bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative analysis of single cell genomics data by coupled nonnegative matrix factorizations
Authors: Duren Zhana , Chen Xi , Zamanighomi Mahdi , Zeng Wanwen , Satpathy Ansuman T , Chang Howard Y. , Wang Yong , Wong Wing Hung 
Published: May 2018

AbstractWhen different types of functional genomics data are generated on single cells from different samples of cells from the same heterogeneous population, the clustering of cells in the different samples should be coupled. We formulate this “coupled clustering” problem as an optimization problem, and propose the method of coupled nonnegative matrix factorizations (coupled NMF) for its solution. The method is illustrated by the integrative analysis of single cell RNA-seq and single cell ATAC-seq data.Significance StatementsBiological samples are often heterogeneous mixtures of different types of cells. Suppose we have two single cell data sets, each providing information on a different cellular feature and generated on a different sample from this mixture. Then, the clustering of cells in the two samples should be coupled as both clusterings are reflecting the underlying cell types in the same mixture. This “coupled clustering” problem is a new problem not covered by existing clustering methods. In this paper we develop an approach for its solution based the coupling of two nonnegative matrix factorizations. The method should be useful for integrative single cell genomics analysis tasks such as the joint analysis of single cell RNA-seq and single cell ATAC-seq data.
A practical generation interval-based approach to inferring the strength of epidemics from their speed
Authors: Park Sang Woo , Champredon David , Weitz Joshua S. , Dushoff Jonathan 
Published: May 2018

AbstractInfectious-disease outbreaks are often characterized by the reproductive number and 𝓡 exponential rate of growthr. 𝓡 provides information about out-break control and predicted final size. Directly estimating 𝓡 is difficult, whilercan often be estimated from incidence data. These quantities are linked by the generation interval – the time between when an individual is infected by an infector, and when that infector was infected. It is often infeasible to ob-tain the exact shape of a generation-interval distribution, and to understand how this shape affects estimates of 𝓡. We show that estimating generation interval mean and variance provides insight into the relationship between and 𝓡r. We use examples based on Ebola, rabies and measles to explore approximations based on gamma-distributed generation intervals, and find that use of these simple approximations are often sufficient to capture ther–𝓡relationship and provide robust estimates of𝓡.
DNA structure change induced by guanosine radicals – a theoretical and spectroscopic study
Authors: Kobierski J. , Lipiec E. 
Published: May 2018

AbstractProton radiation therapy is one of the newest and most promising methods used in modern oncology. Nonetheless, the dissemination of that method may result challenging. This is partially due to the fact that the mechanism of DNA damage induced by protons, which is one of the ways proton radiation interacts with tissues, has not been fully understood yet. It is well known that ionizing radiation especially ions such as protons may directly damage DNA but it also causes the formation of radicals, which may lead to even more serious damage of the DNA sugar-backbone than direct interaction with charged ion. In this article we focus on the influence of guanine radicals on the DNA structure, namely the conformation and stability of the DNA strand. We present the theoretical results of the optimization calculations of DNA structures with guanine radical-adenine pairs as well as calculated Raman spectra. By combining theoretical calculations with the experimental spectra we were able to explain molecular modifications of the DNA sugar-backbone affected by guanine radicals formed upon radiation exposure, which lead to spectral changes between spectra of control and irradiated DNA. Thus we established a pathway of the formation of DNA damage caused by protons.
The SMAC Mimetic AZD5582 is a Potent HIV Latency Reversing Agent
Authors: Sampey Gavin C. , Irlbeck David M. , Browne Edward P. , Kanke Matthew , McAllister Alecia B. , Ferris Robert G. , Brehm Jessica H. , Favre David , Routy Jean-Pierre , Jones Corbin D. , Archin Nancie M. , Margolis David M. , Dunham Richard M. 
Published: May 2018

AbstractThe leading strategy towards eradication of human immunodeficiency virus (HIV) infection is the depletion of viral reservoirs through reversal of viral latency, followed by clearance of persistently infected cells. To date, a latency reversing agent (LRA) that reactivates a majority of the quiescent provirus population, without significant off-target effects, has not been identified. We show here that molecules mimicking the active N-terminal tetrapeptide of the second mitochondrial-derived activator of caspases (SMACm) potently reverse HIV latencyin vitroandex vivowithout the pleotropic cellular effects seen with other LRA. We verified that SMACm facilitate latency reversal through activation of the non-canonical NFkB pathway as exemplified by rapid degradation of cellular inhibitor of apoptosis protein 1 (cIAP1), followed by a slower conversion of the inactive p100 form of NFκB2 into the active p52 transcription factor. A potent representative of this class, AZD5582, increases cell-associated HIV RNA expression in resting CD4+ T cells from ART-suppressed, HIV-infected donors while altering the expression of a restricted number of human genes. These findings represent the first demonstration that SMACm have single agent latency reversal activity in patient-derived cells and support evaluation of this class of molecules in preclinical animal models.
Amino acids stimulate the endosome-to-Golgi trafficking through Ragulator and small GTPase Arl5
Authors: Shi Meng , Chen Bing , Boh Boon Kim , Zhou Yan , Mahajan Divyanshu , Tie Hieng Chiong , Lu Lei 
Published: May 2018

AbstractThe endosome-to-Golgi or endocytic retrograde trafficking pathway is an important post-Golgi recycling route. We made a novel discovery that the retrograde trafficking of cargos is inhibited and stimulated by the absence and presence, respectively, of amino acids (AAs), especially glutamine. By testing components of the AA-stimulated mTORC1 signaling pathway, we demonstrated that SLC38A9, v-ATPase and Ragulator, but not Rag GTPases and mTORC1, are essential for the AA-stimulated trafficking. Arl5, an ARF-like family small GTPase, interacts with Ragulator in an AA-regulated manner and both Arl5 and its effector, the Golgi-associated retrograde protein complex (GARP), are required for the AA-stimulated trafficking. We have therefore identified a mechanistic connection between the nutrient signaling and the retrograde trafficking pathway, whereby SLC38A9 and v-ATPase sense AA-sufficiency and Ragulator functions as a guanine nucleotide exchange factor to activate Arl5, which, together with GARP, a tethering factor, probably facilitates the endosome-to-Golgi trafficking.
Adaptation and inhibition control pathological synchronization in a model of focal epileptic seizure
Authors: Buchin Anatoly , Kerr Cliff C. , Huberfeld Gilles , Miles Richard , Gutkin Boris 
Published: May 2018

AbstractPharmacoresistant epilepsy is a common neurological disorder in which increased neuronal intrinsic excitability and synaptic excitation lead to pathologically synchronous behavior in the brain. In the majority of experimental and theoretical epilepsy models, epilepsy is associated with reduced inhibition in the pathological neural circuits, yet effects of intrinsic excitability are usually not explicitly analyzed. Here we present a novel neural mass model that includes intrinsic excitability in the form of spike-frequency adaptation in the excitatory population. We validated our model using local field potential data recorded from human hippocampal/subicular slices. We found that synaptic conductances and slow adaptation in the excitatory population both play essential roles for generating seizures and pre-ictal oscillations. Using bifurcation analysis, we found that transitions towards seizure and back to the resting state take place via Andronov-Hopf bifurcations. These simulations therefore suggest that single neuron adaptation as well as synaptic inhibition are responsible for orchestrating seizure dynamics and transition towards the epileptic state.Significance statementEpileptic seizures are commonly thought to arise from a pathology of inhibition in the brain circuits. Theoretical models aiming to explain epileptic oscillations usually describe the neural activity solely in terms of inhibition and excitation. Single neuron adaptation properties are usually assumed to have only a limited contribution to seizure dynamics. To explore this issue, we developed a novel neural mass model with adaption in the excitatory population. By including adaptation and intrinsic excitability together with inhibition in this model, we were able to account for several experimentally observed properties of seizures, resting state dynamics, and pre-ictal oscillations, leading to improved understanding of epileptic seizures.
Excitable dynamics of NREM sleep: a unifying model for neocortex and hippocampus
Authors: Levenstein Daniel , Buzsáki György , Rinzel John 
Published: May 2018

ABSTRACTDuring non-rapid eye movement (NREM) sleep, the neocortex and hippocampus alternate between periods of neuronal spiking and inactivity. By directly comparing experimental observations with a mean field model of an adapting, recurrent neuronal population, we find that the neocortical alternations reflect a dynamical regime in which a stable active state is interrupted by transient inactive states (slow waves) while the hippocampal alternations reflect a stable inactive state interrupted by transient active states (sharp waves). We propose that during NREM sleep, hippocampal and neocortical populations are excitable: each in a stable state from which internal fluctuations or external perturbation can evoke the stereotyped population events that mediate NREM functions.
Increased cognitive complexity reveals abnormal brain network activity in individuals with corpus callosum dysgenesis
Authors: Hearne Luke J. , Dean Ryan J. , Robinson Gail A. , Richards Linda J. , Mattingley Jason B. , Cocchi Luca 
Published: May 2018

AbstractCognitive reasoning is thought to require functional interactions between whole-brain networks. Such networks rely on both cerebral hemispheres, with the corpus callosum providing cross-hemispheric communication. Here we used high-field functional magnetic resonance imaging (7T fMRI), a well validated cognitive task, and brain network analyses to investigate the functional networks underlying cognitive reasoning in individuals with corpus callosum dysgenesis (CCD), an anatomical abnormality that affects the corpus callosum. Participants with CCD were asked to solve cognitive reasoning problems while their brain activity was measured using fMRI. The complexity of these problems was parametrically varied by changing the complexity of relations that needed to be established between shapes within each problem matrix. Behaviorally, participants showed a typical reduction in task performance as problem complexity increased. Task-evoked neural activity was observed in brain regions known to constitute two key cognitive control systems: the fronto-parietal and cingulo-opercular networks. Under low complexity demands, network topology and the patterns of local neural activity in the CCD group closely resembled those observed in neurotypical controls. By contrast, when asked to solve more complex problems, participants with CCD showed a reduction in neural activity and connectivity within the fronto-parietal network. These complexity-induced, as opposed to resting-state, differences in functional network activity help resolve the apparent paradox between preserved network architecture found at rest in CCD individuals, and the heterogeneous deficits they display in response to cognitive task demands [preprint: https://doi.org/10.1101/312629].
Evaluation of Sb-1 bacteriophage activity in enhancing antibiotic efficacy against biofilm, degrading the exopolysaccharide matrix and targeting persister cells of Staphylococcus aureus
Authors: Tkhilaishvili Tamta , Lombardi Lisa , Klatt Ann-Brit , Trampuz Andrej , Di Luca Mariagrazia 
Published: May 2018

AbstractMost research on phage therapy focused on planktonic bacteria, whereas bacteriophage activity against biofilms is limited. We evaluated the capability of Staphylococcus aureus-specific bacteriophage Sb-1 to eradicate biofilm alone and in combination with different classes of antibiotics, to degrade the extracellular matrix and target persister cells. Biofilm of methicillin-resistant S. aureus (MRSA) ATCC 43300 was treated with Sb-1 alone or in (simultaneous or staggered) combination with either fosfomycin, rifampin, vancomycin, daptomycin or ciprofloxacin. The matrix was visualized by confocal fluorescent microscopy. Persister cells were treated with 104 and 107 PFU/mL Sb-1 for 3 hours in PBS, followed by CFU counting. Alternatively, bacteria were washed and incubated in fresh BHI medium and the bacterial growth assessed after further 24-hours. Pre-treatment with Sb-1 followed by the administration of sub-inhibitory concentrations of antibiotic exerted a considerable synergistic effect in eradicating MRSA biofilm. Sb-1 determined a dose-dependent reduction of matrix exopolysaccharide. 107 PFU/mL Sb-1 showed direct killing activity on persisters. However, even a lower titer had lytic activity when phage-treated persister cells were inoculated in fresh medium, reverting to a normal-growing phenotype. This study provides valuable data regarding the capability of Sb-1 to enhance antibiotic efficacy, exhibiting specific antibiofilm features. Its ability to degrade the MRSA polysaccharide matrix and target persister cells makes Sb-1 suitable for the therapy of biofilm-associated infections.
Baculovirus utilizes cholesterol transporter Niemann–Pick C1 for host cell entry
Authors: Li Zhihong , Wei Junhong , Fan Youpeng , Mei Xionge , He Qiang , Zhang Yonghua , Li Tian , Long Mengxian , Chen Jie , Liu TongBao , Bao Jialing , Xiang Zhonghuai , Pan Guoqing , Li Chunfeng , Zhou Zeyang 
Published: May 2018

ABSTRACTThe dual roles of baculovirus for the control of natural insect populations as an insecticide, and for foreign gene expression and delivery, have called for a comprehensive understanding of the molecular mechanisms governing viral infection. Here, we demonstrate that theBombyx moriNiemann-Pick C1 (BmNPC1) is essential for baculovirus infection in insect cells. Both pretreatment ofBombyx moriembryonic cells (BmE) with NPC1 antagonists (imipramine or U18666A) and down-regulation of NPC1 expression resulted in a significant reduction in baculovirus BmNPV (Bombyx morinuclear polyhedrosis virus) infectivity. Furthermore, we show that the major glycoprotein gp64 of BmNPV, responsible for both receptor binding and fusion, is able to interact predominantly with the BmNPC1 C domain, with an enhanced binding capacity at low pH conditions, indicating that NPC1 most likely plays a role during viral fusion in endosomal compartments. Our results, combined with previous studies identifying an essential role of hNPC1 in filovirus infection, suggest that the glycoprotein of several enveloped viruses possess a shared strategy of exploiting host NPC1 proteins during virus intracellular entry events.IMPORTANCEBmNPV is one of the most important members of theBaculoviridae; many viruses in this family have been frequently employed as viral vectors for foreign gene delivery or expression and as biopesticides, but their host receptors still remain unclear. Here, we describe that the intracellular cholesterol transporter BmNPC1 is indispensable for BmNPV infection in insect cells, and it interacts with the major viral glycoprotein gp64. Our study on the role of BmNPC1 in baculovirus infection has further expanded the list of the enveloped viruses that require host NPC1 proteins for entry, and will ultimately help us to uncover the molecular mechanism of the involvement of NPC1 proteins in the entry process of many enveloped viruses.
DDX41 recognizes RNA/DNA retroviral reverse transcripts and is critical forin vivocontrol of MLV infection
Authors: Stavrou Spyridon , Aguilera Alexya , Blouch Kristin , Ross Susan R. 
Published: May 2018

AbstractHost recognition of viral nucleic acids generated during infection leads to the activation of innate immune responses essential for early control of virus. Retrovirus reverse transcription creates numerous potential ligands for cytosolic host sensors that recognize foreign nucleic acids, including single-stranded RNA (ssRNA), RNA/DNA hybrids and double stranded DNA (dsDNA). We and others recently showed that the sensors cyclic GMP-AMP synthase (cGAS), dead-box helicase 41 (DDX41) and members of the Aim2-like receptor (ALR) family participate in the recognition of retroviral reverse transcripts. However, why multiple sensors might be required and their relative importance inin vivocontrol of retroviral infection is not known. Here we show that DDX41 primarily senses the DNA/RNA hybrid generated at the first step of reverse transcription, while cGAS recognizes dsDNA generated at the next step. We also show that both DDX41 and cGAS are needed for the anti-retroviral innate immune response to MLV and HIV in primary mouse macrophages and dendritic cells (DC). Using mice with macrophage- or -specific knockout of the DDX41 gene, we show that DDX41 sensing in DCs but not macrophages was critical for controllingin vivoMLV infection. This suggests that DCs are essentialin vivotargets for infection, as well as for initiating the antiviral response. Our work demonstrates that the innate immune response to retrovirus infection depends on multiple host nucleic acid sensors that recognize different reverse transcription intermediates.ImportanceViruses are detected by many different host sensors of nucleic acid, which in turn trigger innate immune responses, such as type I IFN production, required to control infection. We show here that at least two sensors are needed to initiate a highly effective innate immune response to retroviruses – DDX41, which preferentially senses the RNA/DNA hybrid generated at the first step of retrovirus replication and cGAS, which recognizes double-stranded DNA generated at the 2ndstep. Importantly, we demonstrate using mice lacking DDX41 or cGAS, that both sensors are needed for the full antiviral response needed to controlin vivoMLV infection. These findings underscore the need for multiple host factors to counteract retroviral infection.
Proteostasis perturbation destabilizes respiratory complex assembly-intermediates via aggregation of subunits
Authors: Rawat Shivali , Anusha Valpadashi , Jha Manoranjan , Sreedurgalakshmi K , Ghosh Anamika , Ganguly Debabani , Raychaudhuri Swasti 
Published: May 2018

SummaryProteostasis is maintained by optimum expression, folding, transport, and clearance of proteins. Deregulation of any of these processes triggers widespread protein aggregation and loss of function. Here, we perturbed proteostasis by blocking proteasome-mediated protein degradation and investigated proteome partitioning from soluble to insoluble fraction. Aggregation of Respiratory Chain Complex (RCC) subunits highlights the early destabilization event as revealed by proteome redistribution. Sequence analyses followed by microscopy suggest that low complexity regions at the N-terminus are capable to facilitate aggregation of RCC subunits. As a result, respiratory complex assembly process is impaired due to destabilization of sub-complexes marking the onset of mitochondrial dysfunction and ROS accumulation. Redistribution of Histone proteins and their modifications indicated reprogramming of transcription as adaptive response. Together, we demonstrate susceptibility of RCC subunits to aggregation under multiple proteotoxic stresses providing an explanation for the simultaneous deregulation of proteostasis and bioenergetics in age-related degenerative conditions.
Principal component analysis-based unsupervised feature extraction applied to single-cell gene expression analysis1
Authors: Taguchi Y-h. 
Published: May 2018

AbstractDue to missed sample labeling, unsupervised feature selection during single-cell (sc) RNA-seq can identify critical genes under the experimental conditions considered. In this paper, we applied principal component analysis (PCA)-based unsupervised feature extraction (FE) to identify biologically relevant genes from mouse and human embryonic brain development expression profiles retrieved by scRNA-seq. When evaluating the biological relevance of selected genes by various enrichment analyses, the PCA-based unsupervised FE outperformed conventional unsupervised approaches that select highly variable genes as well as bimodal genes in addition to the recently proposed dpFeature.
Single cell RNA-seq reveals profound transcriptional similarity between Barrett’s esophagus and esophageal glands
Authors: Owen Richard Peter , White Michael Joseph , Severson David Tyler , Braden Barbara , Bailey Adam , Goldin Robert , Wang Lai Mun , Maynard Nicholas David , Green Angie , Piazza Paolo , Buck David , Middleton Mark Ross , Ponting Chris Paul , Schuster-Böckler Benjamin , Lu Xin 
Published: May 2018

AbstractBarrett’s esophagus is a precursor of esophageal adenocarcinoma. In this common condition, squamous epithelium in the esophagus is replaced by columnar epithelium in response to acid reflux. Barrett’s esophagus is highly heterogeneous and its relationships to normal tissues are unclear. We investigated the cellular complexity of Barrett’s esophagus and the upper gastrointestinal tract using RNA-sequencing of 2895 single cells from multiple biopsies from four patients with Barrett’s esophagus and two patients without esophageal pathology. We found that uncharacterised cell populations in Barrett’s esophagus, marked byLEFTY1andOLFM4, exhibit a profound transcriptional overlap with a subset of esophageal cells, but not with gastric or duodenal cells. Additionally, SPINK4 and ITLN1 mark cells that precede morphologically identifiable goblet cells in colon and Barrett’s esophagus, potentially aiding the identification of metaplasia. Our findings reveal striking transcriptional relationships between normal tissue populations and cells in a premalignant condition, with implications for clinical practice.