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How Retroactivity Affects the Behavior of Incoherent Feed-Forward Loops

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arXiv 2020年

作者： Wang, Junmin Belta, Calin Isaacson, Samuel A. Bioinformatics Graduate Program Boston University BostonMA United States Department of Mathematics and Statistics Boston University BostonMA United States

An incoherent feed-forward loop (IFFL) is a network motif known for its ability to accelerate responses and generate pulses. Though functions of IFFLs are well studied, most previous computational analysis of IFFLs used ordinary differential equation (ODE) models where retroactivity, the effect downstream binding sites exert on the dynamics of an upstream transcription factor (TF), was not considered. It remains an open question to understand the behavior of IFFLs in contexts with high levels of retroactivity, e.g., in cells transformed/transfected with high-copy plasmids, or in eukaryotic cells where a TF binds to numerous high-affinity binding sites in addition to one or more functional target sites. Here we study the behavior of IFFLs by simulating and comparing ODE models with different levels of retroactivity. We find that increasing retroactivity in an IFFL can increase, decrease, or keep the network’s response time and pulse amplitude constant. This suggests that increasing retroactivity, traditionally considered as an impediment to designing robust synthetic systems, could be exploited to improve the performance of IFFLs. We compare the behaviors of IFFLs to negative autoregulatory loops, another sign-sensitive response-accelerating network motif, and find that increasing retroactivity in a negative autoregulated circuit can only slow the response. The inability of a negative autoregulatory loop to flexibly handle retroactivity may have contributed to its lower abundance in eukaryotic relative to bacterial regulatory networks, a sharp contrast to the significant abundance of IFFLs in both cell types. Copyright © 2020, The Authors. All rights reserved.

关键词： Transcription

Pinned, locked, pushed, and pulled traveling waves in structured environments

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arXiv 2018年

作者： Wang, Ching-Hao Matin, Sakib George, Ashish B. Korolev, Kirill S. Department of Physics Boston University BostonMA02215 United States Department of Physics and Graduate Program in Bioinformatics Boston University BostonMA02215

Traveling fronts describe the transition between two alternative states in a great number of physical and biological systems. Examples include the spread of beneficial mutations, chemical reactions, and the invasions by foreign species. In homogeneous environments, the alternative states are separated by a smooth front moving at a constant velocity. This simple picture can break down in structured environments such as tissues, patchy landscapes, and microfluidic devices. Habitat fragmentation can pin the front at a particular location or lock invasion velocities into specific values. Locked velocities are not sensitive to moderate changes in dispersal or growth and are determined by the spatial and temporal periodicity of the environment. The synchronization with the environment results in discontinuous fronts that propagate as periodic pulses. We characterize the transition from continuous to locked invasions and show that it is controlled by positive density-dependence in dispersal or growth. We also demonstrate that velocity locking is robust to demographic and environmental fluctuations and examine stochastic dynamics and evolution in locked invasions. Copyright © 2018, The Authors. All rights reserved.

关键词： Velocity

Mechanically-driven growth and competition in a Voronoi model of tissues

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arXiv 2024年

作者： Brézin, Louis Korolev, Kirill S. Department of Physics Graduate Program in Bioinformatics Biological Design Center Boston University BostonMA02215 United States

The mechanisms leading cells to acquire a fitness advantage and establish themselves in a population are paramount to understanding the development and growth of cancer. Although there are many works that study separately either the evolutionary dynamics or the mechanics of cancer, little has been done to couple evolutionary dynamics to mechanics. To address this question, we study a confluent model of tissue using a Self-Propelled Voronoi (SPV) model with stochastic growth rates that depend on the mechanical variables of the system. The SPV model is an out-of-equilibrium model of tissue derived from an energy functional that has a jamming/unjamming transition between solid-like and liquid-like states. By considering several scenarios of mutants invading a resident population in both phases, we determine the range of parameters that confer a fitness advantage and show that the preferred area and perimeter are the most relevant ones. We find that the liquid-like state is more resistant to invasion and show that the outcome of the competition can be determined from the simulation of a non-growing mixture. Moreover, a mean-field approximation can accurately predict the fate of a mutation affecting mechanical properties of a cell. Our results can be used to infer evolutionary dynamics from tissue images, understand cancer-suppressing effects of tissue mechanics, and even search for mechanics-based therapies. © 2024, CC BY.

关键词： Tissue

Differentiation and Integration of Machine Learning Feature Vectors

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Differentiation and Integration of Machine Learning Feature ...

International Conference on Machine Learning and Applications (ICMLA)

作者： Xinying Mu Ana B. Pavel Mark Kon Department of Mathematics and Statistics Boston University Boston MA Graduate Program in Bioinformatics Boston University Boston MA Section of Computational Biomedicine School of Medicine Boston MA

ISBN: (纸本)9781509061686

This paper presents a new approach to the production of feature maps for the improvement of classification in machine learning. The idea is based on a calculus of differentiation and integration of feature vectors, which can be viewed as functions on a metric space or network. Based on this we propose a novel network-based binary machine learning classifier. We illustrate our method using molecular networks alone to distinguish phenotypes, including cancer types and subtypes. We include feature sets derived from disease-specific gene co-expression networks in different cancer data sets using The Cancer Genome Atlas (TCGA) along with other previously published studies. We also illustrate our network-based predictor on another data type, based on infrared spectroscopy of lung cancer tissue.

关键词： Cancer Gene expression Correlation Lungs Kernel Laplace equations Proteins

Chirality provides a direct fitness advantage and facilitates intermixing in cellular aggregates

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arXiv 2017年

作者： George, Ashish B. Korolev, Kirill S. Department of Physics Boston University BostonMA02215 United States Department of Physics Graduate Program in Bioinformatics Boston University BostonMA02215 United States

Short Abstract: Is it better to be left- or right-handed? The answer depends on whether the goal is making a handshake or winning a boxing match. The need for coordination favors the handedness of the majority, but being different could also provide an advantage. The same rules could apply to microbial colonies and cancer tumors. Like humans, cells often have handedness (chirality) that reflects the lack of mirror symmetry in their shapes or movement patterns. We find that cells gain a substantial fitness advantage by either increasing the magnitude of their chirality or switching to the opposite handedness. Selection for specific chirality is mediated by the formation of bulges along the colony edge in regions where cells with different chiralities meet. Long Abstract: Chirality in shape and motility can evolve rapidly in microbes and cancer cells. To determine how chirality affects cell fitness, we developed a model of chiral growth in compact aggregates such as microbial colonies and solid tumors. Our model recapitulates previous experimental findings and shows that mutant cells can invade by increasing their chirality or switching their handedness. The invasion results either in a takeover or stable coexistence between the mutant and the ancestor depending on their relative chirality. For large chiralities, the coexistence is accompanied by strong intermixing between the cells, while spatial segregation occurs otherwise. We show that the competition within the aggregate is mediated by bulges in regions where the cells with different chiralities meet. The two-way coupling between aggregate shape and natural selection is described by the chiral Kardar-Parisi-Zhang equation coupled to the Burgers' equation with multiplicative noise. We solve for the key features of this theory to explain the origin of selection on chirality. Overall, our work suggests that chirality could be an important ecological trait that mediates competition, invasion, and spatial structure in

关键词： Chirality

Interactions between species introduce spurious associations in microbiome studies

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arXiv 2017年

作者： Menon, Rajita Ramanan, Vivek Korolev, Kirill S. Department of Physics Boston University BostonMA United States BRITE Bioinformatics REU Program Boston University BostonMA United States Graduate Program in Bioinformatics Boston University BostonMA United States Department of Biology and Computer Science Swarthmore College SwarthmorePA United States

Microbiota contribute to many dimensions of host phenotype, including disease. To link specific microbes to specific phenotypes, microbiome-wide association studies compare microbial abundances between two groups of samples. Abundance differences, however, reflect not only direct associations with the phenotype, but also indirect effects due to microbial interactions. We found that microbial interactions could easily generate a large number of spurious associations that provide no mechanistic insight. Using techniques from statistical physics, we developed a method to remove indirect associations and applied it to the largest dataset on pediatric inflammatory bowel disease. Our method corrected the inflation of p-values in standard association tests and showed that only a small subset of associations is directly linked to the disease. Direct associations had a much higher accuracy in separating cases from controls and pointed to immunomodulation, butyrate production, and the brain-gut axis as important factors in the inflammatory bowel disease. Copyright © 2017, The Authors. All rights reserved.

关键词： Association reactions

METTL4 is an snRNA m6 Am methyltransferase that regulates RNA splicing

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细胞研究（英文版） 2020年第6期30卷 544-547页

作者： Hao Chen Lei Gu Esteban A.Orellana Yuanyuan Wang Jiaojiao Guo Qi Liu Longfei Wang Zhangfei Shen Hao Wu Richard I.Gregory Yi Xing Yang Shi Division of Newborn Medicine and Program in Epigenetics Boston Children's Hospital Harvard Medical School 300 Longwood AvenueBoston MA 02115 USA Stem Cell Program Division of Hematology/Oncology Boston Children's Hospital Department of Biological Chemistry and Molecular Pharmacology Harvard Medical SchoolBoston MA 02115 USA Bioinformatics Interdepartmental Graduate Program University of California Los Angeles Los Angeles CA 90095USA College of Science Northeastern University 360 Huntington Ave. Boston MA 02115 USA Program in Cellular and Molecular Medicine Boston Children's Hospital Boston MA 02115 USA Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston MA 02115 USA Division of Newborn Medicine and Program in Epigenetics Boston Children's Hospital Harvard Medical School 300 Longwood AvenueBoston MA 02115 USA Program in Cellular and Molecular Medicine Boston Children's Hospital Boston MA 02115 USA Department of Biological Chemistry and Molecular Pharmacology Harvard Medical School Boston MA 02115 USA Center for Computational and Genomic Medicine The Children's Hospital of Philadelphia Philadelphia PA 19104 USA Department of Pathology and Laboratory Medicine University of PennsylvaniaPhiladelphia PA 19104 USA

Dear Editor, Protein coding mRNAs and non-coding RNAs are extensively modified by chemical modifications,1 including methylation of the N6 position of adenosine (m6A).2 While mRNA internal m6A methylation is mediated by METTL3 and METTL14, which are members of the MT-A70 family,2 N6-methylation of cap-adjacent N6,2'-O-dimethyladenosine (m6Am) is catalyzed by PCIF1.3-6 Non-coding RNAs are also m6Am methylated internally,7 but the corresponding enzyme remains *** we provide evidence that METTL4 mediates internal m6Am methylation of U2 small nuclear RNA (snRNA).

关键词： Epigenetics RNA modification RNA splicing

Single-cell analysis of experience-dependent transcriptomic states in the mouse visual cortex (vol 21, pg 120, 2018)

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NATURE NEUROSCIENCE 2018年第7期21卷 1017-1017页

作者： Hrvatin, Sinisa Hochbaum, Daniel R. Nagy, M. Aurel Cicconet, Marcelo Robertson, Keiramarie Cheadle, Lucas Zilionis, Rapolas Ratner, Alex Borges-Monroy, Rebeca Klein, Allon M. Sabatini, Bernardo L. Greenberg, Michael E. Department of Neurobiology Harvard Medical School Boston MA USA Society of Fellows Harvard University Cambridge MA USA Department of Neurobiology Howard Hughes Medical Institute Harvard Medical School Boston MA USA Image and Data Analysis Core Harvard Medical School Boston MA USA Department of Systems Biology Harvard Medical School Boston MA USA Vilnius University Institute of Biotechnology Vilnius Lithuania ICCB-L Single Cell Core Harvard Medical School Boston MA USA Program for Bioinformatics and Integrative Genomics Graduate School of Arts and Science Division of Medical Sciences Harvard University Cambridge MA USA

Activity-dependent transcriptional responses shape cortical function. However, a comprehensive understanding of the diversity of these responses across the full range of cortical cell types, and how these changes contribute to neuronal plasticity and disease, is lacking. To investigate the breadth of transcriptional changes that occur across cell types in the mouse visual cortex after exposure to light, we applied high-throughput single-cell RNA sequencing. We identified significant and divergent transcriptional responses to stimulation in each of the 30 cell types characterized, thus revealing 611 stimulus-responsive genes. Excitatory pyramidal neurons exhibited inter- and intralaminar heterogeneity in the induction of stimulus-responsive genes. Non-neuronal cells showed clear transcriptional responses that may regulate experience-dependent changes in neurovascular coupling and myelination. Together, these results reveal the dynamic landscape of the stimulus-dependent transcriptional changes occurring across cell types in the visual cortex; these changes are probably critical for cortical function and may be sites of deregulation in developmental brain disorders.

关键词： Gene expression analysis Molecular neuroscience Oligodendrocyte Transcriptomics Visual system

Genetic load makes cancer cells more sensitive to common drugs: Evidence from Cancer Cell Line Encyclopedia

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arXiv 2017年

作者： Pavel, Ana B. Korolev, Kirill S. Graduate Program in Bioinformatics Boston University 44 Cummington Mall BostonMA02215 United States Department of Physics Boston University 590 Commonwealth Avenue BostonMA02215 United States

Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, that provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer. Copyright © 2017, The Authors. All rights reserved.

关键词： Tumors