scholarly journals A flexible ontology for inference of emergent whole cell function from relationships between subcellular processes

2017 ◽  
Author(s):  
Jens Hansen ◽  
David Meretzky ◽  
Simeneh Woldesenbet ◽  
Gustavo Stolovitzky ◽  
Ravi Iyengar
Keyword(s):  
Cell Biology ◽  
Cell Function ◽  
Biological Knowledge ◽  
Dependent Manner ◽  
Whole Cell ◽  
Cell Functions ◽  
Cell Responses ◽  
Growing Cell ◽  
Cell Ontology ◽  
Context Specific

AbstractWhole cell responses arise from coordinated interactions between diverse human gene products functioning within various pathways underlying sub-cellular processes (SCP). Lower level SCPs interact to form higher level SCPs, often in a context specific manner to give rise to whole cell function. We sought to determine if capturing such relationships enables us to describe the emergence of whole cell functions from interacting SCPs. We developed the “Molecular Biology of the Cell” ontology based on standard cell biology and biochemistry textbooks and review articles. Currently, our ontology contains 5,385 genes, 753 SCPs and 19,180 expertly curated gene-SCP associations. Our algorithm to populate the SCPs with genes enables extension of the ontology on demand and the adaption of the ontology to the continuously growing cell biological knowledge. Since whole cell responses most often arise from the coordinated activity of multiple SCPs, we developed a dynamic enrichment algorithm that flexibly predicts SCP-SCP relationships beyond the current taxonomy. This algorithm enables us to identify interactions between SCPs as a basis for higher order function in a context dependent manner, allowing us to provide a detailed description of how SCPs together can give rise to whole cell functions. We conclude that this ontology can, from omics data sets, enable the development of detailed multidimensional SCP networks for predictive modeling of emergent whole cell functions.

scholarly journals Glucose Triggers ATP Secretion from Bacteria in a Growth-Phase-Dependent Manner

2013 ◽  
Vol 79 (7) ◽  
pp. 2328-2335 ◽  
Author(s):  
Ippei Hironaka ◽  
Tadayuki Iwase ◽  
Shinya Sugimoto ◽  
Ken-ichi Okuda ◽  
Akiko Tajima ◽  
...  
Keyword(s):  
Stationary Phase ◽  
Growth Phase ◽  
Cell Function ◽  
Immune Cell ◽  
Dependent Manner ◽  
T Helper 17 ◽  
Content Type ◽  
Cell Functions ◽  
Atp Secretion ◽  
Enterococcus Gallinarum

ABSTRACTATP modulates immune cell functions, and ATP derived from gut commensal bacteria promotes the differentiation of T helper 17 (Th17) cells in the intestinal lamina propria. We recently reported thatEnterococcus gallinarum, isolated from mice and humans, secretes ATP. We have since found and characterized several ATP-secreting bacteria. Of the tested enterococci,Enterococcus mundtiisecreted the greatest amount of ATP (>2 μM/108cells) after overnight culture. Glucose, not amino acids and vitamins, was essential for ATP secretion fromE. mundtii. Analyses of energy-deprived cells demonstrated that glycolysis is the most important pathway for bacterial ATP secretion. Furthermore, exponential-phaseE. mundtiiandEnterococcus faecaliscells secrete ATP more efficiently than stationary-phase cells. Other bacteria, includingPseudomonas aeruginosa,Escherichia coli, andStaphylococcus aureus, also secrete ATP in exponential but not stationary phase. These results suggest that various gut bacteria, including commensals and pathogens, might secrete ATP at any growth phase and modulate immune cell function.

scholarly journals Mechanical stretch scales centriole number to apical area via Piezo1 in multiciliated cells

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Saurabh Suhas Kulkarni ◽  
Jonathan Marquez ◽  
Priya P Date ◽  
Rosa Ventrella ◽  
Brian Mitchell ◽  
...  
Keyword(s):  
Cell Biology ◽  
Potential Role ◽  
Cell Function ◽  
Mechanical Stretch ◽  
Mechanical Forces ◽  
Dependent Manner ◽  
Multiciliated Cells ◽  
Tensile Forces ◽  
Mechanosensitive Ion Channel ◽  
Apical Area

How cells count and regulate organelle number is a fundamental question in cell biology. For example, most cells restrict centrioles to two in number and assemble one cilium; however, multiciliated cells (MCCs) synthesize hundreds of centrioles to assemble multiple cilia. Aberration in centriole/cilia number impairs MCC function and can lead to pathological outcomes. Yet how MCCs control centriole number remains unknown. Using Xenopus, we demonstrate that centriole number scales with apical area over a remarkable 40-fold change in size. We find that tensile forces that shape the apical area also trigger centriole amplification based on both cell stretching experiments and disruption of embryonic elongation. Unexpectedly, Piezo1, a mechanosensitive ion channel, localizes near each centriole suggesting a potential role in centriole amplification. Indeed, depletion of Piezo1 affects centriole amplification and disrupts its correlation with the apical area in a tension dependent manner. Thus, mechanical forces calibrate cilia/centriole number to the MCC apical area via Piezo1. Our results provide new perspectives to study organelle number control essential for optimal cell function.

scholarly journals Increasing consensus of context-specific metabolic models by integrating data-inferred cell functions

2018 ◽  
Author(s):  
Anne Richelle ◽  
Austin W.T. Chiang ◽  
Chih-Chung Kuo ◽  
Nathan E. Lewis
Keyword(s):  
Cell Lines ◽  
Cell Types ◽  
Extraction Methods ◽  
Specific Model ◽  
Biological Knowledge ◽  
Predictive Capacity ◽  
Cell Functions ◽  
Metabolic Models ◽  
Context Specific ◽  
Diverse Context

AbstractGenome-scale metabolic models provide a valuable context for analyzing data from diverse high-throughput experimental techniques. Models can quantify the activities of diverse pathways and cellular functions. Since some metabolic reactions are only catalyzed in specific environments, several algorithms exist that build context-specific models. However, these methods make differing assumptions that influence the content and associated predictive capacity of resulting models, such that model content varies more due to methods used than cell types. Here we overcome this problem with a novel framework for inferring the metabolic functions of a cell before model construction. For this, we curated a list of metabolic tasks and developed a framework to infer the activity of these functionalities from transcriptomic data. We protected the data-inferred tasks during the implementation of diverse context-specific model extraction algorithms for 44 cancer cell lines. We show that the protection of data-inferred metabolic tasks decreases the variability of models across extraction methods. Furthermore, resulting models better capture the actual biological variability across cell lines. This study highlights the potential of using biological knowledge, inferred from omics data, to obtain a better consensus between existing extraction algorithms. It further provides guidelines for the development of the next-generation of data contextualization methods.

scholarly journals MiR-23~27~24–mediated control of humoral immunity reveals a TOX-driven regulatory circuit in follicular helper T cell differentiation

2019 ◽  
Vol 5 (12) ◽  
pp. eaaw1715 ◽  
Author(s):  
Cheng-Jang Wu ◽  
Sunglim Cho ◽  
Hsi-Yuan Huang ◽  
Chun-Hao Lu ◽  
Jasmin Russ ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Humoral Immunity ◽  
Cell Biology ◽  
Dependent Manner ◽  
Cell Responses ◽  
Follicular Helper ◽  
Regulatory Circuit ◽  
Follicular Helper T Cell ◽  
Immune Challenges ◽  
And Function

Follicular helper T (TFH) cells are essential for generating protective humoral immunity. To date, microRNAs (miRNAs) have emerged as important players in regulating TFH cell biology. Here, we show that loss of miR-23~27~24 clusters in T cells resulted in elevated TFH cell frequencies upon different immune challenges, whereas overexpression of this miRNA family led to reduced TFH cell responses. Mechanistically, miR-23~27~24 clusters coordinately control TFH cells through targeting a network of genes that are crucial for TFH cell biology. Among them, thymocyte selection–associated HMG-box protein (TOX) was identified as a central transcription regulator in TFH cell development. TOX is highly up-regulated in both mouse and human TFH cells in a BCL6-dependent manner. In turn, TOX promotes the expression of multiple molecules that play critical roles in TFH cell differentiation and function. Collectively, our results establish a key miRNA regulon that maintains optimal TFH cell responses for resultant humoral immunity.

New views inside cells with a digital imaging microscope

1991 ◽  
Vol 49 ◽  
pp. 240-241
Author(s):  
F. S. Fay ◽  
Kevin Fogarty ◽  
Richard Tuft ◽  
Walter Carrington
Keyword(s):  
Digital Imaging ◽  
Cell Biology ◽  
Cell Function ◽  
Single Cells ◽  
Low Noise ◽  
Molecular Composition ◽  
Specific Cell ◽  
Wide Field ◽  
High Quantum Efficiency ◽  
Cell Functions

Many current questions in cell biology revolve around questions regarding how changes in cell function are caused by changes in their molecular composition. Given that cells are highly organized structures often carrying out diverse functions in different compartments, it follows that changes in specific cell functions must involve highly localized changes in molecular composition.We have been involved in the development of the digital imaging microscope as a tool to investigate the distribution of molecules inside single living cells. The system measures fluorescence of probes that are highly fluorescent and specific for a molecule or ion of interest and utilizes a wide-field rather than a confocal microscope to produce an image of fluorescence in a single cell. The image is captured by a high quantum efficiency, low noise cooled CCD, thereby providing ultrahigh efficiency in the acquisition of fluorescent images. By utilizing very powerful light sources, the system is capable of generating an image with good signal-to-noise ratio in a millisecond or less, thereby allowing one to follow extremely rapid changes in molecular or ion distribution in single cells.

scholarly journals Yap suppresses T cell function and infiltration in the tumor microenvironment

2019 ◽  
Author(s):  
Eleni Stampouloglou ◽  
Anthony Federico ◽  
Emily Slaby ◽  
Stefano Monti ◽  
Gregory L. Szeto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
T Cell Activation ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
T Cell Responses ◽  
Negative Regulator ◽  
Cell Responses

ABSTRACTA major challenge for cancer immunotherapy is sustaining T cell activation and recruitment in immunosuppressive solid tumors. Here we report that Yap levels are sharply induced upon activation of CD4+ and CD8+ T cells and that Yap functions as an immunosuppressive factor and inhibitor of effector differentiation. Loss of Yap in T cells results in enhanced T cell activation, differentiation and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors. Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T cell responses in the tumor microenvironment and as a key negative regulator of T cell tumor infiltration and patient survival in diverse human cancers. Collectively, our results indicate that Yap plays critical roles in T cell biology, and suggest that inhibiting Yap activity improves T cell responses in cancer.

scholarly journals Sources of variability in cytosolic calcium transients triggered by stimulation of homogeneous uro-epithelial cell monolayers

2015 ◽  
Vol 12 (105) ◽  
pp. 20141403 ◽  
Author(s):  
Peter A. Appleby ◽  
Saqib Shabir ◽  
Jennifer Southgate ◽  
Dawn Walker
Keyword(s):  
Cell Biology ◽  
Mean Field ◽  
Population Level ◽  
Cytosolic Calcium ◽  
Calcium Transients ◽  
Local Context ◽  
Epithelial Tissue ◽  
Specific Cell ◽  
Cell Responses ◽  
Context Specific

Epithelial tissue structure is the emergent outcome of the interactions between large numbers of individual cells. Experimental cell biology offers an important tool to unravel these complex interactions, but current methods of analysis tend to be limited to mean field approaches or representation by selected subsets of cells. This may result in bias towards cells that respond in a particular way and/or neglect local, context-specific cell responses. Here, an automated algorithm was applied to examine in detail the individual calcium transients evoked in genetically homogeneous, but asynchronous populations of cultured non-immortalized normal human urothelial cells when subjected to either the global application of an external agonist or a localized scratch wound. The recorded calcium transients were classified automatically according to a set of defined metrics and distinct sub-populations of cells that responded in qualitatively different ways were observed. The nature of this variability in the homogeneous cell population was apportioned to two sources: intrinsic variation in individual cell responses and extrinsic variability due to context-specific factors of the environment, such as spatial heterogeneity. Statistically significant variation in the features of the calcium transients evoked by scratch wounding according to proximity to the wound edge was identified. The manifestation of distinct sub-populations of cells is considered central to the coordination of population-level response resulting in wound closure.

scholarly journals Decorin promotes apoptosis and autophagy via suppressing c-Met in HTR-8 trophoblasts

Reproduction ◽  
2020 ◽  
Vol 159 (6) ◽  
pp. 669-677 ◽  
Author(s):  
Yeping Wang ◽  
Hongping Zhang ◽  
Yuehui Zhang ◽  
Xiaoqing Li ◽  
Xianqing Hu ◽  
...  
Keyword(s):  
Prolonged Exposure ◽  
Cell Function ◽  
Annexin V ◽  
Dependent Manner ◽  
Aberrant Expression ◽  
Cellular Processes ◽  
Cell Functions ◽  
Downstream Effectors ◽  
Scratch Wound ◽  
Proliferation And Invasion

Decorin (DCN) regulates a vast array of cellular processes including proliferation, migration, apoptosis, and autophagy, and its aberrant expression has been associated with poor extravillous trophoblasts (EVT) invasion of the uterus, which underlies the occurrence of preeclampsia (PE) and intrauterine growth restriction (IUGR). In this study, we aim to elucidate the molecular mechanism of how the DCN regulates the cell functions through the use of trophoblast cell line, HTR-8. Using a series of cell function assays, including CCK8, RTCA, transwell, scratch-wound assay, and Annexin V staining, we found that DCN suppressed proliferation and invasion, while promoted autophagy and apoptosis of HTR-8 in a dose-dependent manner. Transient stimulation of DCN have increased the activity of c-Met and its downstream effectors – Akt, FAK and m-TOR. However, a prolonged exposure to DCN have significantly downregulated the expression of c-Met, leading to suppression of its downstream effectors. Lentivirus that overexpressed c-Met targeting shRNA was used to knockdown c-Met expression and crizotinib was used to selectively inhibit the kinase activity of c-Met in HTR-8 cells. A combination of DCN and c-Met knockdown/inhibition have reduced the proliferation and invasion in HTR-8 cells; however, DCN-induced autophagy and apoptosis were not synergistically enhanced by c-Met inhibition. In conclusion, DCN promotes autophagy and apoptosis predominantly through downregulating c-Met/Akt/mTOR activity in human trophoblasts.

scholarly journals The Nuclear Option: Evidence Implicating the Cell Nucleus in Mechanotransduction

2017 ◽  
Vol 139 (2) ◽  
Author(s):  
Spencer E. Szczesny ◽  
Robert L. Mauck
Keyword(s):  
Nuclear Envelope ◽  
Mathematical Models ◽  
Cell Nucleus ◽  
Cell Biology ◽  
Cell Function ◽  
Mechanical Stimuli ◽  
Cell Functions ◽  
External Forces ◽  
Nuclear Remodeling

Biophysical stimuli presented to cells via microenvironmental properties (e.g., alignment and stiffness) or external forces have a significant impact on cell function and behavior. Recently, the cell nucleus has been identified as a mechanosensitive organelle that contributes to the perception and response to mechanical stimuli. However, the specific mechanotransduction mechanisms that mediate these effects have not been clearly established. Here, we offer a comprehensive review of the evidence supporting (and refuting) three hypothetical nuclear mechanotransduction mechanisms: physical reorganization of chromatin, signaling at the nuclear envelope, and altered cytoskeletal structure/tension due to nuclear remodeling. Our goal is to provide a reference detailing the progress that has been made and the areas that still require investigation regarding the role of nuclear mechanotransduction in cell biology. Additionally, we will briefly discuss the role that mathematical models of cell mechanics can play in testing these hypotheses and in elucidating how biophysical stimulation of the nucleus drives changes in cell behavior. While force-induced alterations in signaling pathways involving lamina-associated polypeptides (LAPs) (e.g., emerin and histone deacetylase 3 (HDAC3)) and transcription factors (TFs) located at the nuclear envelope currently appear to be the most clearly supported mechanism of nuclear mechanotransduction, additional work is required to examine this process in detail and to more fully test alternative mechanisms. The combination of sophisticated experimental techniques and advanced mathematical models is necessary to enhance our understanding of the role of the nucleus in the mechanotransduction processes driving numerous critical cell functions.

scholarly journals Active Compound of Pharbitis Semen (Pharbitis nil Seeds) Suppressed KRAS-Driven Colorectal Cancer and Restored Muscle Cell Function during Cancer Progression

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2864 ◽  
Author(s):  
Jisu Song ◽  
Heejung Seo ◽  
Mi-Ryung Kim ◽  
Sang-Jae Lee ◽  
Sooncheol Ahn ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Muscle Cell ◽  
Cancer Progression ◽  
Active Compound ◽  
Cell Function ◽  
Morning Glory ◽  
Pharbitis Nil ◽  
Dependent Manner ◽  
Cell Functions ◽  
Starting Point

Kirsten rat sarcoma viral oncogene homolog (KRAS)-driven colorectal cancer (CRC) is notorious to target with drugs and has shown ineffective treatment response. The seeds of Pharbitis nil, also known as morning glory, have been used as traditional medicine in East Asia. We focused on whether Pharbitis nil seeds have a suppressive effect on mutated KRAS-driven CRC as well as reserving muscle cell functions during CRC progression. Seeds of Pharbitis nil (Pharbitis semen) were separated by chromatography and the active compound of Pharbitis semen (PN) was purified by HPLC. The compound PN efficiently suppressed the proliferation of mutated KRAS-driven CRC cells and their clonogenic potentials in a concentration-dependent manner. It also induced apoptosis of SW480 human colon cancer cells and cell cycle arrest at the G2/M phase. The CRC related pathways, including RAS/ERK and AKT/mTOR, were assessed and PN reduced the phosphorylation of AKT and mTOR. Furthermore, PN preserved muscle cell proliferation and myotube formation in cancer conditioned media. In summary, PN significantly suppressed mutated KRAS-driven cell growth and reserved muscle cell function. Based on the current study, PN could be considered as a promising starting point for the development of a nature-derived drug against KRAS-mutated CRC progression.

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