , Sutherland Andrew P.R. , Thomas Helen E. , Mannering Stuart I. 
Published: October 2019

AbstractType 1, or autoimmune, diabetes is caused by the T-cell mediated destruction of the insulin-producing pancreatic beta cells. Non-obese diabetic (NOD) mice spontaneously develop autoimmune diabetes akin to human type 1 diabetes. For this reason, the NOD mouse has been the preeminent murine model for human type 1 diabetes research for several decades. However, humanized mouse models are highly sought after because they offer both the experimental tractability of a mouse modelandthe clinical relevance of human-based research. Autoimmune T-cell responses against insulin, and its precursor proinsulin, play central roles in the autoimmune responses against pancreatic beta cells in both humans and NOD mice. As a first step towards developing a murine model of the human autoimmune response against pancreatic beta cells we set out to replace the murine insulin 1 gene (Ins1) with the human insulin gene (INS) using CRISPR/Cas9. Here we describe a NOD mouse strain that expresses human insulin in place of murine insulin 1, referred to as HuPI. HuPI mice express human insulin, and C-peptide, in their serum and pancreata and have normal glucose tolerance. Compared with wild type NOD mice, the incidence of diabetes is much lower in HuPI mice. Only 15-20% of HuPI mice developed diabetes after 300 days, compared to more than 60% of unmodified NOD mice. Immune-cell infiltration into the pancreatic islets of HuPI mice was not detectable at 100 days but was clearly evident by 300 days. This work highlights the feasibility of using CRISPR/Cas9 to create mouse models of human diseases that express proteins pivotal to the human disease. Furthermore, it reveals that even subtle changes in proinsulin protect NOD mice from diabetes.
Bone morphogenetic protein 9 induces osteogenic differentiation of germ cell 1 spermatogonial cells
Authors: Zhang Jiye , Xu Bangfa , Chen Xinping , Zhao Liqiang , Zhang Pei , Wang Fei , Li Xiaojuan , Wang Meiling , Xu Weihua , Zhang Wenwen , Fu Shengmiao 
Published: October 2019

AbstractGerm cell 1 spermatogonial (GC-1spg) cells are multipotent progenitor cells. We previously confirmed that bone morphogenetic protein (BMP) 9 is among the most osteogenic BMPs. However, whether GC-1spg cells are driven toward osteogenic differentiation under proper stimuli is uncertain. Additionally, the molecular mechanism of BMP9 remains unclear. In the present study, we aimed to determine whether BMP9 can induce osteogenic differentiation of GC-1spg cells. Recombinant adenoviruses were generated by the AdEasy system to regulate the BMP9 expression in GC-1spg cells. We identified osteogenic markers by real-time PCR and staining techniquesin vitro. Ectopic ossification assays and histological analysis were also performed to verify thein vivoactivity of BMP9. Finally, potential signaling pathways of BMP9 were assessed by transcriptome sequencing and KEGG enrichment analysis. Using recombinant adenoviruses, we demonstrate that BMP9 upregulates osteogenic markers including Runx2, osteocalcin, osteopontin, and Sox9. BMP9 also activates alkaline phosphatase activity and calcium deposition in GC-1spg cells.In vivoresults show that BMP9 overexpression in GC-1spg cells promotes ectopic bone formation and chondrogenesis. In addition, RNA-sequencing and KEGG pathway analysis demonstrate that several signaling pathways are involved in BMP9-mediated osteogenesis. GC-1spg cells not only maintain spermatogenesis but also retain the ability to form bone tissue. Therefore, BMP9 activity in GC-1spg cells may help identify signaling pathways implicated in bone formation and could be of use in regenerative medicine.
Pooled CRISPRi screening of the cyanobacteriumSynechocystissp. PCC 6803 for enhanced growth, tolerance, and chemical production
Authors: Yao Lun , Shabestary Kiyan , Björk Sara M. , Asplund-Samuelsson Johannes , Joensson Haakan N. , Jahn Michael , Hudson Elton P. 
Published: October 2019

AbstractWe developed an inducible CRISPRi gene repression library in the cyanobacteriumSynechocystissp. PCC 6803, where all annotated genes are targeted for repression. We used the library to estimate gene fitness in multiple conditions. The library revealed several mutants with increased specific growth rates (up to 17%), and transcriptomics of these mutants revealed common upregulation of genes within photosynthetic electron flow. We challenged the library with L-lactate stress to find more tolerant mutants. Repression of the peroxiredoxin Bcp2 increased growth rate by 49% in the presence of 0.1 M L-lactate. Finally, the library was transformed into a L-lactate-secreting strain, and droplet microfluidics sorting of top producers enriched sgRNAs targeting nutrient assimilation, redox modulation, and cyclic-electron flow. Several clones showed increased productivity in batch cultivations (up to 75%). In some cases, tolerance or productivity was enhanced by partial repression of essential genes, which are difficult to access by transposon insertion.
Non-selective response inhibition in equiprobable Go/NoGo task: Bayesian analysis of fMRI data
Authors: Masharipov Ruslan , Korotkov Alexander , Medvedev Svyatoslav , Kireev Maxim 
Published: October 2019

AbstractResponse inhibition is typically considered a brain mechanism selectively triggered by particular “inhibitory” stimuli or events. Based on recent research, an alternative non-selective mechanism was proposed by several authors. Presumably, the inhibitory brain activity may be triggered not only by the presentation of “inhibitory” stimuli but also by any imperative stimuli, including Go stimuli, when the context is uncertain. Earlier support for this notion was mainly based on the absence of a significant difference between neural activity evoked by equiprobable Go and NoGo stimuli. Equiprobable Go/NoGo design with a simple response time task limits potential confounds between response inhibition and accompanying cognitive processes while not preventing prepotent automaticity. However, previous neuroimaging studies utilized classical null hypothesis significance testing, making it impossible to accept the null hypothesis. Therefore, the current research aimed to provide evidence for practical equivalence of neuronal activity in Go and NoGo trials using Bayesian analysis of functional magnetic resonance imaging (fMRI) data. Thirty-four healthy participants performed a cued Go/NoGo task with an equiprobable presentation of Go and NoGo stimuli. To independently localize brain areas associated with response inhibition in similar experimental conditions, we performed a meta-analysis of fMRI studies using equal probability Go/NoGo tasks. As a result, we observed overlap between response inhibition areas and areas demonstrating the practical equivalence of neuronal activity located in the right dorsolateral prefrontal cortex, parietal cortex, premotor cortex, and left inferior frontal gyrus. Thus, obtained results favour the existence of non-selective response inhibition, which can act in settings of contextual uncertainty induced by the equal probability of Go and NoGo stimuli.HighlightsNon-selective response inhibition was assessed by equiprobable Go/NoGo taskBayesian analysis of fMRI data was combined with a meta-analysis of fMRI studiesSeveral nodes of response inhibition system were equally involved in Go and NoGo trialsEvidence for non-selective response inhibition in uncertain context was found
Trem-2 promotes emergence of restorative macrophages and endothelial cells during recovery from hepatic tissue damage
Authors: Coelho Inês , Duarte Nádia , Barros André , Macedo Maria Paula , Penha-Gonçalves Carlos 
Published: October 2019

AbstractMacrophages are pivotal in mounting liver inflammatory and tissue repair reactions upon hepatic injury showing remarkable functional plasticity. Nevertheless, the molecular mechanisms determining macrophage transition from inflammatory to restorative phenotypes in the damaged liver remain unclear. Using mouse models of acute (APAP) or chronic (CCl4) drug-induced hepatotoxic injury we show that the immune receptor Trem-2 controls phenotypic shifts in liver macrophages and impacts endothelial cell differentiation during tissue recovery.Trem-2 gene ablation led to delayed re-population of Kupffer cells correlating with deterred resolution of hepatic damage following acute and chronic injury. We found that during tissue recovery macrophages in transition to the Kupffer cell compartment expressed high levels of Trem-2. Acquisition of the transition phenotype was associated with an unique transcriptomic profile denoting strong responsiveness to oxidative stress and downmodulation of the pro-inflammatory phenotype, which was not observed in absence of Trem-2.During tissue recovery lack of Trem-2 favored accumulation of a liver-damage associated endothelial cell population (LDECs) engaged in a transcriptional program compatible with endothelial de-differentiation. Accordingly, LDECs precursor potential is supported by the downregulation of surface endothelial cell markers and striking in vitro morphological changes towards typical endothelial cells.In conclusion, we found that the dynamics of liver macrophages in response to liver injury is critically controlled by Trem-2 and is interlinked with the de-differentiation of endothelial cells and heightened liver pathology. We propose that Trem-2 promotes the transition from the pro-inflammatory to the tissue repair phase by driving the acquisition of restorative properties of phagocytic macrophages.
Characterizing the dynamic and functional DNA methylation landscape in the developing human cortex
Authors: Perzel Mandell Kira A. , Price Amanda J. , Wilton Richard , Collado-Torres Leonardo , Tao Ran , Eagles Nicholas J. , Szalay Alexander S. , Hyde Thomas M. , Weinberger Daniel R. , Kleinman Joel E. , Jaffe Andrew E. 
Published: October 2019

AbstractDNA methylation (DNAm) is a key epigenetic regulator of gene expression across development. The developing prenatal brain is a highly dynamic tissue, but our understanding of key drivers of epigenetic variability across development is limited. We therefore assessed genomic methylation at over 39 million sites in the prenatal cortex using whole genome bisulfite sequencing and found loci and regions in which methylation levels are dynamic across development. We saw that DNAm at these loci was associated with nearby gene expression and enriched for enhancer chromatin states in prenatal brain tissue. Additionally, these loci were enriched for genes associated with psychiatric disorders and genes involved with neurogenesis. We also found autosomal differences in DNAm between the sexes during prenatal development, though these have less clear functional consequences. We lastly confirmed that the dynamic methylation at this critical period is specifically CpG methylation, with very low levels of CpH methylation. Our findings provide detailed insight into prenatal brain development as well as clues to the pathogenesis of psychiatric traits seen later in life.
Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference
Authors: Hop Paul J. , Luijk René , Daxinger Lucia , van Iterson Maarten , Dekkers Koen F. , Jansen Rick ,   BIOS Consortium, van Meurs Joyce B.J. , ’t Hoen Peter A.C. , Ikram M. Arfan , van Greevenbroek Marleen M.J. , Boomsma Dorret I. , Slagboom P. Eline , Veldink Jan H. , van Zwet Erik W. , Heijmans Bastiaan T. 
Published: October 2019

SUMMARYDNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identified 818 genes that influence DNA methylation patterns in blood using large-scale population genomics data. By employing genetic instruments as causal anchors, we identified directed associations between gene expression and distant DNA methylation levels, whilst ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. We found that DNA methylation patterns are commonly shaped by transcription factors that consistently increase or decrease DNA methylation levels. However, we also observed genes encoding proteins without DNA binding activity with widespread effects on DNA methylation (e.g.NFKBIE, CDCA7(L)andNLRC5) and we suggest plausible mechanisms underlying these findings. Many of the reported genes were unknown to influence DNA methylation, resulting in a comprehensive resource providing insights in the principles underlying epigenetic regulation.
Soluble cyanobacterial carotenoprotein as a robust antioxidant nanocarrier and delivery module
Authors: Maksimov Eugene G. , Zamaraev Alexey V. , Parshina Evgenia Yu. , Slonimskiy Yury B. , Slastnikova Tatiana A. , Abdrakhmanov Alibek A. , Babaev Pavel A. , Efimova Svetlana S. , Ostroumova Olga S. , Stepanov Alexey V. , Ryabova Anastasia V. , Friedrich Thomas , Sluchanko Nikolai N. 
Published: October 2019

AbstractTo counteract oxidative stress, antioxidants including carotenoids are highly promising, yet their exploitation is drastically limited by the poor bioavailability and fast photodestruction, whereas current delivery systems are far from being efficient. Here we demonstrate that the recently discovered nanometer-sized water-soluble carotenoprotein fromAnabaena(termed CTDH) transiently interacts with liposomes to efficiently extract carotenoids via carotenoid-mediated homodimerization, yielding violet-purple protein samples amenable to lyophilization and long-term storage. We characterize spectroscopic properties of the pigment-protein complexes and thermodynamics of liposome-protein carotenoid transfer and demonstrate the highly efficient delivery of echinenone form CTDH into liposomes. Most importantly, we show carotenoid delivery to membranes of mammalian cells, which provides protection from reactive oxygen species. The described carotenoprotein may be considered as part of modular systems for the targeted antioxidant delivery.Significance statementCarotenoids are excellent natural antioxidants but their delivery to vulnerable cells is challenging due to their hydrophobic nature and susceptibility to degradation. Thus, systems securing antioxidant stability and facilitating targeted delivery are of great interest for the design of medical agents. In this work, we have demonstrated that soluble cyanobacterial carotenoprotein can deliver echinenone into membranes of liposomes and mammalian cells with almost 70 % efficiency, which alleviates the induced oxidative stress. Our findings warrant the robustness of the protein-based carotenoid delivery for studies of carotenoid activities and effects on cell models.
Keratin 14-dependent disulfides regulate epidermal homeostasis and barrier function via 14-3-3σ and YAP1
Authors: Guo Yajuan , Leacock Krystynne A. , Redmond Catherine , Jaskula-Ranga Vinod , Coulombe Pierre A. 
Published: October 2019

SummaryThe type I intermediate filament (IF) keratin 14 (K14) provides vital structural support in basal keratinocytes of epidermis. Recent studies evidenced a role for K14-dependent disulfide bonding in the organization and dynamics of keratin IFs in skin keratinocytes. Here we report that knock-in mice harboring a cysteine-to-alanine substitution at codon 373 (C373A) inKrt14exhibit alterations in disulfide-bonded K14 species and a barrier defect secondary to enhanced proliferation, faster transit time and altered differentiation in the epidermis. A proteomics screen identified 14-3-3 as major K14 interacting proteins. Follow-up studies showed that YAP1, a transcriptional effector of Hippo signaling regulated by 14-3-3sigma in skin keratinocytes, shows aberrant subcellular partitioning and function in differentiatingKrt14C373A keratinocytes. Residue C373 in K14, which is conserved in several other type I IFs, is thus revealed as a novel regulator of keratin organization and YAP function in early differentiating keratinocytes, with an impact on cell mechanics, homeostasis and barrier function in the epidermis.
Targeting Viperin to the Mitochondrion Inhibits the Thiolase Activity of the Trifunctional Enzyme Complex
Authors: Dumbrepatil Arti B. , Zegalia Kelcie A. , Sajja Keerthi , Kennedy Robert T. , Marsh E. Neil. G. 
Published: October 2019

AbstractUnderstanding the mechanisms by which viruses evade host cell immune defenses is important for developing improved antiviral therapies. In an unusual twist, human cytomegalovirus (HCMV) co-opts the antiviral radical SAM enzyme, viperin (Virusinhibitoryprotein,endoplasmicreticulum-associated,interferon-inducible), to enhance viral infectivity. This process involves translocation of viperin to the mitochondrion where it binds the β-subunit (HADHB) of the mitochondrial trifunctional enzyme complex that catalyzes the thiolysis of β-ketoacyl-CoA esters as part of fatty acid β-oxidation. We have investigated how the interaction between these two enzymes alters their activities and their effect on cellular ATP levels. Studies with purified enzymes demonstrated that viperin inhibits the thiolase activity of HADHB, but, unexpectedly, HADHB activates viperin to synthesize the antiviral nucleotide 3’-deoxy-3’,4’-didehydro-CTP. Enzyme activities were also measured in lysates prepared from transfected HEK 293T cells transiently expressing these enzymes. Mirroring the studies on purified enzymes, localizing viperin to the mitochondria decreased thiolase activity whereas co-expression of HADHB significantly increased viperin activity. Furthermore, targeting viperin to mitochondria also increased the rate at which HADHB was retro-translocated out of mitochondria and degraded, providing an additional mechanism for reducing HADHB activity. Targeting viperin to the mitochondria decreased cellular ATP levels by over 50 %, consistent with the enzyme disrupting fatty acid catabolism. These results provide biochemical insight into the mechanism by which HCMV subjugates viperin; they also provide a biochemical rational for viperin’s recently discovered role in regulating thermogenesis in adipose tissues.
The Interaction of Viperin with Hepatitis C Virus Non-Structural Protein 5A Inhibits the Catalytic Activity of Viperin
Authors: Ghosh Soumi , Patel Ayesha M. , Grunkemeyer Timothy J. , Dumbrepatil Arti B. , Zegalia Kelcie , Kennedy Robert T. , Marsh E. Neil G. 
Published: October 2019

AbstractThe radical SAM enzyme viperin exerts a wide range of antiviral effects through both the synthesis of the antiviral nucleotide 3’-deoxy-3’, 4’-didehydro-CTP (ddhCTP) and through its interactions with various cellular and viral proteins. Here we investigate the interaction of viperin with hepatitis C virus non-structural protein 5A (NS5A) and the host sterol regulatory protein, vesicle-associated membrane protein A (VAP-33). NS5A and VAP-33 form part of the viral replication complex that is essential for copying the RNA genome of the virus. Using transfected enzymes in HEK293T cells, we show that viperin binds to both NS5A and VAP-33 independently and that this interaction is dependent on all three proteins being localized to the ER membrane. Co-expression of viperin with VAP-33 and NS5A was found to reduce NS5A levels, most likely by increasing the rate of proteasomal degradation. However, co-expression of viperin with VAP-33 and NS5A also reduces the specific activity of viperin by ~ 3-fold. This observation suggests that NS5A may have evolved to bind viperin as a strategy to reduce ddhCTP synthesis, thereby reducing possibility of the replication complex introducing this chain-terminating nucleotide during genome synthesis.