scholarly journals Multiple sources of signal amplification within the B cell Ras/MAPK pathway

2018 ◽  
Author(s):  
Justin D. Mclaurin ◽  
Orion D. Weiner
Keyword(s):  
Positive Feedback ◽  
Signal Amplification ◽  
Mapk Pathway ◽  
Threshold Level ◽  
Cell Types ◽  
Multiple Sources ◽  
Analog To Digital ◽  
Ras Activation ◽  
Wide Range ◽  
Erk Activity

AbstractThe Ras-Map kinase (MAPK) cascade underlies functional decisions in a wide range of cell types and organisms. In B cells, positive feedback-driven Ras activation is the proposed source of the digital (all-or-none) MAPK responses following antigen stimulation. However, an inability to measure endogenous Ras activity in living cells has hampered our ability to test this model directly. Here we leverage biosensors of endogenous Ras and ERK activity to revisit this question. We find that BCR ligation drives switch-like Ras activation and that lower BCR signaling output is required for the maintenance versus the initiation of Ras activation. Surprisingly, digital ERK responses persist in the absence of positive feedback-mediated Ras activation, and digital ERK is observed at a threshold level of Ras activation. These data suggest an independent analog-to-digital switch downstream of Ras activation, and reveals that multiple sources of signal amplification exist within the Ras-ERK module of the BCR pathway.

scholarly journals Multiple sources of signal amplification within the B-cell Ras/MAPK pathway

2019 ◽  
Vol 30 (13) ◽  
pp. 1610-1620
Author(s):  
Justin D. Mclaurin ◽  
Orion D. Weiner
Keyword(s):  
B Cell ◽  
Positive Feedback ◽  
Signal Amplification ◽  
Mapk Pathway ◽  
Threshold Level ◽  
Cell Types ◽  
Cell Receptor ◽  
Multiple Sources ◽  
Ras Activation ◽  
Wide Range

The Ras-Map kinase (MAPK) cascade underlies functional decisions in a wide range of cell types and organisms. In B-cells, positive feedback-driven Ras activation is the proposed source of the digital (all or none) MAPK responses following antigen stimulation. However, an inability to measure endogenous Ras activity in living cells has hampered our ability to test this model directly. Here we leverage biosensors of endogenous Ras and ERK activity to revisit this question. We find that B-cell receptor (BCR) ligation drives switch-like Ras activation and that lower BCR signaling output is required for the maintenance versus the initiation of Ras activation. Surprisingly, digital ERK responses persist in the absence of positive feedback-mediated Ras activation, and digital ERK is observed at a threshold level of Ras activation. These data suggest an independent analogue-to-digital switch downstream of Ras activation and reveal that multiple sources of signal amplification exist within the Ras-ERK module of the BCR pathway.

scholarly journals The atlas of RNase H antisense oligonucleotide distribution and activity in the CNS of rodents and non-human primates following central administration

2020 ◽  
Author(s):  
Paymaan Jafar-nejad ◽  
Berit Powers ◽  
Armand Soriano ◽  
Hien Zhao ◽  
Daniel A Norris ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neurological Diseases ◽  
Cell Types ◽  
Rnase H ◽  
Central Administration ◽  
Spinal Motor Neurons ◽  
New Class ◽  
Wide Range ◽  
Therapeutic Development

Abstract Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.

scholarly journals Energetics of mesoscale cell turbulence in two-dimensional monolayers

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Shao-Zhen Lin ◽  
Wu-Yang Zhang ◽  
Dapeng Bi ◽  
Bo Li ◽  
Xi-Qiao Feng
Keyword(s):  
Kinetic Energy ◽  
Tumor Metastasis ◽  
Cell Types ◽  
Boltzmann Distribution ◽  
Scaling Exponent ◽  
Biological Processes ◽  
Two Dimensional ◽  
Cell Monolayers ◽  
Wide Range ◽  
Epithelial Cell Monolayers

AbstractInvestigation of energy mechanisms at the collective cell scale is a challenge for understanding various biological processes, such as embryonic development and tumor metastasis. Here we investigate the energetics of self-sustained mesoscale turbulence in confluent two-dimensional (2D) cell monolayers. We find that the kinetic energy and enstrophy of collective cell flows in both epithelial and non-epithelial cell monolayers collapse to a family of probability density functions, which follow the q-Gaussian distribution rather than the Maxwell–Boltzmann distribution. The enstrophy scales linearly with the kinetic energy as the monolayer matures. The energy spectra exhibit a power-decaying law at large wavenumbers, with a scaling exponent markedly different from that in the classical 2D Kolmogorov–Kraichnan turbulence. These energetic features are demonstrated to be common for all cell types on various substrates with a wide range of stiffness. This study provides unique clues to understand active natures of cell population and tissues.

scholarly journals Epigenetic control of pheromone MAPK signaling determines sexual fecundity inCandida albicans

2017 ◽  
Vol 114 (52) ◽  
pp. 13780-13785 ◽  
Author(s):  
Christine M. Scaduto ◽  
Shail Kabrawala ◽  
Gregory J. Thomson ◽  
William Scheving ◽  
Andy Ly ◽  
...  
Keyword(s):  
Candida Albicans ◽  
G Protein ◽  
Map Kinases ◽  
Mapk Pathway ◽  
Cell Types ◽  
Mapk Signaling ◽  
Toggle Switch ◽  
Β Subunit ◽  
Epigenetic Control ◽  
Incandida Albicans

Several pathogenicCandidaspecies are capable of heritable and reversible switching between two epigenetic states, “white” and “opaque.” InCandida albicans, white cells are essentially sterile, whereas opaque cells are mating-proficient. Here, we interrogate the mechanism by which the white-opaque switch regulates sexual fecundity and identify four genes in the pheromone MAPK pathway that are expressed at significantly higher levels in opaque cells than in white cells. These genes encode the β subunit of the G-protein complex (STE4), the pheromone MAPK scaffold (CST5), and the two terminal MAP kinases (CEK1/CEK2). To define the contribution of each factor to mating,C. albicanswhite cells were reverse-engineered to express elevated, opaque-like levels of these factors, either singly or in combination. We show that white cells co-overexpressingSTE4,CST5, andCEK2undergo mating four orders of magnitude more efficiently than control white cells and at a frequency approaching that of opaque cells. Moreover, engineered white cells recapitulate the transcriptional and morphological responses of opaque cells to pheromone. These results therefore reveal multiple bottlenecks in pheromone MAPK signaling in white cells and that alleviation of these bottlenecks enables efficient mating by these “sterile” cell types. Taken together, our findings establish that differential expression of several MAPK factors underlies the epigenetic control of mating inC. albicans. We also discuss how fitness advantages could have driven the evolution of a toggle switch to regulate sexual reproduction in pathogenicCandidaspecies.

Memories of Tiananmen

2021 ◽  
Author(s):  
Francis Lee ◽  
Joseph Man Chan
Keyword(s):  
Hong Kong ◽  
Collective Memory ◽  
Digital Media ◽  
Political Communication ◽  
Civil Liberties ◽  
Significant Degree ◽  
Historical Period ◽  
Multiple Sources ◽  
News Reports ◽  
Wide Range

This book analyzes how collective memory regarding the 1989 Beijing student movement and the Tiananmen crackdown was produced, contested, sustained, and transformed in Hong Kong between 1989 and 2019. Drawing on data gathered through multiple sources such as news reports, digital media content, vigil onsite surveys, population surveys, and in-depth interviews with activists, rally participants, and other stakeholders, it identifies six key processes in the dynamics of social remembering: memory formation, memory mobilization, memory institutionalization, intergenerational transfer, memory repair, and memory balkanization. Memories of Tiananmen demonstrates how a socially dominant collective memory, even one the state finds politically irritable, can be generated and maintained through constant negotiation and efforts by a wide range of actors. While the book mainly focuses on the interplay between political changes and Tiananmen commemoration in the historical period within which the society enjoyed a significant degree of civil liberties, it also discusses how the trajectory of the collective memory may take a drastic turn as Hong Kong's autonomy is abridged. The book promises to be a key reference for anyone interested in collective memory studies, social movement research, political communication, and China and Hong Kong studies.

Df31 is a novel nuclear protein involved in chromatin structure in Drosophila melanogaster

2001 ◽  
Vol 114 (1) ◽  
pp. 37-47 ◽  
Author(s):  
G. Crevel ◽  
H. Huikeshoven ◽  
S. Cotterill
Keyword(s):  
Cell Types ◽  
Drosophila Embryo ◽  
Cell Fractionation ◽  
General Function ◽  
Structural Protein ◽  
Chromosomal Structure ◽  
Binding Characteristics ◽  
Wide Range ◽  
Cellular Dna

We originally isolated the Df31 protein from Drosophila embryo extracts as a factor which could decondense Xenopus sperm, by removing the sperm specific proteins and interacting with histones to facilitate their loading onto DNA. We now believe that this protein has a more general function in cellular DNA metabolism. The Df31 gene encodes a very hydrophilic protein with a predicted molecular mass of 18.5 kDa. Immunostaining showed that Df31 was present in a wide range of cell types throughout differentiation and in both dividing and non-dividing cells. In all cases the protein is present in large amounts, comparable with the level of nucleosomes. Injection of antisense oligonucleotides to lower the level of Df31 in embryos caused severe disruption of the nuclear structure. Large irregular clumps of DNA were formed, and in most cases the amount of DNA associated with each clump was more than that found in a normal nucleus. Immunofluorescence, cell fractionation, and formaldehyde cross-linking show that Df31 is associated with chromatin and that a significant fraction of it binds very tightly. It also shows the same binding characteristics when loaded onto chromatin in vitro. Chromatin fractionation shows that Df31 is tightly associated with nucleosomes, preferentially with oligonucleosomes. Despite this no differences were observed in the properties of nucleosomes loaded in the in vitro system in the presence and absence of Df31. These results suggest that Df31 has a role in chromosomal structure, most likely acting as a structural protein at levels of folding higher than that of nucleosomes.

scholarly journals RNA-Seq Data-Mining Allows the Discovery of Two Long Non-Coding RNA Biomarkers of Viral Infection in Humans

2020 ◽  
Vol 21 (8) ◽  
pp. 2748 ◽  
Author(s):  
Ruth Barral-Arca ◽  
Alberto Gómez-Carballa ◽  
Miriam Cebey-López ◽  
María José Currás-Tuala ◽  
Sara Pischedda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Viral Infections ◽  
Umbilical Vein ◽  
Cell Types ◽  
Dermal Fibroblasts ◽  
Learning Approaches ◽  
Rna Seq ◽  
Wide Range ◽  
Healthy Control ◽  
Umbilical Vein Endothelial Cells

There is a growing interest in unraveling gene expression mechanisms leading to viral host invasion and infection progression. Current findings reveal that long non-coding RNAs (lncRNAs) are implicated in the regulation of the immune system by influencing gene expression through a wide range of mechanisms. By mining whole-transcriptome shotgun sequencing (RNA-seq) data using machine learning approaches, we detected two lncRNAs (ENSG00000254680 and ENSG00000273149) that are downregulated in a wide range of viral infections and different cell types, including blood monocluclear cells, umbilical vein endothelial cells, and dermal fibroblasts. The efficiency of these two lncRNAs was positively validated in different viral phenotypic scenarios. These two lncRNAs showed a strong downregulation in virus-infected patients when compared to healthy control transcriptomes, indicating that these biomarkers are promising targets for infection diagnosis. To the best of our knowledge, this is the very first study using host lncRNAs biomarkers for the diagnosis of human viral infections.

The Florey Lecture, 1988 - From egg to embryo: the initiation of cell differentiation in Amphibia

1989 ◽  
Vol 237 (1286) ◽  
pp. 11-25 ◽  
Keyword(s):  
Muscle Cell ◽  
Gene Activation ◽  
Cell Formation ◽  
Gene Promoter ◽  
Cell Types ◽  
Specific Gene ◽  
Embryonic Induction ◽  
Differentiated Cells ◽  
Wide Range ◽  
Muscle Genes

Some of the principles by which different cell types first arise at the beginning of animal development are illustrated by muscle cell formation in Amphibia. If the nucleus of a differentiated muscle cell is transplanted to an enucleated egg, some of the resulting embryos develop into tadpoles with a wide range of normally differentiated cells. These experiments show that genes undergo major changes in activity as a response to components of egg cytoplasm. Two fundamental mechanisms account for the regional activation of genes in early embryos. One involves the effect of localized ‘determinants’ in egg cytoplasm, and the other concerns cell interactions or embryonic induction. Both these mechanisms seem to be responsible for muscle cell formation in amphibian development. The old problem of embryonic induction has recently become accessible to analysis at the molecular level, especially in the case of the mesoderm or muscle-forming induction. This has been greatly facilitated by using a sensitive and quantitative assay to detect the first transcripts of muscle genes a few hours after the start of induction. The role of early events and of interactions among like cells during response to induction is discussed. In analysing specific gene activation following induction, DNA injection into fertilized eggs has shown that a very small part of the cardiac actin gene promoter is sufficient to enable it to respond to induction. Although the experimental work summarized here has been done on amphibian embryos, which are more suitable than other embryos for embryological manipulation, the conclusions reached are believed to be generally applicable to the development of other organisms.

scholarly journals Mapping calcium dynamics in a developing tubular structure

2020 ◽  
Author(s):  
Jorgen Hoyer ◽  
Morsal Saba ◽  
Daniel Dondorp ◽  
Kushal Kolar ◽  
Riccardo Esposito ◽  
...  
Keyword(s):  
Cell Types ◽  
Feedback Mechanism ◽  
Adult Brain ◽  
Actin Dynamics ◽  
Cytoskeletal Network ◽  
Notochord Cell ◽  
Wide Range ◽  
Store Operated Calcium Entry ◽  
And Function ◽  
Cell Intercalation

AbstractCalcium is a ubiquitous and versatile second messenger that plays a central role in the development and function of a wide range of cell types, tissues and organs. Despite significant recent progress in the understanding of calcium (Ca2+) signalling in organs such as the developing and adult brain, we have relatively little knowledge of the contribution of Ca2+ to the development of tubes, structures widely present in multicellular organisms. Here we image Ca2+ dynamics in the developing notochord of Ciona intestinalis. We show that notochord cells exhibit distinct Ca2+ dynamics during specific morphogenetic events such as cell intercalation, cell elongation and tubulogenesis. We used an optogenetically controlled Ca2+ actuator to show that sequestration of Ca2+ results in defective notochord cell intercalation, and pharmacological inhibition to reveal that stretch-activated ion channels (SACs), inositol triphosphate receptor (IP3R) signalling, Store Operated Calcium Entry (SOCE), Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and gap junctions are required for regulating notochord Ca2+ activity during tubulogenesis. Cytoskeletal rearrangements drive the cell shape changes that accompany tubulogenesis. In line with this, we show that Ca2+ signalling modulates reorganization of the cytoskeletal network across the morphogenetic events leading up to and during tubulogenesis of the notochord. We additionally demonstrate that perturbation of the actin cytoskeleton drastically remodels Ca2+ dynamics, suggesting a feedback mechanism between actin dynamics and Ca2+ signalling during notochord development. This work provides a framework to quantitatively define how Ca2+ signalling regulates tubulogenesis using the notochord as model organ, a defining structure of all chordates.

scholarly journals Comparison and evaluation of statistical error models for scRNA-seq

2021 ◽  
Author(s):  
Saket Choudhary ◽  
Rahul Satija
Keyword(s):  
Linear Models ◽  
Negative Binomial ◽  
Statistical Error ◽  
Rna Seq ◽  
Multiple Sources ◽  
Error Models ◽  
Wide Range ◽  
Data Driven Approach ◽  
Downstream Analysis ◽  
Experimental Processing

Heterogeneity in single-cell RNA-seq (scRNA-seq) data is driven by multiple sources, including biological variation in cellular state as well as technical variation introduced during experimental processing. Deconvolving these effects is a key challenge for preprocessing workflows. Recent work has demonstrated the importance and utility of count models for scRNA-seq analysis, but there is a lack of consensus on which statistical distributions and parameter settings are appropriate. Here, we analyze 58 scRNA-seq datasets that span a wide range of technologies, systems, and sequencing depths in order to evaluate the performance of different error models. We find that while a Poisson error model appears appropriate for sparse datasets, we observe clear evidence of overdispersion for genes with sufficient sequencing depth in all biological systems, necessitating the use of a negative binomial model. Moreover, we find that the degree of overdispersion varies widely across datasets, systems, and gene abundances, and argues for a data-driven approach for parameter estimation. Based on these analyses, we provide a set of recommendations for modeling variation in scRNA-seq data, particularly when using generalized linear models or likelihood-based approaches for preprocessing and downstream analysis.

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