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A systems-biology approach connects aging mechanisms with Alzheimer's disease pathogenesis bioRxiv. Syst. Biol. Pub Date : 2024-03-17 Matthew Joseph Leventhal, Camila A Zanella, Byunguk Kang, Jiajie Peng, David Gritsch, Zhixiang Liao, Hassan Bukhari, Tao Wang, Ping-Chieh Pao, Serwah Danquah, Joseph Benetatos, Ralda Nehme, Samouil Farhi, Li-Huei Tsai, Xianjun Dong, Clemens Scherzer, Mel B Feany, Ernest Fraenkel
Age is the strongest risk factor for developing Alzheimer's disease, the most common neurodegenerative disorder. However, the mechanisms connecting advancing age to neurodegeneration in Alzheimer's disease are incompletely understood. We conducted an unbiased, genome-scale, forward genetic screen for age-associated neurodegeneration in Drosophila to identify the underlying biological processes required
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Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations bioRxiv. Syst. Biol. Pub Date : 2024-03-17 Ester Calvo Fernandez, Lorenzo Tomassoni, Xu Zhang, Junqiang Wang, Aleksandar Obradovic, Pasquale Laise, Aaron T. Griffin, Lukas Vlahos, Hanna E. Minns, Diana V. Morales, Christian Simmons, Matthew Gallitto, Hong-Jian Wei, Timothy J. Martins, Pamela S. Becker, John R. Crawford, Theophilos Tzaridis, Robert J. Wechsler-Reya, James Garvin, Robyn D. Gartrell, Luca Szalontay, Stergios Zacharoulis, Cheng-Chia
Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge
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In-gel protein digestion using acidic methanol produces a highly selective methylation of glutamic 1 acid residues. bioRxiv. Syst. Biol. Pub Date : 2024-03-17 Marta Lozano-Prieto, Emilio Camafeita, Inmaculada Jorge, Andrea Laguillo-Gomez, Rafael Barrero-Rodriguez, Cristina A Devesa, Clara Pertusa, Enrique Calvo, Francisco Sanchez-Madrid, Jesus Vazquez, Noa B Martin-Cofreces
Mass-tolerant open search methods allow the high-throughput analysis of modified peptides by mass spectrometry. These techniques have paved the way to unbiased analysis of post-translational modifications (PTMs) in biological contexts, as well as of chemical modifications produced during the manipulation of protein samples. In this work, we have analyzed in-depth a wide variety of samples of different
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Curating models from BioModels: Developing a workflow for creating OMEX files bioRxiv. Syst. Biol. Pub Date : 2024-03-17 Jin Xu, Lucian Smith
The reproducibility of computational biology models can be greatly facilitated by widely adopted standards and public repositories. We examined 50 models from the BioModels Database and attempted to validate the original curation and correct some of them if necessary. For each model, we reproduced these published results using Tellurium. Once reproduced we manually created a new set of files, with
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Understanding the effects of oxytocin receptor variants on OXT-OXT receptor binding: A mathematical model bioRxiv. Syst. Biol. Pub Date : 2024-03-16 Preeti Dubey, Yingye Fang, K. Lionel Tukei, Shobhan Kuila, Xinming Liu, Annika Sahota, Antonina I. Frolova, Erin L. Reinl, Manasi Malik, Sarah K. England, Princess I. Imoukhuede
Approximately half of U.S. women giving birth annually receive Pitocin, the synthetic form of oxytocin (OXT), yet its effective dose can vary significantly. This variability presents safety concerns due to unpredictable responses, which may lead to adverse outcomes for both mother and baby. To address the need for improved dosing, we developed a data-driven mathematical model to predict OXT receptor
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Quantitative effects of co-culture on T cell motility and cancer-T cell interactions bioRxiv. Syst. Biol. Pub Date : 2024-03-16 Xinyue Li, Taoli Jin, Lisha Wang, Ming Li, Weijing Han, Xuefei Li
One of the primary challenges in current cancer immunotherapy is the insufficient infiltration of cytotoxic T cells into solid tumors. Despite ongoing investigations, the mechanisms restricting T cell infiltration in immune-cold tumors remains elusive, hindered by the intricate tumor microenvironment. Here, we co-cultured mouse cancer cell lines with cancer-specific cytotoxic T cells to study the influence
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Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms bioRxiv. Syst. Biol. Pub Date : 2024-03-16 Luke Lambourne, Kaia Mattioli, Clarissa Santoso, Gloria Sheynkman, Sachi Inukai, Babita Kaundal, Anna Berenson, Kerstin Spirohn-Fitzgerald, Anukana Bhattacharjee, Elisabeth Rothman, Shaleen Shrestha, Florent Laval, Zhipeng Yang, Deepa Bisht, Jared A. Sewell, Guangyuan Li, Anisa Prasad, Sabrina Phanor, Ryan Lane, Devlin M. Campbell, Toby Hunt, Dawit Balcha, Marinella Gebbia, Jean-Claude Twizere, Tong
Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization
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A distributed integral control mechanism for the regulation of cholesterol concentration in the human retina. bioRxiv. Syst. Biol. Pub Date : 2024-03-16 Ronel Scheepers, Noa L Levi, Robyn P Araujo
Tight homeostatic control of cholesterol concentration within the complex tissue micro-environment of the retina is a hallmark of the healthy eye. Although the signalling mechanisms that contribute to cholesterol homeostasis at the cellular level have been studied extensively, there is currently no systems-level description of the molecular interactions underlying cholesterol homeostasis at the level
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Defining network topologies that can achieve molecular memory bioRxiv. Syst. Biol. Pub Date : 2024-03-15 Federico Sevlever
In the context of cellular signaling and gene regulatory networks, the concept of molecular memory emerges as a crucial determinant of molecular mechanisms. This study introduces a novel memory quantifier designed to comprehensively capture and quantify the memory of a system in response to transient stimuli. We proposed and validate this quantifier through toy models, showcasing its effectiveness
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Time series-free rhythm profiling using COFE reveals multi-omic circadian rhythms in in-vivo human cancers bioRxiv. Syst. Biol. Pub Date : 2024-03-15 Bharath Ananthasubramaniam, Ramji Venkataramanan
The study of the ubiquitous circadian rhythms in human physiology typically requires regular measurements across time. Repeated sampling of the different internal tissues that house circadian clocks is both practically and ethically infeasible. Here, we present a novel unsupervised machine learning approach (COFE) that can use single high-throughput (omics) samples from individuals to reconstruct circadian
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The protein interactome of Escherichia coli carbohydrate metabolism. bioRxiv. Syst. Biol. Pub Date : 2024-03-14 Shomeek Chowdhury, Stephen Fong, Peter Uetz
Carbohydrate metabolism is strictly regulated by multiple mechanisms to meet cellular needs (i.e. energy production). Several mechanisms modulate the amount and activity of metabolic enzymes. Here, we investigate how carbohydrate metabolism (CHM) in E. coli is regulated by their interaction properties with other proteins and their quantities. We computationally analyze 378 protein-enzyme interactions
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Identification of Key Regulators in Pancreatic Ductal Adenocarcinoma using Network theoretical Approach bioRxiv. Syst. Biol. Pub Date : 2024-03-14 Aryya Ghosh, Kankana Bhattacharjee
Pancreatic Ductal Adenocarcinoma (PDAC) is a devastating disease with poor clinical outcomes which is mainly because of delayed disease detection resistance to chemotherapy and lack of specific targeted therapies. The disease's development involves complex interactions among immunological, genetic, and environmental factors, yet its molecular mechanism remains elusive. A major challenge in understanding
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Self-inhibiting percolation and viral spreading in epithelial tissue bioRxiv. Syst. Biol. Pub Date : 2024-03-14 Xiaochan Xu, Bjarke Frost Nielsen, kim sneppen
SARS-CoV-2 induces delayed type-I/III interferon production, allowing it to escape the early innate immune response. The delay has been attributed to a deficiency in the ability of cells to sense viral replication upon infection, which in turn hampers activation of the antiviral state in bystander cells. Here, we introduce a cellular automaton model to investigate the spatiotemporal spreading of viral
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Protection against APOE4-associated aging phenotypes with the longevity-promoting intervention 17α-estradiol in male mice bioRxiv. Syst. Biol. Pub Date : 2024-03-14 Cassandra J. McGill, Amy Christensen, Wenjie Qian, Max A. Thorwald, Jose G. Lugo, Sara Namvari, Olivia S. White, Caleb Finch, Bérénice Anath Benayoun, Christian J. Pike
The apolipoprotein ϵ4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of APOE4-associated aging phenotypes. Here we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2)
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Analysis of higher order interactions quantifies co-ordination in the epigenome and reveals novel biological relationships in Kabuki syndrome bioRxiv. Syst. Biol. Pub Date : 2024-03-13 Sara Cuvertino, Terence Garner, Evgenii Martirosian, Bridgious Walusimbi, Susan J Kimber, Siddharth Banka, Adam Stevens
Complex direct and indirect relationships between multiple variables are a characteristic of all natural systems and are defined as higher order interactions (HOIs). Traditional differential and network analyses fail to account for the richness of omic datasets and miss HOIs. We investigated genome-wide peripheral blood DNA methylation data from Kabuki syndrome type 1 (KS1) and control individuals
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Navigated range expansion promotes migratory culling bioRxiv. Syst. Biol. Pub Date : 2024-03-13 Yi Zhang, Qingjuan Hu, Yingtong Su, Pan Chu, Ting Wei, Peilei Yu, Chenli Liu, Xiongfei Fu
Motile organisms can expand into new territories and increase their fitness, while nonmotile viruses usually depend on host migration to spread across long distances. In general, faster host motility facilitates virus transmission. However, recent ecological studies have also shown that animal host migration can reduce viral prevalence by removing infected individuals from the migratory group. Here
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Subcellular mRNA kinetic modeling reveals nuclear retention as rate-limiting bioRxiv. Syst. Biol. Pub Date : 2024-03-13 David Steinbrecht, Igor Minia, Miha Milek, Johannes Meisig, Nils Bluethgen, Markus Landthaler
Eukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated
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Association between gene expression plasticity and regulatory network topology bioRxiv. Syst. Biol. Pub Date : 2024-03-13 Apolline J. R. Petit, Anne Genissel, Arnaud Le Rouzic
What drives the evolution of gene network topology? During the last decades, many looked into it to find structures responsible for gene expression patterns. Gene expression plasticity for instance has been associated with many network structures, but both theoretical results and empirical observations were often equivocal. Our objective was to decipher the regulatory causes of gene expression plasticity
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Making predictions using poorly identified mathematical models bioRxiv. Syst. Biol. Pub Date : 2024-03-13 Matthew J Simpson, Oliver J Maclaren
Many mathematical models that are commonly used in the field of mathematical biology involve challenges of parameter non-identifiability. Practical non-identifiability, where the quality and quantity of data does not provide sufficiently precise parameter estimates is often encountered, even with relatively simple models. In particular, the situation where some parameters are identifiable and others
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ZNF143 is a transcriptional regulator of nuclear-encoded mitochondrial genes that acts independently of looping and CTCF bioRxiv. Syst. Biol. Pub Date : 2024-03-12 Mikhail D Magnitov, Michela Maresca, Noemí Alonso Saiz, Hans Teunissen, Luca Braccioli, Elzo de Wit
Gene expression is orchestrated by transcription factors, which function within the context of a three-dimensional genome. Zinc finger protein 143 (ZNF143/ZFP143) is a transcription factor that has been implicated in both gene activation and chromatin looping. To study the direct consequences of ZNF143/ZFP143 loss, we generated a ZNF143/ZFP143 degron line. Our results show that ZNF143/ZFP143 depletion
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Construction, analysis and assessment of relevance of an algebraic model for a class of biochemical networks bioRxiv. Syst. Biol. Pub Date : 2024-03-12 SIDDHARTHA KUNDU
The intracellular milieu presents a complex physicochemical environment where molecular redundancy prevails and infra-threshold perturbations are integrated by biochemical networks. The pathways that result from these interactions are complex and will result in a plethora of signalling cascades. The stoichiometry number matrix for a biochemical network is a suitable way to represent the interactions
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A simple regulatory network coordinates a bacterial stress response in space and time bioRxiv. Syst. Biol. Pub Date : 2024-03-12 Divya Choudhary, Kevin R Foster, Stephan Uphoff
Bacteria employ diverse gene regulatory networks to protect themselves from stressful environments. While transcriptomics and proteomics show that the expression of different genes can shift strongly in response to stress, the underlying logic of large regulatory networks is difficult to understand from bulk measurements performed at discrete time points. As a result, it remains challenging to predict
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Biodiversity is enhanced by sequential resource utilization and environmental fluctuations via emergent temporal niches bioRxiv. Syst. Biol. Pub Date : 2024-03-11 Blox Bloxham, Hyunseok Lee, Jeff Gore
How natural communities maintain their remarkable biodiversity and which species survive in complex communities are central questions in ecology. Resource competition models successfully explain many phenomena but typically predict only as many species as resources can coexist. Here, we demonstrate that sequential resource utilization, or diauxie, with periodic growth cycles can support many more species
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Aedes albopictus is not an arbovirus aficionado - Impacts of sylvatic flavivirus infection in vectors and hosts on mosquito engorgement on non-human primates bioRxiv. Syst. Biol. Pub Date : 2024-03-11 Helene Cecilia, Benjamin M Althouse, Sasha R Azar, Brett A Moehn, Ruimei Yun, Shannan L Rossi, Nikos Vasilakis, Kathryn A Hanley
The contact structure between vertebrate hosts and arthropod vectors plays a key role in the spread of arthropod-borne viruses (arboviruses); thus, it is important to determine whether arbovirus infection of either host or vector alters vector feeding behavior. Here we leveraged a study of the replication dynamics of two arboviruses isolated from their ancestral cycles in paleotropical forests, sylvatic
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An in silico cardiomyocyte reveals the impact of changes in CAMKII signalling on cardiomyocyte kinetics in hypertrophic cardiomyopathy bioRxiv. Syst. Biol. Pub Date : 2024-03-11 Ismail Adeniran, Hafsa Wadee, Hans Degens
Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms by which HCM alters electrophysiological activity
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Histology-guided mathematical model of tumor oxygenation: sensitivity analysis of physical and computational parameters bioRxiv. Syst. Biol. Pub Date : 2024-03-10 Awino Maureiq E Ojwang', Sarah Bazargan, Joseph O. Johnson, Shari Pilon-Thomas, Katarzyna A. Rejniak
A hybrid off-lattice agent-based model has been developed to reconstruct the tumor tissue oxygenation landscape based on histology images and simulated interactions between vasculature and cells with microenvironment metabolites. Here, we performed a robustness sensitivity analysis of that model's physical and computational parameters. We found that changes in the domain boundary conditions, the initial
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Identifying effective evolutionary strategies for uncovering reaction kinetic parameters under the effect of measurement noises bioRxiv. Syst. Biol. Pub Date : 2024-03-10 Hock Chuan Yeo, Vijay Varsheni, Kumar Selvarajoo
The transition from explanative modelling of fitted data to the predictive modelling of unseen data for systems biology endeavors necessitates the effective recovery of reaction parameters. Yet, the relative efficacy of optimization algorithms in doing so remains under-studied, as to the specific reaction kinetics and the effect of measurement noises. To this end, we simulate the reactions of an artificial
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Maximum Likelihood Inference of Time-scaled Cell Lineage Trees with Mixed-type Missing Data bioRxiv. Syst. Biol. Pub Date : 2024-03-10 Uyen Mai, Gillian Chu, Benjamin Raphael
Recent dynamic lineage tracing technologies combine CRISPR-based genome editing with single-cell sequenc- ing to track cell divisions during development. A key computational problem in dynamic lineage tracing is to infer a cell lineage tree from the measured CRISPR-induced mutations. Three features of dynamic lineage tracing data distinguish this problem from standard phylogenetic tree inference. First
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Generally-healthy individuals with aberrant bowel movement frequencies show enrichment for microbially-derived blood metabolites associated with reduced kidney function. bioRxiv. Syst. Biol. Pub Date : 2024-03-09 Johannes P Johnson-Martinez, Christian Diener, Annie E Levine, Tomasz Wilmanski, David L Suskind, Alexandra Ralevski, Jennifer Hadlock, Andrew T Magis, Leroy Hood, Noa Rappaport, Sean M Gibbons
Bowel movement frequency (BMF) has been linked to changes in the composition of the human gut microbiome and to many chronic conditions, like metabolic disorders, neurodegenerative diseases, chronic kidney disease (CKD), and other intestinal pathologies like irritable bowel syndrome and inflammatory bowel disease. Lower BMF (constipation) can lead to compromised intestinal barrier integrity and a switch
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Understanding flux switching in metabolic networks through an analysis of synthetic lethals bioRxiv. Syst. Biol. Pub Date : 2024-03-09 Sowmya Manojna, Tanisha Malpani, Omkar Satyavan Mohite, Saketha Nath, Karthik Raman
Biological systems are extremely robust and exhibit high levels of redundancy for multiple cellular functions. Some of this redundancy manifests as alternative pathways in metabolism. Synthetic double lethals in metabolic networks comprise pairs of reactions, which, when deleted simultaneously, abrogate cell growth. However, when one reaction from such pairs is removed, the cell reroutes its metabolites
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Constructing networks for comparison of collagen types bioRxiv. Syst. Biol. Pub Date : 2024-03-09 Valentin Wesp, Lukas Scholz, Janine M. Ziermann-Canabarro, Stefan Schuster, Heiko Stark
Collagens are structural proteins that are predominantly found in the extracellular matrix of multicellular animals, where they are mainly responsible for the stability and structural integrity of various tissues. All collagens contain polypeptide strands (ɑ-chains). There are several types of collagens, some of which differ significantly in form, function, and tissue specificity. Because of their
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Stoichiometric Rays: A simple method to compute the controllable set of enzymatic reaction systems bioRxiv. Syst. Biol. Pub Date : 2024-03-08 Yusuke Himeoka, Shuhei A Horiguchi, Tetsuya J Kobayashi
A simple method to compute the controllable set of chemical reaction systems with enzyme concentrations as the control parameters is presented. The method features the fact that the catalyst enhances the reaction rate while not changing the equilibrium, and it enables the efficient computation of the global controllability of linear- and nonlinear models. The method is applied to the reversible Brusselator
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Visualizing the Spatio-Temporal Dynamics of Clonal Evolution with LinG3D software bioRxiv. Syst. Biol. Pub Date : 2024-03-07 Anjun Hu, Awino Maureiq Ojwang, Kayode D Olumoyin, Katarzyna A Rejniak
Cancer clonal evolution, especially following anti-cancer treatments, depends on the locations of the mutated cells within the tumor tissue. Cells near the vessels, exposed to higher concentrations of drugs, will undergo a different evolutionary path than cells residing far from the vasculature in the areas of lower drug levels. However, classical representations of cell lineage trees do not account
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Agent-based model demonstrates the impact of nonlinear, complex interactions between cytokines on muscle regeneration bioRxiv. Syst. Biol. Pub Date : 2024-03-07 Megan Haase, Tien Comlekoglu, Alexa Petrucciani, Shayn M Peirce, Silvia S Blemker
Muscle regeneration is a complex process due to dynamic and multiscale biochemical and cellular interactions, making it difficult to identify microenvironmental conditions that are beneficial to muscle recovery from injury using experimental approaches alone. To understand the degree to which individual cellular behaviors impact endogenous mechanisms of muscle recovery, we developed an agent-based
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Integrating mechanism-based T cell phenotypes into a model of tumor-immune cell interactions bioRxiv. Syst. Biol. Pub Date : 2024-03-07 Neel Tangella, Colin G Cess, Geena V Ildefonso, Stacey D Finley
Interactions between cancer cells and immune cells in the tumor microenvironment influence tumor growth and can contribute to the response to cancer immunotherapies. It is difficult to gain mechanistic insights into the effects of cell-cell interactions in tumors using a purely experimental approach. However, computational modeling enables quantitative investigation of the tumor microenvironment, and
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Application of Cancer Cell Line Encyclopedia for Measuring Correlation Between Transcriptomics and Proteomics as a Guide for System-level Insights bioRxiv. Syst. Biol. Pub Date : 2024-03-06 Blake Williams, Darryl Perry, PJ Aspesi, Jefferson Parker, Ted Johnson, Wendy Su, Eduardo Tabacman, Kirk Delisle, Kayvon Avishan, Vic Myer, Felipa Mapa, Michael Hinterberg, Alan Williams, Lori Jennings, Nebojsa Janjic, Joseph Loureiro
Robust and reliable proteome measurements provide mechanistic insights in biomedical research. SOMAmer (Slow Off-rate Modified Aptamer) reagents are modified, DNA-based, affinity reagents that measure defined target proteins with reproducibility and accuracy similar to monoclonal antibodies. Applying SOMAmer reagent technology, we developed SomaScan, a clinical proteome profiling platform with capability
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Revealing global stoichiometry conservation architecture in cells from Raman spectral patterns bioRxiv. Syst. Biol. Pub Date : 2024-03-06 Ken-ichiro F. Kamei, Koseki J. Kobayashi-Kirschvink, Takashi Nozoe, Hidenori Nakaoka, Miki Umetani, Yuichi Wakamoto
Changes in molecular profiles in cells are often correlated and suggested to be effectively low dimensional. However, what kinds of biological principles entail such constraints remains elusive. Here, we measure Raman scattering light from Escherichia coli cells under diverse conditions, whose spectral patterns convey their comprehensive molecular composition. We reveal that dimension-reduced Raman
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Isobaric crosslinking mass spectrometry technology for studying conformational and structural changes in proteins and complexes bioRxiv. Syst. Biol. Pub Date : 2024-03-05 Jeffrey Ranish, Jie Luo
Dynamic conformational and structural changes in proteins and protein complexes play a central and ubiquitous role in the regulation of protein function, yet it is very challenging to study these changes, especially for large protein complexes, under physiological conditions. Here we introduce a novel isobaric crosslinker, Qlinker, for studying conformational and structural changes in proteins and
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Developmental hematopoietic stem cell variation explains clonal hematopoiesis later in life bioRxiv. Syst. Biol. Pub Date : 2024-03-05 Jesse Kreger, Jazlyn A Mooney, Darryl Shibata, Adam L MacLean
Clonal hematopoiesis becomes increasingly common with age, but its cause is enigmatic because driver mutations are often absent. Serial observations infer weak selection indicating variants are acquired much earlier in life with unexplained initial growth spurts. Here we use fluctuating CpG methylation as a lineage marker to track stem cell clonal dynamics of hematopoiesis. We show, via the shared
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The Molecular Landscape of Cellular Metal Ion Biology bioRxiv. Syst. Biol. Pub Date : 2024-03-05 Simran Kaur Aulakh, Oliver Lemke, Lukasz Szyrwiel, Stephan Kamrad, Yu Chen, Johannes Hartl, Michael Muelleder, Jens Nielsen, Markus Ralser
Metal ions play crucial roles in cells, yet the broader impact of metal availability on biological networks remains underexplored. We generated genome-wide resources, systematically quantifying yeast cell growth, metallomic, proteomic, and genetic responses upon varying each of its essential metal ions (Ca, Cu, Fe, K, Mg, Mn, Mo, Na, Zn), over several orders of magnitude. We find that metal ions deeply
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The lipidome of posttraumatic stress disorder bioRxiv. Syst. Biol. Pub Date : 2024-03-05 Aditi Bhargava, Johannes D Knapp, Oliver Fiehn, Thomas C Neylan, Sabra S Inslicht
Posttraumatic stress disorder (PTSD) can develop after trauma exposure. Some studies report that women develop PTSD at twice the rate of men, despite greater trauma exposure in men. Lipids and their metabolites (lipidome) regulate a myriad of key biological processes and pathways such as membrane integrity, oxidative stress, and neuroinflammation in the brain by maintaining neuronal connectivity and
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A Targeted Genome-scale Overexpression Platform for Proteobacteria bioRxiv. Syst. Biol. Pub Date : 2024-03-04 Amy B Banta, Kevin S Myers, Ryan D Ward, Rodrigo A Cuellar, Claire C Freeh, Emily E Bacon, Jason M Peters
Targeted, genome-scale gene perturbation screens using Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi) and activation (CRISPRa) have revolutionized eukaryotic genetics, advancing medical, industrial, and basic research. Although CRISPRi knockdowns have been broadly applied in bacteria, options for genome-scale overexpression face key limitations. Here, we develop a
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In silico modelling of CD8 T cell immune response links genetic regulation to population dynamics bioRxiv. Syst. Biol. Pub Date : 2024-03-04 Thi Nhu Thao Nguyen, Madge Martin, Christophe Arpin, Samuel Bernard, Olivier Gandrillon, Fabien Crauste
The CD8 T cell immune response operates at multiple temporal and spatial scales, including all the early complex biochemical and biomechanical processes, up to long term cell population behavior. In order to model this response, we devised a multiscale agent-based approach using Simuscale software. Within each agent (cell) of our model, we introduced a gene regulatory network (GRN) based upon a piecewise
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Proteome-scale tissue mapping using mass spectrometry based on label-free and multiplexed workflows bioRxiv. Syst. Biol. Pub Date : 2024-03-04 Yumi Kwon, Jongmin Woo, Fengchao Yu, Sarah M Williams, Lye Meng Markillie, Ronald J Moore, Ernesto S Nakaysu, Jing Chen, Martha Campbell-Thompson, Clayton E Mathews, Alexey I Nesvizhskii, Wei-Jun Qian, Ying Zhu
Multiplexed bimolecular profiling of tissue microenvironment, or spatial omics, can provide deep insight into cellular compositions and interactions in both normal and diseased tissues. Proteome-scale tissue mapping, which aims to unbiasedly visualize all the proteins in whole tissue section or region of interest, has attracted significant interest because it holds great potential to directly reveal
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Correlation measures in metagenomic data: the blessing of dimensionality bioRxiv. Syst. Biol. Pub Date : 2024-03-04 Alessandro Fuschi, Alessandra Merlotti, Dong Binh Tran, Hoan Nguyen, George Weinstock, Daniel Remondini
Microbiome analysis has revolutionized our understanding of various biological processes, spanning human health, epidemiology (including antimicrobial resistance and horizontal gene transfer), as well as environmental and agricultural studies. At the heart of microbiome analysis lies the characterization of microbial communities through the quantification of microbial taxa and their dynamics. In the
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Dynamics of morphogen source formation in a growing tissue bioRxiv. Syst. Biol. Pub Date : 2024-03-03 Richard D. J. G. Ho, Kasumi Kishi, Maciej Majka, Anna Kicheva, Marcin Zagorski
A tight regulation of morphogen production is key for morphogen gradient formation and thereby for reproducible and organised organ development. Although many genetic interactions involved in the establishment of morphogen production domains are known, the biophysical mechanisms of morphogen source formation are poorly understood. Here we addressed this by focusing on the morphogen Shh in the vertebrate
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Quantitative profiling of human translation initiation reveals regulatory elements that potently affect endogenous and therapeutically modified mRNAs bioRxiv. Syst. Biol. Pub Date : 2024-03-03 Cole J.T. Lewis, Li Xie, Shivani Bhandarkar, Danni Jin, Kyrillos S. Abdallah, Austin S. Draycott, Yixuan Chen, Carson C. Thoreen, Wendy V Gilbert
mRNA therapeutics offer a potentially universal strategy for the efficient development and delivery of therapeutic proteins. Current mRNA vaccines include chemically modified nucleotides to reduce cellular immunogenicity. Here, we develop an efficient, high-throughput method to measure human translation initiation on therapeutically modified as well as endogenous RNAs. Using systems-level biochemistry
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Multiplex single-cell analysis of serotonergic neuron function in planarians reveals widespread effects in diverse cell types bioRxiv. Syst. Biol. Pub Date : 2024-03-02 Elena Emili, Dianali Rodriguez-Fernandez, Alberto Perez-Posada, Helena Garcia-Castro, Jordi Solana
Neurons function by interacting with each other and with other cell types, often exerting organism-wide regulation. Serotonergic neurons play a systemic role in processes such as appetite, sleep and motor control. Functional studies in the planarian Schmidtea mediterranea have shown that impairment of serotonergic neurons results in systemic effects. Studying neurons and the tissues they interact with
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Complex Traits Heritability is Highly Clustered in the eQTL Bipartite Network bioRxiv. Syst. Biol. Pub Date : 2024-03-01 Katherine L Stone, John Platig, John Quackenbush, Maud Fagny
Single Nucleotide Polymorphisms (SNPs) associated with traits typically explain a small part of the trait genetic heritability---with the remainder thought to be distributed throughout the genome. Such SNPs are likely to alter expression levels of biologically relevant genes. Expression Quantitative Trait Locus (eQTL) networks analysis has helped to functionally characterize such variants. We systematically
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Inferring fungal growth rates from optical density data bioRxiv. Syst. Biol. Pub Date : 2024-03-01 Tara Hameed, Natasha Motsi, Elaine Bignell, Reiko J Tanaka
Quantifying fungal growth underpins our ability to effectively treat severe fungal infections. Current methods quantify fungal growth rates from time-course morphology-specific data, such as hyphal length data. However, automated large-scale collection of such data lies beyond the scope of most clinical microbiology laboratories. In this paper, we propose a mathematical model of fungal growth to estimate
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Investigating RNA splicing as a source of cellular diversity using a binomial mixture model bioRxiv. Syst. Biol. Pub Date : 2024-03-01 Keren Isaev, David A Knowles
Alternative splicing (AS) contributes significantly to RNA and protein variability yet its role in defining cellular diversity is not fully understood. While Smart-seq2 offers enhanced coverage across transcripts compared to 10X single cell RNA-sequencing (scRNA-seq), current computational methods often miss the full complexity of AS. Most approaches for single cell based differential splicing analysis
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Model Agnostic Semi-Supervised Meta-Learning Elucidates Understudied Out-of-distribution Molecular Interactions bioRxiv. Syst. Biol. Pub Date : 2024-03-01 You Wu, Li Xie, Yang Liu, Lei Xie
Many biological problems are understudied due to experimental limitations and human biases. Although deep learning is promising in accelerating scientific discovery, its power compromises when applied to problems with scarcely labeled data and data distribution shifts. We developed a semi-supervised meta learning framework - Meta Model Agnostic Pseudo Label Learning (MMAPLE) - to address these challenges
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Discovering Genetic Modulators of the Protein Homeostasis System through Multilevel Analysis bioRxiv. Syst. Biol. Pub Date : 2024-02-29 Vishal Sarsani, Berent Aldikacti, Tingting Zhao, Shai He, Peter Chien, Patrick Flaherty
Every protein progresses through a natural lifecycle from birth to maturation to death; this process is coordinated by the protein homeostasis system. Environmental or physiological conditions trigger pathways that maintain the homeostasis of the proteome. An open question is how these pathways are modulated to respond to the many stresses that an organism encounters during its lifetime. To address
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CONVERGENCE, SAMPLING AND TOTAL ORDER ESTIMATOR EFFECTS ON PARAMETER ORTHOGONALITY IN GLOBAL SENSITIVITY ANALYSIS bioRxiv. Syst. Biol. Pub Date : 2024-02-29 Harry Saxton, Xu Xu, Torsten Schenkel, Richard H. Clayton, Ian Halliday
Dynamical system models typically involve numerous input parameters whose ``effects'' and orthogonality need to be quantified through sensitivity analysis, to identify inputs contributing the greatest uncertainty. Whilst prior art has compared total-order estimators’ role in recovering “true” effects, assessing their ability to recover robust parameter orthogonality for use in identifiability metrics
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Holimap: an accurate and efficient method for solving stochastic gene network dynamics bioRxiv. Syst. Biol. Pub Date : 2024-02-28 Chen Jia, Ramon Grima
Gene-gene interactions are crucial to the control of sub-cellular processes but our understanding of their stochastic dynamics is hindered by the lack of simulation methods that can accurately and efficiently predict how the distributions of protein numbers for each gene vary across parameter space. To overcome these difficulties, here we present Holimap (high-order linear-mapping approximation), an
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Differential Responses of Dynamic and Entropic Aging Factors to Longevity Interventions bioRxiv. Syst. Biol. Pub Date : 2024-02-28 Kristina Perevoshchikova, Peter O Fedichev
Aging across most species, including mice and humans, is characterized by an exponential acceleration of mortality rates. In search for the molecular basis of this phenomenon, we analyzed DNA methylation (DNAm) changes in aging mice. Utilizing principal component analysis (PCA) on DNAm profiles, we identified a primary aging signature with an exponential age dependency, closely reflecting the Gompertz
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TISSUE-SPECIFIC METABOLOMIC REPROGRAMMING DETERMINES THE DISEASE PATHOPHYSIOLOGY OF SARS-COV-2 VARIANTS IN HAMSTER MODEL bioRxiv. Syst. Biol. Pub Date : 2024-02-27 Urvinder Kaur Sardarni, Anoop Ambikan, Arpan Acharya, Samuel D Johnson, Sean N Avedissian, Akos Vegvari, Ujjwal Neogi, Siddappa Byrareddy
Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between organs and specific SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem
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The unreasonable effectiveness of the total quasi-steady state approximation, and its limitations bioRxiv. Syst. Biol. Pub Date : 2024-02-27 Justin Eilertsen, Santiago Schnell, Sebastian Walcher
In this note, we discuss the range of parameters for which the total quasi-steady-state approximation of the Michaelis--Menten reaction mechanism holds validity. We challenge the prevalent notion that total quasi-steady-state approximation is "roughly valid" across all parameters, showing that its validity cannot be assumed, even roughly, across the entire parameter space - when the initial substrate
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ENQUIRE RECONSTRUCTS AND EXPANDS CONTEXT-SPECIFIC CO-OCCURRENCE NETWORKS FROM BIOMEDICAL LITERATURE bioRxiv. Syst. Biol. Pub Date : 2024-02-27 Luca Musella, Xin Lai, Max Widmann, Julio Vera Gonzalez
The accelerating growth of scientific literature overwhelms our capacity to manually distil complex phenomena like molecular networks linked to diseases. Moreover, biases in biomedical research and database annotation limit our interpretation of facts and generation of hypotheses. ENQUIRE (Expanding Networks by Querying Unexpectedly Inter-Related Entities) offers a time- and resource-efficient alternative
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Deep plasma proteomics with data-independent acquisition: A fastlane towards biomarkers identification. bioRxiv. Syst. Biol. Pub Date : 2024-02-26 Bradley Ward, Sebastien Pyr dit Ruys, Jean-Luc Balligand, Leila Belkhir, Patrice D Cani, Jean-Francois Collet, Julien De Greef, Laurent Gatto, Vincent Haufroid, Sebastien Jodogne, Benoit Kabamba, Maxime Lingurski, Jean Cyr Yombi, Didier Vertommen, Laure Elens
Plasma proteomic is a precious tool in human disease research, but requires extensive sample preparation in order to perform in-depth analysis and biomarker discovery using traditional Data-Dependent Acquisition (DDA). Here, we highlight the efficacy of combining moderate plasma prefractionation and Data-Independent Acquisition (DIA) to significantly improve proteome coverage and depth, while remaining