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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 65,094 bioRxiv papers from 288,491 authors.

Most downloaded bioRxiv papers, since beginning of last month

in category systems biology

1,798 results found. For more information, click each entry to expand.

1: A Quantitative Proteome Map of the Human Body
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Posted to bioRxiv 08 Oct 2019

A Quantitative Proteome Map of the Human Body
1,440 downloads systems biology

Lihua Jiang, Meng Wang, Shin Lin, Ruiqi Jian, Xiao Li, Joanne Chan, Huaying Fang, Guanlan Dong, GTEx Consortium, Hua Tang, Michael P Snyder

Determining protein levels in each tissue and how they compare with RNA levels is important for understanding human biology and disease as well as regulatory processes that control protein levels. We quantified the relative protein levels from 12,627 genes across 32 normal human tissue types prepared by the GTEx project. Known and new tissue specific or enriched proteins (5,499) were identified and compared to transcriptome data. Many ubiquitous transcripts are found to encode highly tissue specific proteins. Discordance in the sites of RNA expression and protein detection also revealed potential sites of synthesis and action of protein signaling molecules. Overall, these results provide an extraordinary resource, and demonstrate that understanding protein levels can provide insights into metabolism, regulation, secretome, and human diseases. Summary Quantitative proteome study of 32 human tissues and integrated analysis with transcriptome data revealed that understanding protein levels could provide in-depth knowledge to post transcriptional or translational regulations, human metabolism, secretome, and diseases.

2: A pan-plant protein complex map reveals deep conservation and novel assemblies
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Posted to bioRxiv 24 Oct 2019

A pan-plant protein complex map reveals deep conservation and novel assemblies
899 downloads systems biology

Claire McWhite, Ophelia Papoulas, Kevin Drew, Rachael M Cox, Viviana June, Oliver X Dong, Taejoon Kwon, Cuihong Wan, Mari L Salmi, Stanley J Roux, Karen S Browning, Z. Jeffrey Chen, Pamela Ronald, Edward M Marcotte

Plants are foundational to global ecological and economic systems, yet most plant proteins remain uncharacterized. Protein interaction networks often suggest protein functions and open new avenues to characterize genes and proteins. We therefore systematically determined protein complexes from 13 plant species of scientific and agricultural importance, greatly expanding the known repertoire of stable protein complexes in plants. Using co-fractionation mass spectrometry, we recovered known complexes, confirmed complexes predicted to occur in plants, and identified novel interactions conserved over 1.1 billion years of green plant evolution. Several novel complexes are involved in vernalization and pathogen defense, traits critical to agriculture. We also uncovered plant analogs of animal complexes with distinct molecular assemblies, including a megadalton-scale tRNA multi-synthetase complex. The resulting map offers the first cross-species view of conserved, stable protein assemblies shared across plant cells and provides a mechanistic, biochemical framework for interpreting plant genetics and mutant phenotypes.

3: Functional single-cell genomics of human cytomegalovirus infection
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Posted to bioRxiv 03 Oct 2019

Functional single-cell genomics of human cytomegalovirus infection
639 downloads systems biology

Marco Hein, Jonathan S Weissman

Understanding how host factors and hundreds of viral genes orchestrate the complex life cycle of herpesviruses represents a fundamental problem in virology. Here, we use CRISPR/Cas9-based screening to scan at high-resolution for functional elements in the genome of human cytomegalovirus (HCMV), and to generate a genome-wide mapping of host dependency and restriction factors. Our data reveal an architecture of functional modules in the HCMV genome and host factor pathways involved in virus adhesion and entry, membrane trafficking, and innate immune response. Single-cell analysis shows that the large majority of cells follow a stereotypical trajectory in viral gene expression space. Perturbation of host factors does not alter this trajectory, but can accelerate or stall progression. Conversely, perturbation of viral factors creates discrete alternate 'dead-end' trajectories. Our results reveal a fundamental dichotomy between the roles of host and viral factors in orchestrating the viral replication cycle and more generally provide a road map for high-resolution dissection of host-pathogen interactions.

4: A Consensus Proteomic Analysis of Alzheimer's Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation
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Posted to bioRxiv 13 Oct 2019

A Consensus Proteomic Analysis of Alzheimer's Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation
611 downloads systems biology

Erik Johnson, Eric B Dammer, Duc M Duong, Lingyan Ping, Maotian Zhou, Luming Yin, Lenora A. Higginbotham, Andrew Guajardo, Bartholomew White, Juan C. Troncoso, Madhav Thambisetty, Thomas J. Montine, Edward B. Lee, John Q. Trojanowski, Thomas G Beach, Eric M Reiman, Vahram Haroutunian, Minghui Wang, Eric Schadt, Bin Zhang, Dennis W. Dickson, Nilufer Ertekin-Taner, Todd E Golde, Vladislav A Petyuk, Phillip L. De Jager, David A. Bennett, Thomas S. Wingo, Srikant Rangaraju, Ihab Hajjar, Joshua M Shulman, James J Lah, Allan I Levey, Nicholas T Seyfried

Our understanding of the biological changes in the brain associated with Alzheimer's disease (AD) pathology and cognitive impairment remains incomplete. To increase our understanding of these changes, we analyzed dorsolateral prefrontal cortex of control, asymptomatic AD, and AD brains from four different centers by label-free quantitative mass spectrometry and weighted protein co-expression analysis to obtain a consensus protein co-expression network of AD brain. This network consisted of 13 protein co-expression modules. Six of these modules correlated with amyloid-β plaque burden, tau neurofibrillary tangle burden, cognitive function, and clinical functional status, and were altered in asymptomatic AD, AD, or in both disease states. These modules reflected synaptic, mitochondrial, sugar metabolism, extracellular matrix, cytoskeletal, and RNA binding/splicing biological functions. The identified protein network modules were preserved in a community-based cohort analyzed by a different quantitative mass spectrometry approach. They were also preserved in temporal lobe and precuneus brain regions. Some of the modules were influenced by aging, and showed changes in other neurodegenerative diseases such as frontotemporal dementia and corticobasal degeneration. The module most strongly associated with AD pathology and cognitive impairment was the sugar metabolism module, which was enriched in AD genetic risk factors and correlated with APOE genetic risk. This module was also highly enriched in microglia and astrocyte protein markers associated with an anti-inflammatory state, suggesting that the biological functions it represents serve a protective role in AD. Proteins from this module were increased in cerebrospinal fluid from asymptomatic AD and AD cases, highlighting their potential as biomarkers of the altered brain network. In this study of >2000 brains and nearly 400 cerebrospinal fluid samples by quantitative proteomics, we identify proteins and biological processes in AD brain that may serve as therapeutic targets and fluid biomarkers for the disease.

5: Predicting cellular position in the Drosophila embryo from Single-Cell Transcriptomics data
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Posted to bioRxiv 10 Oct 2019

Predicting cellular position in the Drosophila embryo from Single-Cell Transcriptomics data
458 downloads systems biology

Jovan Tanevski, Thin Nguyen, Buu Truong, Nikos Karaiskos, Mehmet Eren Ahsen, Xinyu Zhang, Chang Shu, Ke Xu, Xiaoyu Liang, Ying Hu, Hoang V.V. Pham, Li Xiaomei, Thuc D. Le, Adi L. Tarca, Gaurav Bhatti, Roberto Romero, Nestoras Karathanasis, Phillipe Loher, Yang Chen, Zhengqing Ouyang, Disheng Mao, Yuping Zhang, Maryam Zand, Jianhua Ruan, Christoph Hafemeister, Peng Qiu, Duc Tran, Tin Nguyen, Attila Gabor, Thomas Yu, Enrico Glaab, Roland Krause, Peter Banda, DREAM SCTC Consortium, Gustavo Stolovitzky, Nikolaus Rajewsky, Julio Saez-Rodriguez, Pablo Meyer

Single-cell RNA-seq technologies are rapidly evolving but while very informative, in standard scRNAseq experiments the spatial organization of the cells in the tissue of origin is lost. Conversely, spatial RNA-seq technologies designed to keep the localization of the cells have limited throughput and gene coverage. Mapping scRNAseq to genes with spatial information increases coverage while providing spatial location. However, methods to perform such mapping have not yet been benchmarked. To bridge the gap, we organized the DREAM Single-Cell Transcriptomics challenge focused on the spatial reconstruction of cells from the Drosophila embryo from scRNAseq data, leveraging as gold standard genes with in situ hybridization data from the Berkeley Drosophila Transcription Network Project reference atlas. The 34 participating teams used diverse algorithms for gene selection and location prediction, while being able to correctly localize rare subpopulations of cells. Selection of predictor genes was essential for this task and such genes showed a relatively high expression entropy, high spatial clustering and the presence of prominent developmental genes such as gap and pair-ruled genes and tissue defining markers.

6: Gene expression is encoded in all parts of a co-evolving interacting gene regulatory structure
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Posted to bioRxiv 04 Oct 2019

Gene expression is encoded in all parts of a co-evolving interacting gene regulatory structure
434 downloads systems biology

Jan Zrimec, Filip Buric, Azam Sheikh Muhammad, Rhongzen Chen, Vilhelm Verendel, Mats Töpel, Aleksej Zelezniak

Understanding the genetic regulatory code that governs gene expression is a primary, yet challenging aspiration in molecular biology that opens up possibilities to cure human diseases and solve biotechnology problems. However, the fundamental question of how each of the individual coding and non-coding regions of the gene regulatory structure interact and contribute to the mRNA expression levels remains unanswered. Considering that all the information for gene expression regulation is already present in living cells, here we applied deep learning on over 20,000 mRNA datasets in 7 model organisms ranging from bacteria to Human. We show that in all organisms, mRNA abundance can be predicted directly from the DNA sequence with high accuracy, demonstrating that up to 82% of the variation of gene expression levels is encoded in the gene regulatory structure. Coding and non-coding regions carry both overlapping and orthogonal information and additively contribute to gene expression levels. By searching for DNA regulatory motifs present across the whole gene regulatory structure, we discover that motif interactions can regulate gene expression levels in a range of over three orders of magnitude. The uncovered co-evolution of coding and non-coding regions challenges the current paradigm that single motifs or regions are solely responsible for gene expression levels. Instead, we show that the correct combination of all regulatory regions must be established in order to accurately control gene expression levels. Therefore, the holistic system that spans the entire gene regulatory structure is required to analyse, understand, and design any future gene expression systems.

7: Undulating changes in human plasma proteome across lifespan are linked to disease
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Posted to bioRxiv 01 Sep 2019

Undulating changes in human plasma proteome across lifespan are linked to disease
370 downloads systems biology

Benoit Lehallier, David Gate, Nicholas Schaum, Tibor Nanasi, Song Eun Lee, Hanadie Yousef, Patricia Moran Losada, Daniela Berdnik, Andreas Keller, Joe Verghese, Sanish Sathyan, Claudio Franceschi, Sofiya Milman, Nir Barzilai, Tony Wyss-Coray

Aging is the predominant risk factor for numerous chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, pointing to the intriguing possibility that age-related molecular changes in blood can provide novel insight into disease biology. We measured 2,925 plasma proteins from 4,331 young adults to nonagenarians and developed a novel bioinformatics approach which uncovered profound non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways, and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways of aging and disease and offers potential pathways for aging interventions.

8: High-Throughput Translational Profiling with riboPLATE-seq
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Posted to bioRxiv 25 Oct 2019

High-Throughput Translational Profiling with riboPLATE-seq
359 downloads systems biology

Jordan B. Metz, Nicholas J. Hornstein, Sohani Das Sharma, Jeremy Worley, Peter A. Sims

Protein synthesis is dysregulated in many diseases, but we lack a systems-level picture of how signaling molecules and RNA binding proteins interact with the translational machinery, largely due to technological limitations. Here we present riboPLATE-seq, a scalable method for generating paired libraries of ribosome-associated and total mRNA. As an extension of the PLATE-seq protocol, riboPLATE-seq utilizes barcoded primers for pooled library preparation, but additionally leverages rRNA immunoprecipitation on whole polysomes to measure ribosome association (RA). We demonstrate the performance of riboPLATE-seq and its utility in detecting translational alterations induced by inhibition of protein kinases.

9: High-throughput single-cell proteomics quantifies the emergence of macrophage heterogeneity
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Posted to bioRxiv 09 Jun 2019

High-throughput single-cell proteomics quantifies the emergence of macrophage heterogeneity
349 downloads systems biology

Harrison Specht, Edward Emmott, David H. Perlman, Antonius Koller, Nikolai Slavov

The fate and physiology of individual cells are controlled by networks of proteins. Yet, our ability to quantitatively analyze protein networks in single cells has remained limited. To overcome this barrier, we developed SCoPE2. It integrates concepts from Single-Cell ProtEomics by Mass Spectrometry (SCoPE-MS) with automated and miniaturized sample preparation, substantially lowering cost and hands-on time. SCoPE2 uses data-driven analytics to optimize instrument parameters for sampling more ion copies per protein, thus supporting quantification with improved count statistics. These advances enabled us to analyze the emergence of cellular heterogeneity as homogeneous monocytes differentiated into macrophage-like cells in the absence of polarizing cytokines. We used SCoPE2 to quantify over 2,000 proteins in 356 single monocytes and macrophages in about 85 hours of instrument time, and the quantified proteins allowed us to discern single cells by cell type. Furthermore, the data uncovered a continuous gradient of proteome states for the macrophage-like cells, suggesting that macrophage heterogeneity may emerge even in the absence of polarizing cytokines. Our methodology lays the foundation for quantitative analysis of protein networks at single-cell resolution.

10: Accelerating Protein Design Using Autoregressive Generative Models
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Posted to bioRxiv 05 Sep 2019

Accelerating Protein Design Using Autoregressive Generative Models
349 downloads systems biology

Adam J Riesselman, Jung-Eun Shin, Aaron W Kollasch, Conor McMahon, Elana Simon, Chris Sander, Aashish Manglik, Andrew C. Kruse, Debora S. Marks

A major biomedical challenge is the interpretation of genetic variation and the ability to design functional novel sequences. Since the space of all possible genetic variation is enormous, there is a concerted effort to develop reliable methods that can capture genotype to phenotype maps. State-of-art computational methods rely on models that leverage evolutionary information and capture complex interactions between residues. However, current methods are not suitable for a large number of important applications because they depend on robust protein or RNA alignments. Such applications include genetic variants with insertions and deletions, disordered proteins, and functional antibodies. Ideally, we need models that do not rely on assumptions made by multiple sequence alignments. Here we borrow from recent advances in natural language processing and speech synthesis to develop a generative deep neural network-powered autoregressive model for biological sequences that captures functional constraints without relying on an explicit alignment structure. Application to unseen experimental measurements of 43 deep mutational scans predicts the effect of insertions and deletions while matching state-of-art missense mutation prediction accuracies. We then test the model on single domain antibodies, or nanobodies, a complex target for alignment-based models due to the highly variable complementarity determining regions. We fit the model to a naïve llama immune repertoire and generate a diverse, optimized library of 105 nanobody sequences for experimental validation. Our results demonstrate the power of the 'alignment-free' autoregressive model in mutation effect prediction and design of traditionally challenging sequence families.

11: Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease
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Posted to bioRxiv 16 Oct 2019

Integrated Proteomics Reveals Brain-Based Cerebrospinal Fluid Biomarkers in Asymptomatic and Symptomatic Alzheimer’s Disease
334 downloads systems biology

Lenora Higginbotham, Lingyan Ping, Eric B Dammer, Duc M Duong, Maotian Zhou, Marla Gearing, Erik Johnson, Ihab Hajjar, James J Lah, Allan I Levey, Nicholas T Seyfried

Alzheimer’s disease (AD) features a complex web of pathological processes beyond amyloid accumulation and tau-mediated neuronal death. To meaningfully advance AD therapeutics, there is an urgent need for novel biomarkers that comprehensively reflect these disease mechanisms. Here we applied an integrative proteomics approach to identify cerebrospinal fluid (CSF) biomarkers linked to a diverse set of pathophysiological processes in the diseased brain. Using multiplex proteomics, we identified >3,500 proteins across 40 CSF samples from control and AD patients and >12,000 proteins across 48 postmortem brain tissues from control, asymptomatic AD (AsymAD), AD, and other neurodegenerative cases. Co-expression network analysis of the brain tissues resolved 44 protein modules, nearly half of which significantly correlated with AD neuropathology. Fifteen modules robustly overlapped with proteins quantified in the CSF, including 271 CSF markers highly altered in AD. These 15 overlapping modules were collapsed into five panels of brain-linked fluid markers representing a variety of cortical functions. Neuron-enriched synaptic and metabolic panels demonstrated decreased levels in the AD brain but increased levels in diseased CSF. Conversely, glial-enriched myelination and immunity panels were highly increased in both the brain and CSF. Using high-throughput proteomic analysis, proteins from these panels were validated in an independent CSF cohort of control, AsymAD, and AD samples. Remarkably, several validated markers were significantly altered in AsymAD CSF and appeared to stratify subpopulations within this cohort. Overall, these brain-linked CSF biomarker panels represent a promising step toward a physiologically comprehensive tool that could meaningfully enhance the prognostic and therapeutic management of AD.

12: History of rare diseases and their genetic causes - a data driven approach
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Posted to bioRxiv 01 Apr 2019

History of rare diseases and their genetic causes - a data driven approach
331 downloads systems biology

Friederike Ehrhart, Egon Willighagen, Martina Kutmon, Max van Hoften, Nasim Bahram Sangani, Leopold Curfs, Chris Evelo

This dataset provides information about monogenic, rare diseases with a known genetic cause supplemented with manually extracted provenance of both the disease and the discovery of the underlying genetic cause of the disease. We collected 4166 rare monogenic diseases according to their OMIM identifier, linked them to 3163 causative genes which are annotated with Ensembl identifiers and HGNC symbols. The PubMed identifier of the scientific publication, which for the first time describes the rare disease, and the publication which found the gene causing this disease were added using information from OMIM, Wikipedia, Google Scholar, Whonamedit, and PubMed. The data is available as a spreadsheet and as RDF in a semantic model modified from DisGeNET. This dataset relies on publicly available data and publications with a PubMed IDs but this is to our knowledge the first time this data has been linked and made available for further study under a liberal license. Analysis of this data reveals the timeline of rare disease and causative genes discovery and links them to developments in methods and databases.

13: Phenotype-Based Probabilistic Analysis of Heterogeneous Responses to Cancer Drugs and Their Combination Efficacy
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Posted to bioRxiv 08 Oct 2019

Phenotype-Based Probabilistic Analysis of Heterogeneous Responses to Cancer Drugs and Their Combination Efficacy
324 downloads systems biology

Natacha Comandante-Lou, Mehwish Khaliq, Divya Venkat, Mohan Manikkam, Mohammad Fallahi-Sichani

Cell-to-cell variability generates subpopulations of drug-tolerant cells that diminish the efficacy of cancer drugs. Efficacious combination therapies are thus needed to block drug-tolerant cells via minimizing the impact of heterogeneity. Probabilistic models such as Bliss independence are developed to evaluate drug interactions and their combination efficacy based on probabilities of specific actions mediated by drugs individually and in combination. In practice, however, these models are often applied to conventional dose-response curves in which a normalized parameter with a value between zero and one, generally referred to as fraction of cells affected ( fa ), is used to evaluate the efficacy of drugs and their combined interactions. We use basic probability theory, computer simulations, time-lapse live cell microscopy, and single-cell analysis to show that fa metrics may bias our assessment of drug efficacy and combination effectiveness. This bias may be corrected when dynamic probabilities of drug-induced phenotypic events, i.e. induction of cell death and inhibition of division, at a single-cell level are used as metrics to assess drug efficacy. Probabilistic phenotype metrics offer the following three benefits. First, in contrast to the commonly used fa metrics, they directly represent probabilities of drug action in a cell population. Therefore, they deconvolve differential degrees of drug effect on tumor cell killing versus inhibition of cell division, which may not be correlated for many drugs. Second, they increase the sensitivity of short-term drug response assays to cell-to-cell heterogeneities and the presence of drug-tolerant subpopulations. Third, their probabilistic nature allows them to be used directly in unbiased evaluation of synergistic efficacy in drug combinations using probabilistic models such as Bliss independence. Altogether, we envision that probabilistic analysis of single-cell phenotypes complements currently available assays via improving our understanding of heterogeneity in drug response, thereby facilitating the discovery of more efficacious combination therapies to block drug-tolerant cells.

14: Dynamic allocation of computational resources for deep learning-enabled cellular image analysis with Kubernetes
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Posted to bioRxiv 22 Dec 2018

Dynamic allocation of computational resources for deep learning-enabled cellular image analysis with Kubernetes
319 downloads systems biology

Dylan Bannon, Erick Moen, Morgan Schwartz, Enrico Borba, Sunny Cui, Kevin Huang, Isabella Camplisson, Nora Koe, Daniel Kyme, Takamasa Kudo, Brian Chang, Edward Pao, Erik Osterman, William Graf, David Van Valen

Deep learning is transforming the ability of life scientists to extract information from images. These techniques have better accuracy than conventional approaches and enable previously impossible analyses. As the capability of deep learning methods expands, they are increasingly being applied to large imaging datasets. The computational demands of deep learning present a significant barrier to large-scale image analysis. To meet this challenge, we have developed DeepCell 2.0, a platform for deploying deep learning models on large imaging datasets (>105-megapixel images) in the cloud. This software enables the turnkey deployment of a Kubernetes cluster on all commonly used operating systems. By using a microservice architecture, our platform matches computational operations with their hardware requirements to reduce operating costs. Further, it scales computational resources to meet demand, drastically reducing the time necessary for analysis of large datasets. A thorough analysis of costs demonstrates that cloud computing is economically competitive for this application. By treating hardware infrastructure as software, this work foreshadows a new generation of software packages for biology in which computational resources are a dynamically allocated resource.

15: DDIA: data dependent-independent acquisition proteomics - DDA and DIA in a single LC-MS/MS run
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Posted to bioRxiv 13 Oct 2019

DDIA: data dependent-independent acquisition proteomics - DDA and DIA in a single LC-MS/MS run
299 downloads systems biology

Shenheng Guan, Paul P. Taylor, Ziwei Han, Michael F Moran, Bin Ma

Data dependent acquisition (DDA) and data independent acquisition (DIA) are traditionally separate experimental paradigms in bottom-up proteomics. In this work, we developed a strategy combining the two experimental methods into a single LC-MS/MS run. We call the novel strategy, data dependent-independent acquisition proteomics, or DDIA for short. Peptides identified by conventional and robust DDA identification workflow provide useful information for interrogation of DIA scans. Deep learning based LC-MS/MS property prediction tools, developed previously can be used repeatedly to produce spectral libraries facilitating DIA scan extraction. A complete DDIA data processing pipeline, including modules for iRT vs RT calibration curve generation, DIA extraction classifier training, FDR control has been developed. A key advantage of the DDIA method is that it requires minimal information for processing its data.

16: Single cell transcriptomics of human epidermis reveals basal stem cell transition states
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Posted to bioRxiv 30 Sep 2019

Single cell transcriptomics of human epidermis reveals basal stem cell transition states
289 downloads systems biology

Shuxiong Wang, Michael L Drummond, Christian F Guerrero-Juarez, Eric Tarapore, Adam L MacLean, Adam R. Stabell, Stephanie C Wu, Guadalupe Gutierrez, Bao T That, Claudia A Benavente, Qing Nie, Scott X Atwood

How stem cells give rise to human interfollicular epidermis is unclear despite the crucial role the epidermis plays in barrier and appendage formation. Here we use single cell-RNA sequencing to interrogate basal stem cell heterogeneity of human interfollicular epidermis and find at least four spatially distinct stem cell populations that decorate the top and bottom of rete ridge architecture and hold transitional positions between the basal and suprabasal epidermal layers. Cell-cell communication modeling through co-variance of cognate ligand-receptor pairs indicate that the basal cell populations distinctly serve as critical signaling hubs that maintain epidermal communication. Combining pseudotime, RNA velocity, and cellular entropy analyses point to a hierarchical differentiation lineage supporting multi-stem cell interfollicular epidermal homeostasis models and suggest the transitional basal stem cells are stable states essential for proper stratification. Finally, alterations in differentially expressed transitional basal stem cell genes result in severe thinning of human skin equivalents, validating their essential role in epidermal homeostasis and reinforcing the critical nature of basal stem cell heterogeneity.

17: Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration
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Posted to bioRxiv 17 Jul 2019

Longitudinal single cell transcriptomics reveals Krt8+ alveolar epithelial progenitors in lung regeneration
286 downloads systems biology

Maximilian Strunz, Lukas M Simon, Meshal Ansari, Laura F Mattner, Ilias Angelidis, Christoph H Mayr, Jaymin Kathiriya, Min Yee, Paulina Ogar, Arunima Sengupta, Igor Kukhtevich, Robert Schneider, Zhongming Zhao, Jens H.L. Neumann, Juergen Behr, Carola Voss, Tobias Stoeger, Mareike Lehmann, Melanie Koenigshoff, Gerald Burgstaller, Michael O'Reilly, Harold A. Chapman, Fabian J. Theis, Herbert B Schiller

Lung injury activates quiescent stem and progenitor cells to regenerate alveolar structures. The sequence and coordination of transcriptional programs during this process has largely remained elusive. Using single cell RNA-seq, we first generated a whole-organ birds-eye view on cellular dynamics and cell-cell communication networks during mouse lung regeneration from ~30,000 cells at six timepoints. We discovered an injury-specific progenitor cell state characterized by Krt8 in flat epithelial cells covering alveolar surfaces. The number of these cells peaked during fibrogenesis in independent mouse models, as well as in human acute lung injury and fibrosis. Krt8+ alveolar progenitors featured a highly distinct connectome of receptor-ligand pairs with endothelial cells, fibroblasts, and macrophages. To sky dive into epithelial differentiation dynamics, we sequenced >30,000 sorted epithelial cells at 18 timepoints and computationally derived cell state trajectories that were validated by lineage tracing genetic reporter mice. Airway stem cells within the club cell lineage and alveolar type-2 cells underwent transcriptional convergence onto the same Krt8+ progenitor cell state, which later resolved by terminal differentiation into alveolar type-1 cells. We derived distinct transcriptional regulators as key switch points in this process and show that induction of NFkB, p53, and hypoxia driven gene expression programs precede a Sox4, Ctnnb1, and Wwtr1 driven commitment towards alveolar type-1 cell fate. We show that epithelial cell plasticity can induce non-gradual transdifferentiation, involving intermediate progenitor cell states that may persist and promote disease if checkpoint signals for terminal differentiation are perturbed.

18: A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators
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Posted to bioRxiv 31 Oct 2019

A Compendium of Kinetic Cell Death Modulatory Profiles Identifies Ferroptosis Regulators
252 downloads systems biology

Megan Conlon, Carson Poltorack, Giovanni C. Forcina, Alex Wells, Melodie Mallais, Alexis Kahanu, Leslie Magtanong, Derek Pratt, Scott J. Dixon

Cell death can be executed by regulated apoptotic and non-apoptotic pathways, including the iron-dependent process of ferroptosis. Small molecules are essential tools for studying the regulation of cell death. Using live-cell, time-lapse imaging, and a library of 1,833 small molecules including FDA-approved drugs and investigational agents, we assemble a large compendium of kinetic cell death modulatory profiles for inducers of apoptosis and ferroptosis. From this dataset we identified dozens of small molecule inhibitors of ferroptosis, including numerous investigational and FDA-approved drugs with unexpected off-target antioxidant or iron chelating activities. ATP-competitive mechanistic target of rapamycin (mTOR) inhibitors, by contrast, were on-target ferroptosis inhibitors. Further investigation revealed both mTOR-dependent and mTOR-independent mechanisms linking amino acid levels to the regulation of ferroptosis sensitivity in cancer cells. These results highlight widespread bioactive compound pleiotropy and link amino acid sensing to the regulation of ferroptosis.

19: Parallel accumulation – serial fragmentation combined with data-independent acquisition (diaPASEF): Bottom-up proteomics with near optimal ion usage
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Posted to bioRxiv 31 May 2019

Parallel accumulation – serial fragmentation combined with data-independent acquisition (diaPASEF): Bottom-up proteomics with near optimal ion usage
249 downloads systems biology

Florian Meier, Andreas-David Brunner, Max Frank, Annie Ha, Eugenia Voytik, Stephanie Kaspar-Schoenefeld, Markus Lubeck, Oliver Raether, Ruedi Aebersold, Ben C. Collins, Hannes L Röst, Matthias Mann

Bottom-up proteomics produces complex peptide populations that are identified and quantified at the precursor or fragment ion level. Data dependent acquisition methods sequentially isolate and fragment particular precursors, whereas data independent acquisition (DIA) modes isolate and concurrently fragment populations of different precursors by cycling deterministically through segments of a predefined precursor m/z range. Although the selection windows of DIA collectively cover the entire mass range of interest, only a few percent of the ion current are sampled due to the consecutive selection of acquisition windows. Making use of the correlation of molecular weight and ion mobility in a trapped ion mobility device (timsTOF Pro), we here devise a novel scan mode that samples up to 100% of the peptide precursor ion current. We analyze the acquired data by extending established targeted data extraction workflow for the analysis of DIA data by the additional ion mobility dimension, providing additional specificity in the precursor identification. Data acquired from simple protein mixtures verify the expected data completeness and data in single runs of a whole proteome digest demonstrate deep proteome coverage and a very high degree of reproducibility and quantitative accuracy, even from 10 ng sample amounts.

20: A streamlined mass spectrometry-based proteomics workflow for large scale FFPE tissue analysis
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Posted to bioRxiv 23 Sep 2019

A streamlined mass spectrometry-based proteomics workflow for large scale FFPE tissue analysis
246 downloads systems biology

Fabian Coscia, Sophia Doll, Jacob Mathias Bech, Andreas Mund, Ernst Lengyel, Jan Lindebjerg, Gunvor Iben Madsen, Jos&eacute M.A. Moreira, Matthias Mann

Formalin fixation and paraffin-embedding (FFPE) is the most common method to preserve human tissue for clinical diagnosis and FFPE archives represent an invaluable resource for biomedical research. Proteins in FFPE material are stable over decades but their efficient extraction and streamlined analysis by mass spectrometry (MS)-based proteomics has so far proven challenging. Here, we describe an MS-based proteomic workflow for quantitative profiling of large FFPE tissue cohorts directly from pathology glass slides. We demonstrate broad applicability of the workflow to clinical pathology specimens and variable sample amounts, including less than 10,000 cancer cells isolated by laser-capture microdissection. Using state-of-the-art data dependent acquisition (DDA) and data independent (DIA) MS workflows, we consistently quantify a large part of the proteome in 100 min single-run analyses. In an adenoma cohort comprising more than 100 samples, total work up took less than a day. We observed a moderate trend towards lower protein identifications in long-term stored samples (>15 years) but clustering into distinct proteomic subtypes was independent of archival time. Our results underline the great promise of FFPE tissues for patient phenotyping using unbiased proteomics and prove the feasibility of analyzing large tissue cohorts in a robust, timely and streamlined manner.

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