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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 52,871 bioRxiv papers from 244,990 authors.

Most tweeted bioRxiv papers, last 24 hours

218 results found. For more information, click each entry to expand.

41: PaKman: Scalable Assembly of Large Genomes on Distributed Memory Machines
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Posted to bioRxiv 17 Jan 2019

PaKman: Scalable Assembly of Large Genomes on Distributed Memory Machines
4 tweets bioinformatics

Priyanka Ghosh, Sriram Krishnamoorthy, Ananth Kalyanaraman

De novo genome assembly is a fundamental problem in the field of bioinformatics, that aims to assemble the DNA sequence of an unknown genome from numerous short DNA fragments (aka reads) obtained from it. With the advent of high-throughput sequencing technologies, billions of reads can be generated in a matter of hours, necessitating efficient parallelization of the assembly process. While multiple parallel solutions have been proposed in the past, conducting a large-scale assembly at scale remains a challenging problem because of the inherent complexities associated with data movement, and irregular access footprints of memory and I/O operations. In this paper, we present a novel algorithm, called PaKman, to address the problem of performing large-scale genome assemblies on a distributed memory parallel computer. Our approach focuses on improving performance through a combination of novel data structures and algorithmic strategies for reducing the communication and I/O footprint during the assembly process. PaKman presents a solution for the two most time-consuming phases in the full genome assembly pipeline, namely, k-mer counting and contig generation.A key aspect of our algorithm is its graph data structure, which comprises fat nodes (or what we call "macro-nodes") that reduce the communication burden during contig generation. We present an extensive performance and qualitative evaluation of our algorithm, including comparisons to other state-of-the-art parallel assemblers. Our results demonstrate the ability to achieve near-linear speedups on up to 8K cores (tested); outperform state-of-the-art distributed memory and shared memory tools in performance while delivering comparable (if not better) quality; and reduce time to solution significantly. For instance, PaKman is able to generate a high-quality set of assembled contigs for complex genomes such as the human and wheat genomes in a matter of minutes on 8K cores.

42: Differential Treatment Benefit Prediction For Treatment Selection in Depression: A Deep Learning Analysis of STAR*D and CO-MED Data
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Posted to bioRxiv 23 Jun 2019

Differential Treatment Benefit Prediction For Treatment Selection in Depression: A Deep Learning Analysis of STAR*D and CO-MED Data
4 tweets neuroscience

Joseph Mehltretter, Robert Fratila, David Benrimoh, Adam Kapelner, Kelly Perlman, Emily Snook, Sonia Israel, Marc Miresco, Gustavo Turecki

Background: Depression affects one in nine people, but treatment response rates remain low. There is significant potential in the use of computational modelling techniques to predict individual patient responses and thus provide more personalized treatment. Deep learning is a promising computational technique that can be used for differential treatment selection based on predicted remission probability. Methods: Using STAR*D and CO-MED trial data, we employed deep neural networks to predict remission after feature selection. Differential treatment benefit was estimated in terms of improvement of population remission rates after application of the model for treatment selection using both naive and conservative approaches. The naive approach assessed population remission rate in five sets of 200 patients held apart from the training set; the conservative approach used bootstrapping for sample generation and focused on population remission rate for patients who actually received the drug predicted by the model compared to the general population. Results: Our deep learning model predicted remission in a pooled CO-MED/STAR*D dataset (including four treatments) with an AUC of 0.69 using 17 input features. Our naive analysis showed an improvement of remission of over 30% (from a 34.33% population remission rate to 46.12%). Our conservative analysis showed a 7.2% improvement in population remission rate (p= 0.01, C.I. 2.48% +/- .5%). Conclusion: Our model serves as proof-of-concept that deep learning has utility in differential prediction of antidepressant response when selecting from a number of treatment options. These models may have significant real-world clinical implications.

43: Animal-aided design - using a species life-cycle to improve open space planning and conservation in cities and elsewhere
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Posted to bioRxiv 15 Jun 2017

Animal-aided design - using a species life-cycle to improve open space planning and conservation in cities and elsewhere
4 tweets ecology

Wolfgang Weisser, Thomas Hauck

Biodiversity underlies many of the ecosystem services demanded by humans. For cities, the design of ‘green infrastructures’ or ‘nature-based solutions’ has been proposed to maintain the provisioning of these services and the preservation of biodiversity. It is unclear, however, how such green infrastructure can be implemented given existing planning practices that generally ignore biodiversity. Urban open spaces are normally designed by landscape architects with a primary focus on plants, aesthetic design and functionality for human users. As a consequence, conservation of species only plays a minor role, in fact, protected animals are often considered detrimental to the design, e.g. when the need to conserve a protected species demand modifications of a building project. Conversely, conservationists are often in favor of protected areas, also in cities, with little access of humans and no human design. We propose ‘Animal-Aided Design’ (AAD) as a methodology for the design of urban open spaces, to integrate conservation into open space planning. The basic idea of AAD is to include the presence of animals in the planning process, such that they are an integral part of the design. For AAD, the desired species are chosen at the beginning of a project. The requirements of the target species then not only set boundary conditions for the design, but also serve as an inspiration for the design itself. The aim of AAD is to establish a stable population at the project site, or contribute to population growth of species with larger habitats. AAD thus allows a combination of good urban design with species conservation. We illustrate our approach with designs for urban spaces in Munich.

44: Repurposing protein degradation for optogenetic modulation of protein activities
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Posted to bioRxiv 23 Jun 2019

Repurposing protein degradation for optogenetic modulation of protein activities
4 tweets bioengineering

Payel Mondal, Vishnu V. Krishnamurthy, Savanna R. Sharum, Neeka Haack, Kai Zhang

Non-neuronal optogenetic approaches empower precise regulation of protein dynamics in live cells but often require target-specific protein engineering. To address this challenge, we developed a generalizable light modulated protein stabilization system (GLIMPSe) to control intracellular protein level independent of its functionality. We applied GLIMPSe to control two distinct classes of proteins: mitogen-activated protein kinase phosphatase 3 (MKP3), a negative regulator of the extracellular signal-regulated kinase (ERK) pathway, as well as a constitutively active form of MEK (CA MEK), a positive regulator of the same pathway. Kinetics study showed that light-induced protein stabilization could be achieved within 1 minute of blue light stimulation. GLIMPSe enables target-independent optogenetic control of protein activities and therefore minimizes the systematic variation embedded within different photoactivatable proteins. Overall, GLIMPSe promises to achieve light-mediated post-translational stabilization of a wide array of target proteins in live cells.

45: Towards a gold standard for benchmarking gene set enrichment analysis
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Posted to bioRxiv 19 Jun 2019

Towards a gold standard for benchmarking gene set enrichment analysis
4 tweets bioinformatics

Ludwig Geistlinger, Gergely Csaba, Mara Santarelli, Marcel Ramos, Lucas Schiffer, Charity W Law, Nitesh Turaga, Sean Davis, Vincent Carey, Martin Morgan, Ralf Zimmer, Levi Waldron

Background: Although gene set enrichment analysis has become an integral part of high-throughput gene expression data analysis, the assessment of enrichment methods remains rudimentary and ad hoc. In the absence of suitable gold standards, evaluations are commonly restricted to selected data sets and biological reasoning on the relevance of resulting enriched gene sets. However, this is typically incomplete and biased towards the goals of individual investigations. Results: We present a general framework for standardized and structured benchmarking of enrichment methods based on defined criteria for applicability, gene set prioritization, and detection of relevant processes. This framework incorporates a curated compendium of 75 expression data sets investigating 42 different human diseases. The compendium features microarray and RNA-seq measurements, and each dataset is associated with a precompiled GO/KEGG relevance ranking for the corresponding disease under investigation. We perform a comprehensive assessment of 10 major enrichment methods on the benchmark compendium, identifying significant differences in (i) runtime and applicability to RNA-seq data, (ii) fraction of enriched gene sets depending on the type of null hypothesis tested, and (iii) recovery of the a priori defined relevance rankings. Based on these findings, we make practical recommendations on (i) how methods originally developed for microarray data can efficiently be applied to RNA-seq data, (ii) how to interpret results depending on the type of gene set test conducted, and (iii) which methods are best suited to effectively prioritize gene sets with high relevance for the phenotype investigated. Conclusion: We carried out a systematic assessment of existing enrichment methods, and identified best performing methods, but also general shortcomings in how gene set analysis is currently conducted. We provide a directly executable benchmark system for straightforward assessment of additional enrichment methods. Availability: http://bioconductor.org/packages/GSEABenchmarkeR

46: Consequences of consumer origin and omnivory on stability in experimental food web modules
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Posted to bioRxiv 27 Mar 2019

Consequences of consumer origin and omnivory on stability in experimental food web modules
4 tweets ecology

Monica Granados, Katie S Pagnucco, Anthony Ricciardi

1. Food web stability, a fundamental characteristic of ecosystems, is influenced by the nature and strength of species interactions. Theory posits that food webs are stabilized by omnivory and disrupted by novel consumers. 2. To test the effects of secondary consumer origin and trophic level on basal resource stability, we constructed crayfish-snail-algae modules using four congeneric species of crayfish (Faxonius spp.), two from native populations (F. propinquus and F. virilis) and two from non-native populations (F. limosus and F. rusticus). We performed surgical manipulations of crayfish feeding structures to create omnivore food web and predator food chain modules. We compared the temporal stability of these modules using measures of the coefficient of variation of the basal resource (benthic algae). 3. Consistent with theoretical and empirical predictions, food web modules with omnivory had the lowest coefficient of variation. However, contrary to prediction, we did not find consistently higher coefficients of variation in modules with non-native species. Rather, across species, we found the lowest coefficient of variation in modules with one of the non-native species (F. rusticus) and one native species (F. virilis), owing to stronger interactions between these crayfish species and their snail and algal food resources. 4. The results suggest that omnivory is indeed stabilizing and that very weak interactions or very low attack rates of the consumer on the basal resource can be unstable. Thus, we demonstrate that omnivores may have different impacts than predators when introduced into a novel ecosystem, differences that can supersede the effect of species identity.

47: Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors
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Posted to bioRxiv 22 Jun 2019

Molecular profiling predicts meningioma recurrence and reveals loss of DREAM complex repression in aggressive tumors
4 tweets cancer biology

Akash J Patel, Ying-Wooi Wan, Rami Al-Ouran, Jean-Pierre Revelli, Maria F. Cardenas, Mazen Oneissi, Liu Xi, Ali Jalali, John Magnotti, Donna M. Muzny, HarshaVardhan Doddapaneni, Sherly Sebastian, Kent A Heck, Jerry Clay Goodman, Shankar P Gopinath, Zhandong Liu, Ganesh Rao, Sharon E. Plon, Daniel Yoshor, David A Wheeler, Huda Y. Zoghbi, Tiemo J Klisch

Meningiomas account for roughly one-third of all primary brain tumors. Although typically benign, about 20% of meningiomas are aggressive, and despite the rigor of the current histopathological classification system, there remains considerable uncertainty in predicting tumor behavior. Here we analyzed 160 tumors from all three WHO grades (I-III) using clinical, gene expression and sequencing data. Unsupervised clustering analysis identified three molecular groups that reliably predicted clinical severity. These groups did not directly correlate with the WHO grading system, which would classify more than half of the tumors in the most aggressive molecular group as benign. Transcriptional and biochemical analyses revealed that aggressive meningiomas involve loss of the repressor function of the DREAM complex, resulting in cell cycle activation, and only tumors in this group tend to recur after full resection. These findings should improve our ability to predict recurrence and develop targeted treatments for these clinically challenging tumors.

48: Type I-F CRISPR-Cas resistance against virulent phage infection triggers abortive infection and provides population-level immunity
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Posted to bioRxiv 21 Jun 2019

Type I-F CRISPR-Cas resistance against virulent phage infection triggers abortive infection and provides population-level immunity
4 tweets microbiology

Bridget NJ Watson, Reuben B Vercoe, George PC Salmond, Edze R Westra, Raymond HJ Staals, Peter Fineran

Type I CRISPR-Cas systems are the most abundant and widespread adaptive immune systems of bacteria and can greatly enhance bacterial survival in the face of temperate phage infection. However, it is less clear how these systems protect against virulent phages. Here we experimentally show that type I CRISPR immunity of Pectobacterium atrosepticum leads to rapid suppression of two unrelated virulent phages, ΦTE and ΦM1. However, unlike the case where bacteria are infected with temperate phages, this is the result of an abortive infection-like phenotype, where infected cells do not survive the infection but instead become metabolically inactive and lose their membrane integrity. Our findings challenge the view of CRISPR-Cas as a system that protects the individual cell and supports growing evidence of an Abi-like function for some types of CRISPR-Cas systems.

49: Improved Sensitivity in Low-Input Proteomics using Micro-Pillar Array-based Chromatography
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Posted to bioRxiv 21 Jun 2019

Improved Sensitivity in Low-Input Proteomics using Micro-Pillar Array-based Chromatography
4 tweets biochemistry

Johannes Stadlmann, Otto Hudecz, Gabriela Krssakova, Gert Van Raemdonck, Jeff Op De Beeck, Gert Desmet, Josef M. Penninger, Paul Jacobs, Karl Mechtler

Capitalizing on the massive increase in sample concentrations which are produced by extremely low elution volumes, nano-LC-ESI-MS/MS is currently one of the most sensitive analytical technologies for the comprehensive characterization of complex protein samples. However, despite tremendous technological improvements made in the production and the packing of monodisperse spherical particles for nano-flow HPLC, current state-of-the-art systems still suffer from limits in operation at the maximum potential of the technology. With the recent introduction of the muPAC system, which provides perfectly ordered micro-pillar array based chromatographic support materials, completely new chromatographic concepts for optimization towards the needs of ultra-sensitive proteomics become available. Here we report on a series of benchmarking experiments comparing the performance of a commercially available 50 cm micro-pillar array column to a widely used nano-flow HPLC column for the proteomics analysis of 10 ng tryptic HeLa cell digest. Comparative analysis of LC-MS/MS-data corroborated that micro-pillar array cartridges provide outstanding chromatographic performance, excellent retention time stability, increase sensitivity in the analysis of low-input proteomics samples, and thus repeatedly yielded almost twice as many unique peptide and unique protein group identifications when compared to conventional nano-flow HPLC columns.

50: Principles of self-organization and load adaptation by the actin cytoskeleton during clathrin-mediated endocytosis
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Posted to bioRxiv 21 Jun 2019

Principles of self-organization and load adaptation by the actin cytoskeleton during clathrin-mediated endocytosis
4 tweets cell biology

Matthew Akamatsu, Ritvik Vasan, Daniel Serwas, Michael Ferrin, Padmini Rangamani, David G. Drubin

Force generation due to actin assembly is a fundamental aspect of membrane sculpting for many essential processes. In this work, we use a multiscale computational model constrained by experimental measurements to show that a minimal branched actin network is sufficient to internalize endocytic pits against physiological membrane tension. A parameter sweep identified the number of Arp2/3 complexes as particularly important for robust internalization, which prompted the development of a molecule-counting method in live mammalian cells. Using this method, we found that ~200 Arp2/3 complexes assemble at sites of clathrin-mediated endocytosis in human cells. Our simulations also revealed that actin networks self-organize in a radial branched array with barbed filament ends oriented to grow toward the base of the pit, and that the distribution of linker proteins around the endocytic pit is critical for this organization. Surprisingly, our model predicted that long actin filaments bend from their attachment sites in the coat to the base of the pit and store elastic energy that can be harnessed to drive endocytosis. This prediction was validated using cryo-electron tomography on cells, which revealed the presence of bent actin filaments along the endocytic site. Furthermore, we predict that under elevated membrane tension, the self-organized actin network directs more growing filaments toward the base of the pit, increasing actin nucleation and bending for increased force production. Thus, our study reveals that spatially constrained actin filament assembly utilizes an adaptive mechanism that enables endocytosis under varying physical constraints.

51: Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain
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Posted to bioRxiv 21 Jun 2019

Cryo-EM structure of the complete and ligand-saturated insulin receptor ectodomain
4 tweets biochemistry

Theresia Gutmann, Ingmar Schaefer, Chetan Poojari, Beate Brankatschk, Ilpo Vattulainen, Mike Strauss, Uenal Coskun

Glucose homeostasis and growth essentially depend on the peptide hormone insulin engaging its receptor. Despite biochemical and structural advances, a fundamental contradiction has persisted in the current understanding of insulin ligand-receptor interactions. While biochemistry predicts two distinct insulin binding sites, 1 and 2, recent structural analyses have only resolved site 1. Using a combined approach of cryo-EM and atomistic molecular dynamics simulation, we determined the structure of the entire dimeric insulin receptor ectodomain saturated with four insulin molecules. Complementing the previously described insulin-site 1 interaction, we present the first view of insulin bound to the discrete insulin receptor site 2. Insulin binding stabilizes the receptor ectodomain in a T-shaped conformation wherein the membrane-proximal domains converge and contact each other. These findings expand the current models of insulin binding to its receptor and of its regulation. In summary, we provide the structural basis enabling a comprehensive description of ligand-receptor interactions that ultimately will inform new approaches to structure-based drug design.

52: A Multi-State Birth-Death model for Bayesian inference of lineage-specific birth and death rates
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Posted to bioRxiv 11 Oct 2018

A Multi-State Birth-Death model for Bayesian inference of lineage-specific birth and death rates
4 tweets evolutionary biology

Joelle Barido-Sottani, Timothy G Vaughan, Tanja Stadler

Heterogeneous populations can lead to important differences in birth and death rates across a phylogeny. Taking this heterogeneity into account is thus critical to obtain accurate estimates of the underlying population dynamics. We present a new multi-state birth-death model (MSBD) that can estimate lineage-specific birth and death rates. For species phylogenies, this corresponds to estimating lineage-dependent speciation and extinction rates. Contrary to existing models, we do not require a prior hypothesis on a trait driving the rate differences and we allow the same rates to be present in different parts of the phylogeny. Using simulated datasets, we show that the MSBD model can reliably infer the presence of multiple evolutionary regimes, their positions in the tree, and the birth and death rates associated with each. We also present a re-analysis of two empirical datasets and compare the results obtained by MSBD and by the existing software BAMM. The MSBD model is implemented as a package in the Bayesian inference software BEAST2, which allows joint inference of the phylogeny and the model parameters.

53: Maltotriose consumption by hybrid Saccharomyces pastorianus is heterotic and results from regulatory cross-talk between parental sub-genomes
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Posted to bioRxiv 22 Jun 2019

Maltotriose consumption by hybrid Saccharomyces pastorianus is heterotic and results from regulatory cross-talk between parental sub-genomes
3 tweets microbiology

Nick Brouwers, Anja Brickwedde, Arthur R Gorter de Vries, Marcel van den Broek, Susan M Weening, Lieke F van den Eijnden, Jasper A Diderich, Feng-Yan Bai, Jack T Pronk, Jean-Marc G Daran

S. pastorianus strains are hybrids of S. cerevisiae and S. eubayanus that have been domesticated for several centuries in lager-beer brewing environments. As sequences and structures of S. pastorianus genomes are being resolved, molecular mechanisms and evolutionary origin of several industrially relevant phenotypes remain unknown. This study investigates how maltotriose metabolism, a key feature in brewing, may have arisen in early S. eubayanus x S. cerevisiae hybrids. To address this question, we generated a near-complete genome assembly of Himalayan S. eubayanus strains of the Holarctic subclade. This group of strains have been proposed to be the origin of the S. eubayanus subgenome of current S. pastorianus strains. The Himalayan S. eubayanus genomes harbored several copies of a SeAGT1 alpha-oligoglucoside transporter gene with high sequence identity to genes encountered in S. pastorianus. Although Himalayan S. eubayanus strains are unable to grown on maltose and maltotriose, their maltose-hydrolase and SeMALT1 and SeAGT1 maltose-transporter genes complemented the corresponding null mutants of S. cerevisiae. Expression, in a Himalayan S. eubayanus strain, of a functional S. cerevisiae maltose-metabolism regulator gene (MALx3) enabled growth on oligoglucosides. The hypothesis that the maltotriose-positive phenotype in S. pastorianus is a result of heterosis was experimentally tested by constructing a S. cerevisiae x S. eubayanus laboratory hybrid with a complement of maltose-metabolism genes that resembles that of current S. pastorianus strains. The ability of this hybrid to consume maltotriose in brewer s wort demonstrated regulatory cross talk between sub-genomes and thereby validated this hypothesis. These results provide experimental evidence of the evolutionary origin of an essential phenotype of lager-brewing strains and valuable knowledge for industrial exploitation of laboratory-made S. pastorianus-like hybrids.

54: The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis
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Posted to bioRxiv 21 Jun 2019

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in maintaining mitochondrial metabolic homeostasis
3 tweets cell biology

Abhinav Joshi, Joyce Dai, Jungsoon Lee, Nastaran Mohammadi Ghahhari, Gregory Segala, Kristin Beebe, Francis T. F. Tsai, Len Neckers, Didier Picard

Background: The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other. Results: We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline or an increase in OXPHOS. Conclusions: Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

55: Persister Cells Resuscitate via Ribosome Modification by 23S rRNA Pseudouridine Synthase RluD
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Posted to bioRxiv 21 Jun 2019

Persister Cells Resuscitate via Ribosome Modification by 23S rRNA Pseudouridine Synthase RluD
3 tweets molecular biology

Sooyeon Song, Thomas K Wood

Upon a wide range of stress conditions (e.g., nutrient, antibiotic, oxidative), a subpopulation of bacterial cells known as persisters survive by halting metabolism. These cells resuscitate rapidly to reconstitute infections once the stress is removed and nutrients are provided. However, how these dormant cells resuscitate is not understood well but involves reactivating ribosomes. By screening 10,000 compounds directly for stimulating Escherichia coli persister cell resuscitation, we identified that 2-{[2-(4-bromophenyl)-2-oxoethyl]thio}-3-ethyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (BPOET) stimulates resuscitation. Critically, by screening 4,267 E. coli proteins, we determined that BPOET activates hibernating ribosomes via 23S rRNA pseudouridine synthase RluD, which increases ribosome activity. Corroborating the increased waking with RluD, production of RluD increased the number of active ribosomes in persister cells. Also, inactivating the small RNA RybB which represses rluD led to faster persister resuscitation. Hence, persister cells resuscitate via activation of RluD.

56: Ab-initio discovery of tumoricidal oligonucleotides in a DNA sequencing machine
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Posted to bioRxiv 07 May 2019

Ab-initio discovery of tumoricidal oligonucleotides in a DNA sequencing machine
3 tweets synthetic biology

Noam Mamet, Itai Rusinek, Gil Harari, Zvi Shapira, Adva Zamir, Noam Borovsky, Noah Joseph, Maria Motin, Dekel Saban, Ido Bachelet

We describe a technique for the rapid ab-initio discovery of target-tailored tumoricidal DNA oligonucleotides inside an Illumina sequencing chip. By sequencing oligonucleotide pools we generate a physical microfluidic map of hundreds of millions of potential oligo clusters, in which every cluster is mapped to a specific set of spatial coordinates. Tumor cells, pre-loaded with a fluorogenic reporter of apoptosis, are then injected into the chip and monitored over time. Apoptotic tumor cells are identified and analyzed across the entire map, automatically revealing the coordinates of oligos that induced this effect. We demonstrate this method by identifying, within just a few hours, new oligos capable of directly and selectively inducing apoptosis in primary human tumor cells. Such a major capability could lead to a new paradigm of personalized cancer therapy.

57: H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis
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Posted to bioRxiv 21 Jun 2019

H3K9me2 orchestrates inheritance of spatial positioning of peripheral heterochromatin through mitosis
3 tweets cell biology

Andrey Poleshko, Cheryl L Smith, Son C. Nguyen, Priya Sivaramakrishnan, John Isaac Murray, Melike Lakadamyali, Eric F. Joyce, Raj Jain, Jonathan A Epstein

Cell-type-specific 3D organization of the genome is unrecognizable during mitosis. It remains unclear how essential positional information is transmitted through cell division such that a daughter cell recapitulates the spatial genome organization of the parent. Lamina-associated domains (LADs) are regions of repressive heterochromatin positioned at the nuclear periphery that vary by cell type and contribute to cell-specific gene expression. Here we show that histone 3 lysine 9 dimethylation (H3K9me2) specifically marks peripheral heterochromatin and is retained through mitosis when phosphorylation of histone 3 serine 10 shields the H3K9me2 mark allowing for dissociation from the nuclear lamina. The H3K9me2 modification of peripheral heterochromatin ensures that positional information is safeguarded through cell division such that individual LADs are re-established at the nuclear periphery in daughter nuclei. Thus, H3K9me2 acts as a 3D architectural mitotic guidepost. Our data establish a mechanism for epigenetic memory and inheritance of spatial organization of the genome.

58: High-dimensional geometry of population responses in visual cortex
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Posted to bioRxiv 22 Jul 2018

High-dimensional geometry of population responses in visual cortex
3 tweets neuroscience

Carsen Stringer, Marius Pachitariu, Nicholas Steinmetz, Matteo Carandini, Kenneth D. Harris

A neuronal population encodes information most efficiently when its activity is uncorrelated and high-dimensional, and most robustly when its activity is correlated and lower-dimensional. Here, we analyzed the correlation structure of natural image coding, in large visual cortical populations recorded from awake mice. Evoked population activity was high dimensional, with correlations obeying an unexpected power-law: the n-th principal component variance scaled as 1/n. This was not inherited from the 1/f spectrum of natural images, because it persisted after stimulus whitening. We proved mathematically that the variance spectrum must decay at least this fast if a population code is smooth, i.e. if small changes in input cannot dominate population activity. The theory also predicts larger power-law exponents for lower-dimensional stimulus ensembles, which we validated experimentally. These results suggest that coding smoothness represents a fundamental constraint governing correlations in neural population codes.

59: Trickle infection and immunity to Trichuris muris
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Posted to bioRxiv 19 Jun 2019

Trickle infection and immunity to Trichuris muris
3 tweets immunology

Maya Glover, Stefano Adriano Pericle Colombo, David J Thornton, Richard Karl Grencis

The majority of experiments investigating the immune response to gastrointestinal helminth infection use a single bolus infection. However, in situ individuals are repeatedly infected with low doses. Therefore, to model natural infection, mice were repeatedly infected (trickle infection) with low doses of Trichuris muris. Trickle infection resulted in the slow acquisition of immunity reflected by a gradual increase in worm burden followed by a partial expulsion. Flow cytometry revealed that the CD4+ T cell response shifted from Th1 dominated to Th2 dominated, which coincided with an increase in Type 2 cytokines. The development of resistance following trickle infection was associated with increased worm expulsion effector mechanisms including goblet cell hyperplasia, Muc5ac production and increased epithelial cell turn over. Depletion of CD4+ T cells reversed resistance confirming their importance in protective immunity following trickle infection. In contrast, depletion of group 2 innate lymphoid cells did not alter protective immunity. T. muris trickle infection resulted in a dysbiotic mircrobiota which began to recover alpha diversity following the development of resistance. These data support trickle infection as a robust and informative model for analysis of immunity to chronic intestinal helminth infection more akin to that observed under natural infection conditions and confirms the importance of CD4+ T cell adaptive immunity in host protection.

60: Dolosigranulum pigrum cooperation and competition in human nasal microbiota
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Posted to bioRxiv 21 Jun 2019

Dolosigranulum pigrum cooperation and competition in human nasal microbiota
3 tweets microbiology

Silvio D Brugger, Sara M Eslami, Melinda M Pettigrew, Isabel Fernandez Escapa, Matthew M Henke, Yong Kong, Katherine P Lemon

Multiple epidemiological studies identify Dolosigranulum pigrum as a candidate beneficial bacterium based on its positive association with health, including negative associations with nasal/nasopharyngeal colonization by the pathogenic species Staphylococcus aureus and Streptococcus pneumoniae . To gain insight into D. pigrum 's functions, we used a multipronged strategy. We identified in vivo community-level and in vitro phenotypic cooperation by specific nasal Corynebacterium species. D. pigrum inhibited S. aureus growth in vitro . Whereas, D. pigrum plus a nasal Corynebacterium were needed to inhibit S. pneumoniae growth. Moreover, D. pigrum L-lactic-acid production was insufficient for this inhibition. Genomic analysis of 11 strains revealed that D. pigrum has a small genome (average 1.86 Mb) and multiple predicted auxotrophies, which indicate that D. pigrum relies on its human host and cocolonizing bacteria for key nutrients. This shift to genomic and phenotypic experimentation marks a significant advance in understanding D. pigrum 's role in human nasal microbiota.

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