bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia
Authors: Aasebø Elise , Berven Frode S. , Bartaula-Brevik Sushma , Stokowy Tomasz , Hovland Randi , Vaudel Marc , Døskeland Stein Ove , McCormack Emmet , Batth Tanveer S. , Olsen Jesper V. , Bruserud Øystein , Selheim Frode , Hernandez-Valladares Maria 
Published: October 2019

AbstractAcute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.
Predicting cellular position in the Drosophila embryo from Single-Cell Transcriptomics data
Authors: Tanevski Jovan , Nguyen Thin , Truong Buu , Karaiskos Nikos , Ahsen Mehmet Eren , Zhang Xinyu , Shu Chang , Xu Ke , Liang Xiaoyu , Hu Ying , Pham Hoang V.V. , Xiaomei Li , Le Thuc D. , Tarca Adi L. , Bhatti Gaurav , Romero Roberto , Karathanasis Nestoras , Loher Phillipe , Chen Yang , Ouyang Zhengqing , Mao Disheng , Zhang Yuping , Zand Maryam , Ruan Jianhua , Hafemeister Christoph , Qiu Peng , Tran Duc , Nguyen Tin , Gabor Attila , Yu Thomas , Glaab Enrico , Krause Roland , Banda Peter ,   DREAM SCTC Consortium, Stolovitzky Gustavo , Rajewsky Nikolaus , Saez-Rodriguez Julio , Meyer Pablo 
Published: October 2019

AbstractSingle-cell RNA-seq technologies are rapidly evolving but while very informative, in standard scRNAseq experiments the spatial organization of the cells in the tissue of origin is lost. Conversely, spatial RNA-seq technologies designed to keep the localization of the cells have limited throughput and gene coverage. Mapping scRNAseq to genes with spatial information increases coverage while providing spatial location. However, methods to perform such mapping have not yet been benchmarked. To bridge the gap, we organized the DREAM Single-Cell Transcriptomics challenge focused on the spatial reconstruction of cells from the Drosophila embryo from scRNAseq data, leveraging as gold standard genes with in situ hybridization data from the Berkeley Drosophila Transcription Network Project reference atlas. The 34 participating teams used diverse algorithms for gene selection and location prediction, while being able to correctly localize rare subpopulations of cells. Selection of predictor genes was essential for this task and such genes showed a relatively high expression entropy, high spatial clustering and the presence of prominent developmental genes such as gap and pair-ruled genes and tissue defining markers.
A 5’ UTR G-quadruplex controls localisation and translation of a potassium leak channel mRNA
Authors: Maltby Connor J. , Schofield James P. R. , Houghton Steven D. , O’Kelly Ita , Vargas-Caballero Mariana , Deinhardt Katrin , Coldwell Mark J. 
Published: October 2019

ABSTRACTRNA G-quadruplexes (G4s) are non-canonical secondary structures that have been proposed to function as regulators of post-transcriptional mRNA localisation and translation. G4s within 3’ UTRs of some neuronal mRNAs are known to control their distal localisation and local translation, contributing to the distinct local proteomes that facilitate the synaptic remodelling attributed to normal cellular function. In this study, we characterise the G4 formation of a (GGN)13repeat found within the 5’ UTR of KCNK9 mRNA, encoding the potassium 2-pore domain leak channel Task3. Using circular dichroism, we show that this (GGN)13repeat forms a parallel G4 that exhibits the stereotypical potassium specificity of a G4, remaining thermostable under physiological ionic conditions. The G4 is inhibitory to translation of Task3, which can be overcome through the activity of the G4-specific helicase DHX36, consequently increasing K+leak currents and decreasing resting membrane potentials in HEK293 cells. Additionally, we observe that this G4 is fundamental to ensuring the delivery of Task3 mRNA to distal primary cortical neurites. It has previously been shown that abnormal Task3 expression correlates with neuronal dysfunction, we therefore posit that this G4 is required for regulated local expression of Task3 leak channels that maintain K+leak currents within neurons.
A multilayer network model of neuron-astrocyte populations in vitro reveals mGluR5inhibition is protective following traumatic injury
Authors: Schroeder Margaret E. , Bassett Danielle S. , Meaney David F. 
Published: October 2019

ABSTRACTAstrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. Despite recent advances in understanding neuron-astrocyte signaling, little is known about astrocytic modulation of neuronal activity at the population level, particularly in disease or following injury. We used high-speed calcium imaging of mixed cortical culturesin vitroto determine how population activity changes after disruption of glutamatergic signaling and mechanical injury. We constructed a multilayer network model of neuron-astrocyte connectivity, which captured distinct topology and response behavior from single cell type networks. mGluR5inhibition decreased neuronal activity, but did not on its own disrupt functional connectivity or network topology. In contrast, injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in networks pre-treated with mGluR5inhibition. Comparison of spatial and functional connectivity revealed that functional connectivity is largely independent of spatial proximity at the microscale, but mechanical injury increased the spatial-functional correlation. Finally, we found that astrocyte segments of the same cell often belong to separate functional communities based on neuronal connectivity, suggesting that astrocyte segments function as independent entities. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations.AUTHOR SUMMARYAstrocytes communicate bidirectionally with neurons, enhancing synaptic plasticity and promoting the synchronization of neuronal microcircuits. We constructed a multilayer network model of neuron-astrocyte connectivity based on calcium activity in mixed cortical cultures, and used this model to evaluate the effect of glutamatergic inhibition and mechanical injury on network topology. We found that injury increased the strength, clustering, and efficiency of neuronal but not astrocytic networks, an effect that was not observed in injured networks pre-treated with a glutamate receptor antagonist. Our findings demonstrate the utility of multilayer network models for characterizing the multiscale connectivity of two distinct but functionally dependent cell populations.
North American Birds Require Mitigation and Adaptation to Reduce Vulnerability to Climate Change
Authors: Bateman Brooke L. , Wilsey Chad , Taylor Lotem , Wu Joanna , LeBaron Geoffrey S. , Langham Gary 
Published: October 2019

AbstractBiodiversity is being lost at an alarming rate across the globe, with extinction rates up to a hundred times greater than historical norms. Climate change will only exacerbate this crisis. The rapid pace of projected climate change is set to push birds to seek new locations, drastically reshuffling the avian communities of North America. In an emerging climate crisis, effective conservation requires both adaptation and mitigation to improve the resilience of species. However, the pledged reductions in greenhouse gas emissions outlined in the Paris Agreement framework would still lead to a 3.2°C or greater increase in global mean temperature by the end of this century. In this study, we use big data analytics to develop species distribution models and assess the vulnerability of 604 North American birds to multiple climate change scenarios. We assess how climate change mitigation can affect the number of species vulnerable to climate change, as well as the species and locations at risk if emissions continue unchecked. Our results indicate that over two-thirds of North American birds are moderately or highly vulnerable to climate change under a 3.0°C global warming scenario. Of these climate-vulnerable species, 76% would have reduced vulnerability and 38% of those would be considered non-vulnerable if warming were stabilized at 1.5°C. Thus, the current pledge in greenhouse gas reductions set by the Paris Agreement is inadequate to reduce vulnerability to birds. Additionally, if climate change proceeds on its current trajectory, arctic birds, waterbirds and boreal and western forest birds will be highly vulnerable to climate change; groups that are currently not considered of high conservation concern. Thus, there is an urgent need for both aggressive policies to mitigate emissions and focused conservation adaptation actions to protect birds and the places they need in a changing climate.
Priming enables a NEK7-independent route of NLRP3 activation
Authors: Schmacke Niklas A. , Gaidt Moritz M. , Szymanska Inga , O’Duill Fionan , Stafford Che A. , Chauhan Dhruv , Fröhlich Adrian L. , Nagl Dennis , Pinci Francesca , Schmid-Burgk Jonathan L. , Hornung Veit 
Published: October 2019

ABSTRACTThe NLRP3 inflammasome plays a central role in antimicrobial defense, as well as in sterile inflammatory conditions. NLRP3 activity is governed by two independent signals. The first signal primes NLRP3, allowing it to respond to its activation signal. In the murine system, the mitotic spindle kinase NEK7 has been identified as a crucial factor in relaying the activation signal to NLRP3. Here we show that the requirement for NEK7 can be bypassed by TAK1-dependent post-translational priming. Under pro-inflammatory conditions that activate TAK1, NEK7 was dispensable for NLRP3 inflammasome formation in human and murine cells. Intriguingly, dissecting the NEK7 requirement in iPSC-derived primary human macrophages revealed that this NEK7-independent mechanism constitutes the predominant NLRP3 priming pathway in these cells. In summary, our results suggest that NEK7 functions as an NLRP3 priming – rather than activation – factor that can work in synergy or redundancy with other priming pathways to accelerate inflammasome activation.
Disinhibition-assisted LTP in the prefrontal-amygdala pathway via suppression of somatostatin-expressing interneurons
Authors: Ito Wataru , Fusco Brendon , Morozov Alexei 
Published: October 2019

AbstractNatural brain adaptations often involve changes in synaptic strength. The artificial manipulations can help investigate the role of synaptic strength in a specific brain circuit not only in various physiological phenomena like correlated neuronal firing and oscillations but also in behaviors. High and low-frequency stimulation at presynaptic sites has been used widely to induce long-term potentiation (LTP) and depression (LTD), respectively. This approach is effective in many brain areas, but not in the basolateral amygdala (BLA), because the robust local GABAergic tone inside the BLA restricts synaptic plasticity. Here, we identified the subclass of GABAergic neurons that gate LTP in the BLA afferents from the dorsomedial prefrontal cortex (dmPFC). Chemogenetic suppression of somatostatin-positive interneurons (Sst-INs) enabled the ex vivo LTP by high-frequency stimulation of the afferent, but the suppression of parvalbumin-positive interneurons (PV-INs) did not. Moreover, optogenetic suppression of Sst-INs with Arch also enabled LTP of the dmPFC-BLA synapses both ex vivo and in vivo. These findings reveal that Sst-INs but not PV-INs gate LTP in the dmPFC-BLA pathway and provide a method for artificial synaptic facilitation in BLA.
Potent CRISPR-Cas9 inhibitors from Staphylococcus genomes
Authors: Watters Kyle E. , Shivram Haridha , Fellmann Christof , Lew Rachel J. , McMahon Blake , Doudna Jennifer A. 
Published: October 2019

AbstractAnti-CRISPRs (Acrs) are small proteins that inhibit the RNA-guided DNA targeting activity of CRISPR-Cas enzymes. Encoded by bacteriophage and phage-derived bacterial genes, Acrs prevent CRISPR-mediated inhibition of phage infection and can also block CRISPR-Cas-mediated genome editing in eukaryotic cells. To identify Acrs capable of inhibiting Staphylococcus aureus Cas9 (SauCas9), an alternative to the most commonly used genome editing protein Streptococcus pyogenes Cas9 (SpyCas9), we used both self-targeting CRISPR screening and guilt-by-association genomic search strategies. Here we describe three new potent inhibitors of SauCas9 that we name AcrIIA13, AcrIIA14 and AcrIIA15. These inhibitors share a conserved N-terminal sequence that is dispensable for anti-CRISPR function, and have divergent C-termini that are required in each case for selective inhibition of SauCas9-catalyzed DNA cleavage. In human cells, we observe robust and specific inhibition of SauCas9-induced genome editing by AcrIIA13 and moderate inhibition by AcrIIA14 and AcrIIA15. We also find that the conserved N-terminal domain of AcrIIA13-15 binds to an inverted repeat sequence in the promoter of these Acr genes, consistent with its predicted helix-turn-helix DNA binding structure. These data demonstrate an effective strategy for Acr discovery and establish AcrIIA13-15 as unique bifunctional inhibitors of SauCas9.
Genome duplication inLeishmania majorrelies on DNA replication outside S phase
Authors: Damasceno Jeziel D. , Marques Catarina A. , Beraldi Dario , Crouch Kathryn , Lapsley Craig , Obonaga Ricardo , Tosi Luiz R. O. , McCulloch Richard 
Published: October 2019

AbstractOnce every cell cycle, DNA replication takes place to allow cells to duplicate their genome and segregate the two resulting copies into offspring cells. In eukaryotes, the number of DNA replication initiation loci, termed origins, is proportional to chromosome size. However, previous studies have suggested that inLeishmania, a group of single-celled eukaryotic parasites, DNA replication starts from just a single origin per chromosome, which is predicted to be insufficient to secure complete genome duplication within S phase. Here, we show that the paucity of origins activated in early S phase is balanced by DNA synthesis activity outside S phase. Simultaneous recruitment of acetylated histone H3 (AcH3), modified base J and the kinetochore factor KKT1 is exclusively found at the origins used in early S phase, while subtelomeric DNA replication can only be linked to AcH3 and displays persistent activity through the cell cycle, including in G2/M and G1 phases. We also show that subtelomeric DNA replication, unlike replication from the previously mapped origins, is sensitive to hydroxyurea and dependent on subunits of the 9-1-1 complex. Our work indicates thatLeishmaniagenome transmission relies on an unconventional DNA replication programme, which may have implications for genome stability in this important parasite.
CIC is a Critical Regulator of Neuronal Differentiation
Authors: Hwang Inah , Pan Heng , Yao Jun , Elemento Olivier , Zheng Hongwu , Paik Jihye 
Published: October 2019

ABSTRACTCapicua (CIC), a member of the high mobility group (HMG)-box superfamily of transcriptional repressors, is frequently mutated in human oligodendrogliomas. But its function in brain development and tumorigenesis remains poorly understood. Here, we report that brain-specific deletion of Cic compromises developmental transition of neuroblast to immature neurons in mouse hippocampus and compromises normal neuronal differentiation. Combined gene expression and ChIP-seq analyses identified VGF as an important CIC-repressed transcriptional surrogates involved in neuronal lineage regulation. Aberrant VGF expression promotes neural progenitor cell proliferation by suppressing their differentiation. Mechanistically, we demonstrated that CIC represses VGF expression by tethering SIN3-HDAC to form a transcriptional corepressor complex. Mass spectrometry analysis of CIC-interacting proteins further identified BRG1 containing mSWI/SNF complex of which function is necessary for transcriptional repression by CIC. Together, this study uncovers a novel regulatory pathway of CIC-dependent neuronal differentiation and provides molecular insights into the etiology of CIC-dependent brain tumors.
Age-linked heterogeneity among oligodendrocyte precursor cells in the cerebral cortex of mice and human
Authors: Bribián A , Medina-Rodríguez EM , Josa-Prado F , García-Álvarez I , Machín-Díaz I , Murcia-Belmonte V , Vega-Zelaya L , Pastor J , Garrido L , de Castro F 
Published: October 2019

ABSTRACTOligodendrocyte precursor cells (OPCs) are responsible for spontaneous remyelination after a demyelinating lesion. They are present in large parts of the mouse and human central nervous system, both during development and in adulthood, yet how their physiological behaviour is modified throughout life remains largely unknown. Moreover, the activity of adult human OPCs is still not fully understood. Significantly, most of the molecules involved in OPC-mediated remyelination are also involved in their development, a phenomenon that may be clinically relevant. In this article, we have systematically analyzed the intrinsic properties of OPCs isolated from the cerebral cortex of neonatal, postnatal and adult mice, as well as those recovered from neurosurgical adult human cerebral cortex tissue. We also analyze the response of these cells to two molecules that have known effects on OPC biology during development and that are overexpressed in individuals with Multiple Sclerosis (MS): FGF2 and anosmin-1. By analyzing intact OPCs for the first time with H-1 HR-MAS NMR spectroscopy, we show that these cells behave distinctly and that they have different metabolic patterns in function of their stage of maturity. Moreover, their response to FGF-2 and anosmin-1 differs in relation to their developmental stage and in function of the species. Our data reveal that the behaviour of adult human and mouse OPCs differs in a very dynamic way that should be considered when testing drugs and for the proper design of effective pharmacological and/or cell therapies for MS.
A dual role for shape skeletons in human vision: perceptual organization and object recognition
Authors: Ayzenberg Vladislav , Kamps Frederik S. , Dilks Daniel D. , Lourenco Stella F. 
Published: October 2019

AbstractShape perception is crucial for object recognition. However, it remains unknown exactly how shape information is represented, and, consequently, used by the visual system. Here, we hypothesized that the visual system represents “shape skeletons” to both (1) perceptually organize contours and component parts into a shape percept, and (2) compare shapes to recognize objects. Using functional magnetic resonance imaging (fMRI) and representational similarity analysis (RSA), we found that a model of skeletal similarity explained significant unique variance in the response profiles of V3 and LO, regions known to be involved in perceptual organization and object recognition, respectively. Moreover, the skeletal model remained predictive in these regions even when controlling for other models of visual similarity that approximate low- to high-level visual features (i.e., Gabor-jet, GIST, HMAX, and AlexNet), and across different surface forms, a manipulation that altered object contours while preserving the underlying skeleton. Together, these findings shed light on the functional roles of shape skeletons in human vision, as well as the computational properties of V3 and LO.
Bacterial cell cycle control by citrate synthase independent of enzymatic activity
Authors: Bergé Matthieu , Pezzatti Julian , González-Ruiz Víctor , Degeorges Laurence , Rudaz Serge , Viollier Patrick H. 
Published: October 2019

ABSTRACTCoordination of cell cycle progression with central metabolism is fundamental to all cell types and likely underlies differentiation into dispersal cells in bacteria. How central metabolism is monitored to regulate cell cycle functions is poorly understood. A forward genetic selection for cell cycle regulators in the polarized alpha-proteobacteriumCaulobacter crescentusunearthed the uncharacterized CitA citrate synthase, a TCA (tricarboxylic acid) cycle enzyme, as unprecedented checkpoint regulator of the G1→S transition. We show that loss of the CitA protein provokes a (p)ppGpp alarmone-dependent G1-phase arrest without apparent metabolic or energy insufficiency. While S-phase entry is still conferred when CitA is rendered catalytically inactive, the paralogous CitB citrate synthase has no overt role other than sustaining TCA cycle activity when CitA is absent. With eukaryotic citrate synthase paralogs known to fulfill regulatory functions, our work extends the moonlighting paradigm to citrate synthase coordinating central (TCA) metabolism with development and perhaps antibiotic tolerance in bacteria.
Persons post-stroke restore step length symmetry by walking asymmetrically
Authors: Padmanabhan Purnima , Sreekanth Rao Keerthana , Gulhar Shivam , Cherry-Allen Kendra M. , Leech Kristan A. , Roemmich Ryan T. 
Published: October 2019

ABSTRACTBackgroundRestoration of step length symmetry is a common rehabilitation goal after stroke. Persons post-stroke often retain the capacity to walk with symmetric step lengths (“symmetric steps”); however, the resulting walking pattern remains effortful. Two key questions with direct implications for rehabilitation have emerged: 1) how do persons post-stroke generate symmetric steps, and 2) why do symmetric steps remain so effortful?ObjectiveTo understand how persons post-stroke generate symmetric steps and how the resulting gait pattern relates to the metabolic cost of transport.MethodsTen persons post-stroke walked on an instrumented treadmill under two conditions: preferred walking and symmetric stepping (using visual feedback). We recorded kinematic, kinetic, and metabolic data during both conditions.ResultsPersons post-stroke restored step length symmetry using energetically expensive, asymmetric patterns. Impaired paretic propulsion and abnormal vertical movement of the center of mass were evident during both preferred walking and symmetric stepping. These deficits contributed to diminished positive work performed by the paretic limb on the center of mass in both conditions. Decreased positive paretic work correlated with increased metabolic cost of transport, decreased self-selected walking speed, and increased asymmetry in limb kinematics.ConclusionsIt is important to consider the mechanics used to restore symmetric steps when designing interventions to improve walking after stroke. Facilitating symmetric steps via increased paretic propulsion or enabling paretic limb advancement without excessive vertical movement may enable persons post-stroke to walk with a less effortful, more symmetric gait pattern.