bluuebunny/crossref_metadata_2025 huggingface dataset:
Embedding containerized workflows inside data science notebooks enhances reproducibility
Authors: Hu Jiaming , Hung Ling-Hong , Yeung Ka Yee
Published: May 2018

Data science notebooks, such as Jupyter, combine text documentation with dynamically editable and executable code and have become popular for sharing computational methods. We present nbdocker, an extension that integrates Docker software containers into Jupyter notebooks. nbdocker transforms notebooks into autonomous, self-contained, executable and reproducible modules that can document and disseminate complicated data science workflows containing code written in different languages and executables requiring different software environments.
Characterization of Animal Movement Patterns using Information Theory: a Primer
Authors: Owoeye Kehinde , Musolesi Mirco , Hailes Stephen
Published: May 2018

Understanding the movement patterns of animals across different spatio-temporal scales, conditions, habitats and contexts is becoming increasingly important for addressing a series of questions in animal behaviour studies, such as mapping migration routes, evaluating resource use, modelling epidemic spreading in a population, developing strategies for animal conservation as well as understanding several emerging patterns related to feeding, growth and reproduction. In recent times, information theory has been successfully applied in several fields of science, in particular for understanding the dynamics of complex systems and characterizing adaptive social systems, such as dynamics of entities as individuals and as part of groups.

In this paper, we describe a series of non-parametric information-theoretic measures that can be used to derive new insights about animal behaviour with a specific focus on movement patterns, namely Shannon entropy, Mutual information, Kullback-Leibler divergence and Kolmogorov complexity. In particular, we believe that the metrics presented in this paper can be used to formulate new hypotheses that can be verified potentially through a set of different observations and be complementary to existing techniques. We show how these measures can be used to characterize the movement patterns of several animals across different habitats and scales. Specifically, we show the effectiveness in using Shannon entropy to characterize the movement of sheep with Batten disease, mutual information to measure association in pigeons, Kullback-Leibler divergence to study the flights of Turkey vulture, and Kolmogorov complexity to find similarities in the movement patterns of animals across different scales and habitats. Finally, we discuss the limitations of these methods and we outline the challenges in this research area.
DeepPVP: phenotype-based prioritization of causative variants using deep learning
Authors: Boudellioua Imane , Kulmanov Maxat , Schofield Paul N , Gkoutos Georgios V , Hoehndorf Robert
Published: May 2018

Background

Prioritization of variants in personal genomic data is a major challenge. Recently, computational methods that rely on comparing phenotype similarity have shown to be useful to identify causative variants. In these methods, pathogenicity prediction is combined with a semantic similarity measure to prioritize not only variants that are likely to be dysfunctional but those that are likely involved in the pathogenesis of a patient’s phenotype.

Results

We have developed DeepPVP, a variant prioritization method that combined automated inference with deep neural networks to identify the likely causative variants in whole exome or whole genome sequence data. We demonstrate that DeepPVP performs significantly better than existing methods, including phenotype-based methods that use similar features. DeepPVP is freely available at https://github.com/bio-ontology-research-group/phenomenet-vp.

Conclusions

DeepPVP further improves on existing variant prioritization methods both in terms of speed as well as accuracy.
Network controllability: viruses are driver agents in dynamic molecular systems
Authors: Ravindran Vandana , Nacher Jose Carlos , Akutsu Tatsuya , Ishitsuka Masayuki , Osadcenco Adrian , Sunitha V , Bagler Ganesh , Schwartz Jean-Marc , Robertson David L
Published: May 2018

In recent years control theory has been applied to biological systems with the aim of identifying the minimum set of molecular interactions that can drive the network to a required state. However in an intra-cellular network it is unclear what ‘control’ means. To address this limitation we use viral infection, specifically HIV-1 and HCV, as a paradigm to model control of an infected cell. Using a large human signalling network comprised of over 6000 human proteins and more than 34000 directed interactions, we compared two dynamic states: normal/uninfected and infected. Our network controllability analysis demonstrates how a virus efficiently brings the dynamic host system into its control by mostly targeting existing critical control nodes, requiring fewer nodes than in the uninfected network. The driver nodes used by the virus are distributed throughout the pathways in specific locations enabling effective control of the cell via the high ‘control centrality’ of the viral and targeted host nodes. Furthermore, this viral infection of the human system permits discrimination between available network-control models, and demonstrates the minimum-dominating set (MDS) method better accounts for how biological information and signals are transferred than the maximum matching (MM) method as it identified most of the HIV-1 proteins as critical driver nodes and goes beyond identifying receptors as the only critical driver nodes. This is because MDS, unlike MM, accounts for the inherent non-linearity of signalling pathways. Our results demonstrate control-theory gives a more complete and dynamic understanding of the viral hijack mechanism when compared with previous analyses limited to static single-state networks.
Positively interacting strains that circulate in a network structured population induce cycling epidemics of Mycoplasma Pneumoniae
Authors: Zhang Xu-Sheng , Zhao Hongxin , Vynnycky Emilia , Chalker Vicki
Published: May 2018

In many countriesMycoplasma pneumoniae(MP) epidemics last approximately one to two years and occur every three to seven years. Poor understanding of the drivers of recurrent MP epidemics limits the predictability of and dynamic responses to the outbreak. Taking into account network structured contacts among people and co-circulating strains of MP, we propose a multi-strain SIRS network model of epidemics of MP where different strains interact during re-infection and within secondary infection. Simulations show that although strain interactions and network-mediated spatial correlations are two separate mechanisms for MP epidemics cycling, each requires very restricted model parameter values such as strong strain interactions and strong network contacts, respectively. When both mechanisms work collectively, MP recurrent epidemics become feasible within the plausible ranges of model parameters. This indicates that positively interacting strains that co-circulate within network contacts induce periodicity and dominant strain shift in observed MP incidence.
Intrinsic and Extrinsic Modulation of C. elegans Locomotion
Authors: Denham Jack E. , Ranner Thomas , Cohen Netta
Published: May 2018

Animal locomotion describes the coordinated self-propelled movement of a body, subject to the combined effects of internal muscle forcing and external forces. Here we use an integrated neuromechanical computational model to study the combined effects of neural modulation, mechanical modulation and modulation of the external environments on undulatory forward locomotion in the nematodeC. elegans. In particular we use a proprioceptively driven neural control circuit to consider the effects of proprioception, body elasticity and environmental drag on the waveform, frequency and speed of undulations. We find qualitative differences in the frequency-wavelength relationship obtained under extrinsic modulation of the environmental fluid or body elasticity versus intrinsic modulation due to changes in the sensorimotor control. We consider possible targets of modulation by the worm and implications of our results for our understanding of the neural control of locomotion in this system.
Membrane insertion of α-xenorhabdolysin in near-atomic detail
Authors: Schubert Evelyn , Vetter Ingrid R. , Prumbaum Daniel , Penczek Pawel A. , Raunser Stefan
Published: May 2018

α-Xenorhabdolysins (Xax) are α-pore-forming toxins (α-PFT) from pathogenic bacteria that form 1-1.3 MDa large pore complexes to perforate the host cell membrane. PFTs are used by a variety of bacterial pathogens as an offensive or defensive mechanism to attack host cells. Due to the lack of structural information, the molecular mechanism of action of Xax toxins is poorly understood. Here, we report the cryo-EM structure of the XaxAB pore complex from Xenorhabdus nematophila at an average resolution of 4.0 Å and the crystal structures of the soluble monomers of XaxA and XaxB at 2.5 Å and 3.4 Å, respectively. The structures reveal that XaxA and XaxB are built similarly and appear as heterodimers in the 12-15 subunits containing pore. The structure of the XaxAB pore represents therefore the first structure of a bi-component α-PFT. Major conformational changes in XaxB, including the swinging out of an amphipathic helix are responsible for membrane insertion. XaxA acts as an activator and stabilizer for XaxB that forms the actual transmembrane pore. Based on our results, we propose a novel structural model for the mechanism of action of Xax toxins.
A Real Time PCR Assay for Quantification of Parasite Burden in Murine Models of Leishmaniasis
Authors: Antonia Alejandro L. , Wang Liuyang , Ko Dennis C.
Published: May 2018

Eukaryotic parasites in the genusLeishmaniaplace approximately 350 million people per year at risk of disease. In addition to their global health significance,Leishmaniaspp. have served as an important model for delineating basic concepts in immunology such as T-helper cell polarization. There have been many qPCR based assays reported for measuring parasite burden in humans and animals. However, these are largely optimized for use in clinical diagnosis and not specifically for animal models. This has led several of these assays to have suboptimal characteristics for use in animal models. For example, multi-copy number genes have been frequently used to increase sensitivity, but are subject to greater plasticity within the genome and thus may confound effects of experimental manipulations in animal models. In this study, we develop a sybr-green based quantitative touchdown PCR assay for a highly conserved and single copy, putative RNA binding protein, DRBD3. With primers nearly perfectly conserved across allLeishmaniaspp., this assay rivals the sensitivity of previously reported qPCR based methods of parasite quantitation and successfully detectedL. majorfrom mouse infection. Use of this protocol in the future will lead to improved accuracy in animal based models and help to tease apart differences in biology of host-parasite interactions.
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

When 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 Statements

Biological 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.
Neuromechanical phase lag predicts material and neural control properties inCaenorhabditis elegans
Authors: Denham Jack E. , Ranner Thomas , Cohen Netta
Published: May 2018

In all animals, the successful orchestration of motor programs hinges on appropriate coupling between components of the system, from neural circuit dynamics, through muscles and body properties to the physical environment. We study this coupling in undulatory locomotion, with a view to better understanding the relative roles of central and reflex-driven control. We ask how the coupling between neural control and body mechanics is affected by sensory inputs during undulatory locomotion inC. elegans.To address this question, we use a biomechanical simulation framework, within which we separately model feed forward and feedback controlled undulations. We characterize neuromechanical phase lag and locomotion speed using body stiffness as a control parameter. We show that sensory entrainment can suppress neuromechanical phase lag, that would otherwise emerge under centrally generated feed forward control.
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

Infectious-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

Proton 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

The 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

The 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

Pharmacoresistant 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 statement

Epileptic 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

During 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

Cognitive 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

Most 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

The 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.

IMPORTANCE

BmNPV 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

Host 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.

Importance

Viruses 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

Proteostasis 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

Due 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

Barrett’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.
Hunter-gatherers maintain assortativity in cooperation despite high-levels of residential change and mixing
Authors: Smith Kristopher M. , Larroucau Tomás , Mabulla Ibrahim A. , Apicella Coren L.
Published: May 2018

Widespread cooperation is a defining feature of human societies from hunter-gatherer bands to nation states. But explaining its evolution remains a challenge. While positive assortment – of cooperators with cooperators – is recognized as a basic requirement for the evolution of cooperation, the mechanisms governing assortment are debated. Moreover, the social structure of modern hunter-gatherers, characterized by high mobility, residential mixing and low genetic relatedness, undermine assortment and add to the puzzle of how cooperation evolved. Here, we analyze four years of data (2010, 2013, 2014, 2016) tracking residence and levels of cooperation elicited from a public goods game (PG), in Hadza hunter-gatherers of Tanzania. Data were collected from 56 camps, comprising 383 unique individuals, 137 of whom we have data for two or more years. Despite significant residential mixing, we observe a robust pattern of assortment necessary for cooperation to evolve: In every year, Hadza camps exhibit high between-camp and low within-camp variation in cooperation. We further consider the role of homophily in generating this assortment. We find little evidence that cooperative behavior within individuals is stable over time or that similarity in cooperation between dyads predicts their future cohabitation. Both sets of findings are inconsistent with homophilic models that assume stable cooperative and selfish types. Consistent with social norms, culture and reciprocity theories, the data suggest that the strongest predictor of an individual’s level of cooperation in any given year is the mean cooperation of their campmates in that year. These findings underscore the adaptive nature of human cooperation – particularly its responsiveness to social contexts – as a feature important in generating the assortment necessary for cooperation to evolve.
Comparative analysis of droplet-based ultra-high-throughput single-cell RNA-seq systems
Authors: Zhang Xiannian , Li Tianqi , Liu Feng , Chen Yaqi , Yao Jiacheng , Li Zeyao , Huang Yanyi , Wang Jianbin
Published: May 2018

Since its establishment in 2009, single-cell RNA-seq has been a major driver behind progress in biomedical research. In developmental biology and stem cell studies, the ability to profile single cells confers particular benefits. While most studies still focus on individual tissues or organs, the recent development of ultra-high-throughput single-cell RNA-seq has demonstrated potential power in characterizing more complex systems or even the entire body. However, although multiple ultra-high-throughput single-cell RNA-seq systems have attracted attention, no systematic comparison of these systems has been performed. Here, we focus on three widely used droplet-based ultra-high-throughput single-cell RNA-seq systems, inDrop, Drop-seq, and 10X Genomics Chromium. While each system is capable of profiling single-cell transcriptomes, their detailed comparison revealed the distinguishing features and suitable applications for each system.
ngsReports: An R Package for managing FastQC reports and other NGS related log files
Authors: Ward Christopher M. , To Hein , Pederson Stephen M
Published: May 2018

Motivation

High throughput next generation sequencing (NGS) has become exceedingly cheap facilitating studies to be undertaken containing large sample numbers. Quality control (QC) is an essential stage during analytic pipelines and can be found in the outputs of popular bioinformatics tools such as FastQC and Picard. Although these tools provide considerable power when carrying out QC, large sample numbers can make identification of systemic bias a challenge.

Results

We present ngsReports, an R package designed for the management and visualization of NGS reports from within an R environment. The available methods allow direct import into R of FastQC output as well as that from aligners such as HISAT2, STAR and Bowtie2. Visualization can be carried out across many samples using heatmaps rendered using ggplot2 and plotly. Moreover, these can be displayed in an interactive shiny app or a HTML report. We also provide methods to assess observed GC content in an organism dependent manner for both transcriptomic and genomic datasets. Importantly, hierarchical clustering can be carried out on heatmaps with large sample sizes to quickly identify outliers and batch effects.

Availability and Implementation

ngsReports is available at https://github.com/UofABioinformaticsHub/ngsReports.
Misoprostol regulates Bnip3 repression and alternative splicing to control cellular calcium homeostasis during hypoxic stress
Authors: Field Jared T. , Martens Matthew D. , Mughal Wajihah , Hai Yan , Chapman Donald , Hatch Grant M. , Ivanco Tammy L. , Diehl-Jones William , Gordon Joseph W.
Published: May 2018

The cellular response to hypoxia involves the activation of a conserved pathway for gene expression regulated by the transcription factor complex called hypoxia-inducible factor (HIF). This pathway has been implicated in both the adaptive response to hypoxia and in several hypoxic-ischemic related pathologies. Perinatal hypoxic injury, often associated with prematurity, leads to multi-organ dysfunction resulting in significant morbidity and mortality. Using a rodent model of neonatal hypoxia and several representative cell lines, we observed HIF1α activation and down-stream induction of the cell death gene Bnip3 in brain, large intestine, and heart which was mitigated by administration of the prostaglandin E1 analog misoprostol. Mechanistically, we determined that misoprostol inhibits full-length Bnip3 (Bnip3-FL) expression through PKA-mediated NF-κB (P65) nuclear retention, and the induction of pro-survival splice variants. We observed that the dominant small pro-survival variant of Bnip3 in mouse cells lacks the third exon (Bnip3ΔExon3), whereas human cells produce a pro-survival BNIP3 variant lacking exon 2 (BNIP3ΔExon2). In addition, these small Bnip3 splice variants prevent mitochondrial dysfunction, permeability transition, and necrosis triggered by Bnip3-FL by blocking calcium transfer from the sarco/endoplasmic reticulum to the mitochondria. Furthermore, misoprostol and Bnip3ΔExon3 promote nuclear calcium accumulation, resulting in HDAC5 nuclear export, NFAT activation, and adaptive changes in cell morphology and gene expression. Collectively, our data suggests that misoprostol can mitigate the potential damaging effects of hypoxia on multiple cell types by activating adaptive cell survival pathways through Bnip3 repression and alternative splicing.
A single pair of leucokinin neurons are modulated by feeding state and regulate sleep-metabolism interactions
Authors: Yurgel Maria E. , Kakad Priyanka , Zandawala Meet , Nassel Dick , Godenschwege Tanja A. , Keene Alex C.
Published: May 2018

Dysregulation of sleep and feeding has widespread health consequences. Despite extensive epidemiological evidence for interactions between sleep and metabolic function, little is known about the neural or molecular basis underlying the integration of these processes. Drosophila melanogaster potently suppress sleep in response to starvation, and powerful genetic tools allow for mechanistic investigation of sleep-metabolism interactions. We have previously identified neurons expressing the neuropeptide leucokinin (Lk) as being required for starvation-mediated changes in sleep. Here, we demonstrate an essential role for Lk neuropeptide in metabolic regulation of sleep. Further, we find that the activity of Lk neurons is modulated by feeding state and circulating nutrients, with reduced activity in response to glucose and increased activity under starvation conditions. Both genetic silencing and laser-mediated microablation localize Lk-mediated sleep regulation to a single pair of Lk neurons within the lateral horn (LHLK) that project near primary sleep and metabolic centers of the brain. A targeted screen identified a critical role for AMP-activated protein kinase (AMPK) in starvation-modulated changes in sleep. Disruption of AMPK function in Lk neurons suppresses sleep and increases LHLK activity in fed flies, phenocopying the starvation state. Taken together, these findings localize feeding state-dependent regulation of sleep to a single pair of neurons within the fruit fly brain and provide a system for investigating the cellular basis of sleep-metabolism interactions.
Environmental factors shape methionine metabolism in p16/MTAP deleted cells
Authors: Sanderson Sydney M. , Mikhael Peter , Dai Ziwei , Locasale Jason W.
Published: May 2018

The co-deletion of a common tumor suppressor locus and neighboring metabolic gene is an attractive possible synthetic dependency of tumor suppression on metabolism. However, the general impact that these co-deletions have on metabolism, which also dependent on nutrient availability and the tissue of origin, is unknown. As a model to investigate this question, we considered a set of tissue-matched cancer cells with homozygous co-deletions in CDKN2a and MTAP, genes respectively encoding the most commonly deleted tumor suppressor p16 and an enzyme involved in methionine metabolism. A comparative metabolomics analysis revealed that while there exists a definite pan-cancer metabolic signature of MTAP-deletion, this signature was not preserved when cells were subjected to changes in the availability of methionine, serine, or cysteine, nutrients related to methionine metabolism. Notably, the heterogeneity exhibited by these cells in their responsiveness to nutrient availability dominated both MTAP status and tissue-of-origin. Furthermore, re-expression of MTAP exerted a modest effect on metabolism. Together these findings demonstrate that environmental factors, particularly nutrition and tissue identity, may overwhelm the genetic effects of collateral deletions of metabolic genes.
A Rev-CBP80-eIF4AI complex drives Gag synthesis from the HIV-1 unspliced mRNA
Authors: Toro-Ascuy Daniela , Rojas-Araya Bárbara , García-de-Gracia Francisco , Rojas-Fuentes Cecilia , Pereira-Montecinos Camila , Gaete-Argel Aracelly , Valiente-Echeverría Fernando , Ohlmann Théophile , Soto-Rifo Ricardo
Published: May 2018

Gag synthesis from the full-length unspliced mRNA is critical for the production of the viral progeny during human immunodeficiency virus type-1 (HIV-1) replication. While most spliced mRNAs follow the canonical gene expression pathway in which the recruitment of the nuclear cap-binding complex (CBC) and the exon junction complex (EJC) largely stimulates the rates of nuclear export and translation, the unspliced mRNA relies on the viral protein Rev to reach the cytoplasm and recruit the host translational machinery. Here, we confirm that Rev ensures high levels of Gag synthesis by driving nuclear export and translation of the unspliced mRNA. These functions of Rev are supported by the CBC subunit CBP80, which binds Rev and the unspliced mRNA in the nucleus and the cytoplasm. We also demonstrate that Rev interacts with the DEAD-box RNA helicase eIF4AI, which translocates to the nucleus and cooperates with Rev to promote Gag synthesis. Interestingly, molecular docking analyses revealed the assembly of a Rev-CBP80-eIF4AI complex that is organized around the Rev response element (RRE). Together, our results provide further evidence towards the understanding of the molecular mechanisms by which Rev drives Gag synthesis from the unspliced mRNA during HIV-1 replication.
Four decades of plant community change along a continental gradient of warming
Authors: Becker-Scarpitta Antoine , Vissault Steve , Vellend Mark
Published: May 2018

Many studies of individual sites have revealed biotic changes consistent with climate warming (e.g., upward elevational distribution shifts), but our understanding of the tremendous variation among studies in the magnitude of such biotic changes is minimal. In this study we re-surveyed forest vegetation plots 40 years after the initial surveys in three protected areas along a west-to-east gradient of increasingly steep recent warming trends in eastern Canada (Québec). Consistent with the hypothesis that climate warming has been an important driver of vegetation change, we found an increasing magnitude of changes in species richness and composition from west to east among the three parks. For the two mountainous parks, we found no changes in elevational species’ distributions in the eastern most park where warming has been minimal (Forillon Park), and significant upward distribution shifts in the centrally located park where the recent warming trend has been marked (Mont-Mégantic). Community temperature indices (CTI), reflecting the average affinities of locally co-occurring to temperature conditions across their geographic ranges (“species temperature indices”), did not change over time as predicted. However, close examination of the underpinnings of CTI values suggested a high sensitivity to uncertainty in individual species’ temperature indices, and so a potentially limited responsiveness to warming. Overall, by testing a priori predictions concerning variation among parks in the direction and magnitude of vegetation changes, we have provided stronger evidence for a link between climate warming and biotic responses than otherwise possible, and provided a potential explanation for large variation among studies in warming-related biotic changes.