scholarly journals A molecular mechanism for probabilistic bet hedging and its role in viral latency

2020 ◽  
Vol 117 (29) ◽  
pp. 17240-17248 ◽  
Author(s):  
Sonali Chaturvedi ◽  
Jonathan Klein ◽  
Noam Vardi ◽  
Cynthia Bolovan-Fritts ◽  
Marie Wolf ◽  
...  
Keyword(s):  
Viral Replication ◽  
Molecular Mechanisms ◽  
Environmental Variability ◽  
Phenotypic Variability ◽  
Viral Latency ◽  
Human Herpesvirus ◽  
Bet Hedging ◽  
Large Variability ◽  
Superresolution Imaging ◽  
Extreme Variability

Probabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Superresolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein—the major viral transactivator protein—exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.

scholarly journals A Molecular Mechanism for Probabilistic Bet-hedging and its Role in Viral Latency

2020 ◽  
Author(s):  
Sonali Chaturvedi ◽  
Jonathan Klein ◽  
Noam Vardi ◽  
Cynthia Bolovan-Fritts ◽  
Marie Wolf ◽  
...  
Keyword(s):  
Viral Replication ◽  
Molecular Mechanisms ◽  
Environmental Variability ◽  
Phenotypic Variability ◽  
Viral Latency ◽  
Human Herpesvirus ◽  
Super Resolution ◽  
Bet Hedging ◽  
Large Variability ◽  
Unpredictable Environments

ABSTRACTProbabilistic bet hedging, a strategy to maximize fitness in unpredictable environments by matching phenotypic variability to environmental variability, is theorized to account for the evolution of various fate-specification decisions, including viral latency. However, the molecular mechanisms underlying bet-hedging remain unclear. Here, we report that large variability in protein abundance within individual herpesvirus virion particles enables probabilistic bet hedging between viral replication and latency. Super-resolution imaging of individual virions of the human herpesvirus cytomegalovirus (CMV) showed that virion-to-virion levels of pp71 tegument protein—the major viral transactivator protein—exhibit extreme variability. This super-Poissonian tegument variability promoted alternate replicative strategies: high virion pp71 levels enhance viral replicative fitness but, strikingly, impede silencing, whereas low virion pp71 levels reduce fitness but promote silencing. Overall, the results indicate that stochastic tegument packaging provides a mechanism enabling probabilistic bet hedging between viral replication and latency.SIGNIFICANCEProbabilistic bet hedging is a generalized diversification strategy to maximize fitness in unpredictable environments, and has been proposed as an evolutionary basis for herpesvirus latency. However, the molecular mechanisms enabling probabilistic bet hedging have remained elusive. Here, we find that the human herpesvirus cytomegalovirus—a major cause of birth defects and transplant failures—utilizes stochastic variability in the abundance of a protein packaged into individual viral particles to enable probabilistic bet hedging between alternate viral states.

TAMM HORSFALL PROTEIN: THE MEN BEHIND THE EPONYM

2019 ◽  
Vol 23 (2) ◽  
pp. 117-119 ◽  
Author(s):  
D. N. Paskalev ◽  
B. T. Galunska ◽  
D. Petkova-Valkova
Keyword(s):  
Viral Replication ◽  
Research Team ◽  
Molecular Mechanisms ◽  
Thick Ascending Limb ◽  
Rockefeller Institute ◽  
The Usa ◽  
Natural Inhibitor ◽  
Simplex Virus ◽  
First Time ◽  
New Protein

Tamm–Horsfall Protein (uromodulin) is named after Igor Tamm and Franc Horsfall Jr who described it for the first time in 1952. It is a glycoprotein, secreted by the cells in the thick ascending limb of the loop of Henle. This protein will perform a number of important pathophysiological functions, including protection against uroinfections, especially caused by E. Сoli, and protection against formation of calcium concernments in the kidney. Igor Tamm (1922-1995) is an outstanding cytologist, virologist and biochemist. He is one of the pioneers in the study of viral replication. He was born in Estonia and died in the USA. In 1964 he was elected for a professorship in Rockefeller Institute for Medical Research, where has been working continuously. Since 1959, he became a head of the virology lab established by his mentor and co-author Franc Horsfall. In the course of studies on the natural inhibitor of viral replication, Tamm and Horsfall isolated and characterized biochemically a new protein named after their names. Franc Lappin Horsfall Jr (1906-1971) was a well-known clinician and virologist with remarkable achievements in internal medicine. He was born and died in the USA. He worked in the Rockefeller Hospital from 1934 to 1960, then in the Center for Cancer Research at the Sloan-Kettering Institute. Here he was a leader of a research team studying the molecular mechanisms of immunity, the effects of chemotherapy with benzimidazole compounds (together with I. Tamm), coxsackie viruses, herpes simplex virus, etc. 

scholarly journals Transcriptomic responses to environmental change in fishes: Insights from RNA sequencing

FACETS ◽  
2017 ◽  
Vol 2 (2) ◽  
pp. 610-641 ◽  
Author(s):  
Rebekah A. Oomen ◽  
Jeffrey A. Hutchings
Keyword(s):  
Climate Change ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Environmental Variability ◽  
Global Climate ◽  
Genetic Research ◽  
Model Organisms ◽  
Rna Seq ◽  
Transcriptomic Responses ◽  
Ecological Importance

The need to better understand how plasticity and evolution affect organismal responses to environmental variability is paramount in the face of global climate change. The potential for using RNA sequencing (RNA-seq) to study complex responses by non-model organisms to the environment is evident in a rapidly growing body of literature. This is particularly true of fishes for which research has been motivated by their ecological importance, socioeconomic value, and increased use as model species for medical and genetic research. Here, we review studies that have used RNA-seq to study transcriptomic responses to continuous abiotic variables to which fishes have likely evolved a response and that are predicted to be affected by climate change (e.g., salinity, temperature, dissolved oxygen concentration, and pH). Field and laboratory experiments demonstrate the potential for individuals to respond plastically to short- and long-term environmental stress and reveal molecular mechanisms underlying developmental and transgenerational plasticity, as well as adaptation to different environmental regimes. We discuss experimental, analytical, and conceptual issues that have arisen from this work and suggest avenues for future study.

scholarly journals Lineage EM Algorithm for Inferring Latent States from Cellular Lineage Trees

2018 ◽  
Author(s):  
So Nakashima ◽  
Yuki Sughiyama ◽  
Tetsuya J. Kobayashi
Keyword(s):  
Em Algorithm ◽  
Latent Variable ◽  
Phenotypic Variability ◽  
Estimation Algorithm ◽  
Bet Hedging ◽  
Alternative Approach ◽  
Survivorship Bias ◽  
Survivor Bias ◽  
Lineage Trees ◽  
Statistical Estimations

Phenotypic variability in a population of cells can work as the bet-hedging of the cells under an unpredictably changing environment, the typical example of which is the bacterial persistence. To understand the strategy to control such phenomena, it is indispensable to identify the phenotype of each cell and its inheritance. Although recent advancements in microfluidic technology offer us useful lineage data, they are insufficient to directly identify the phenotypes of the cells. An alternative approach is to infer the phenotype from the lineage data by latent-variable estimation. To this end, however, we must resolve the bias problem in the inference from lineage called survivorship bias. In this work, we clarify how the survivor bias distorts statistical estimations. We then propose a latent-variable estimation algorithm without the survivorship bias from lineage trees based on an expectation-maximization (EM) algorithm, which we call Lineage EM algorithm (LEM). LEM provides a statistical method to identify the traits of the cells applicable to various kinds of lineage data.

scholarly journals Characteristics of epidemiological and molecular relationships between allergic diseases and helminth disorders in Opisthorchis endemic region

2008 ◽  
Vol 7 (4) ◽  
pp. 37-44
Author(s):  
L. M. Ogorodova ◽  
O. S. Fyodorova ◽  
M. B. Freidin ◽  
M. B. Vasil’yeva ◽  
N. A. Cherevko ◽  
...  
Keyword(s):  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Phenotypic Variability ◽  
Allergic Diseases ◽  
Endemic Region ◽  
Gene Differential Expression ◽  
Atopic Bronchial Asthma ◽  
Growth Factor Beta ◽  
Molecular Relationships

To elucidate the molecular mechanisms of O. felineus impact into phenotypic variability of allergic diseases in the opisthorchis endemic region, we studied 104 patients with opisthorchosis, 92 patients with atopic bronchial asthma, 52 patients with a combination of both diseases, and 120 healthy persons. Standard clinical, immunological, and genetic methods were used. An association of opisthorchis invasion with the improvement of lung function signs and bronchial hyperreactivity was found. It was established, that IL-4-dependent mechanisms of atopy were suppressed by O. felineus antigens, in particular due to hyperproduction of IL-10 and transforming growth factor-beta. However, IL-5-dependant mechanisms were supported. A phenomenology of the cytokine gene differential expression was established, disclosing the molecular basis of the immune system function in diseases with polar immune response in the helminth endemic region.

scholarly journals Bet-hedging across generations can affect the evolution of variance-sensitive strategies within generations

2019 ◽  
Vol 286 (1916) ◽  
pp. 20192070 ◽  
Author(s):  
Thomas R. Haaland ◽  
Jonathan Wright ◽  
Irja I. Ratikainen
Keyword(s):  
Life Histories ◽  
Environmental Variability ◽  
Geometric Mean ◽  
Simulation Models ◽  
Arithmetic Mean ◽  
Bet Hedging ◽  
Individual Fitness ◽  
Mean Fitness ◽  
Selection For ◽  
Independent Decision

In order to understand how organisms cope with ongoing changes in environmental variability, it is necessary to consider multiple adaptations to environmental uncertainty on different time scales. Conservative bet-hedging (CBH) represents a long-term genotype-level strategy maximizing lineage geometric mean fitness in stochastic environments by decreasing individual fitness variance, despite also lowering arithmetic mean fitness. Meanwhile, variance-prone (aka risk-prone) strategies produce greater variance in short-term payoffs, because this increases expected arithmetic mean fitness if the relationship between payoffs and fitness is accelerating. Using evolutionary simulation models, we investigate whether selection for such variance-prone strategies is counteracted by selection for bet-hedging that works to adaptively reduce fitness variance. In our model, variance proneness evolves in fine-grained environments (lower correlations among individuals in energetic state and/or payoffs), and with larger numbers of independent decision events over which resources accumulate prior to selection. Conversely, multiplicative fitness accumulation, caused by coarser environmental grain and fewer decision events selection, favours CBH via greater variance aversion. We discuss examples of variance-sensitive strategies in optimal foraging, migration, life histories and cooperative breeding using this bet-hedging perspective. By linking disparate fields of research studying adaptations to variable environments, we should be better able to understand effects of human-induced rapid environmental change.

scholarly journals Nuclear Factor NF45 Interacts with Viral Proteins of Infectious Bursal Disease Virus and Inhibits Viral Replication

2010 ◽  
Vol 84 (20) ◽  
pp. 10592-10605 ◽  
Author(s):  
Ruth L. O. Stricker ◽  
Sven-Erik Behrens ◽  
Egbert Mundt
Keyword(s):  
Viral Replication ◽  
Disease Virus ◽  
Infectious Bursal Disease Virus ◽  
Molecular Mechanisms ◽  
Viral Proteins ◽  
Infectious Bursal Disease ◽  
Nuclear Factor ◽  
Replication Process ◽  
Bursal Disease ◽  
Infected Cells

ABSTRACT Two of the central issues in developing new strategies to interfere with viral infections concern the identification of cellular proteins involved in viral replication and/or antiviral measures and the dissection of the underlying molecular mechanisms. To gain initial insight into the role of host proteins in the life cycle of infectious bursal disease virus (IBDV), a double-stranded RNA virus, we examined the cellular nuclear factor 45 (NF45). NF45 was previously indicated to be involved in the replication process of other types of RNA viruses. Interestingly, by performing immunofluorescence studies, we found that in IBDV-infected cells the mainly nuclear NF45 accumulated at the sites of viral replication in the cytoplasm. NF45 was shown to specifically colocalize with the viral RNA-dependent RNA polymerase VP1, the capsid protein VP2, and the ribonucleoprotein VP3. Immunoprecipitation experiments indicated protein-protein associations between NF45 and VP1, VP2, and VP3. Expression of the individual VP3 or the combination of expression of VP1 and VP3 did not result in a cytoplasmic accumulation of NF45, which, among other data, showed that recruitment of the cellular protein in infected cells functionally correlates with the viral replication process. Since small interfering RNA(siRNA)-mediated downregulation of NF45 resulted in an approximately 5-fold increase of virus yield, our study suggests that NF45, by association with viral proteins, is part of a yet-uncharacterized cellular defense mechanism against IBDV infections.

scholarly journals Epigenetic profiling of Italian patients identified methylation sites associated with hereditary transthyretin amyloidosis

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Antonella De Lillo ◽  
Gita A. Pathak ◽  
Flavio De Angelis ◽  
Marco Di Girolamo ◽  
Marco Luigetti ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Regression Coefficient ◽  
Phenotypic Variability ◽  
Interaction Network ◽  
Fiber Formation ◽  
Transthyretin Amyloidosis ◽  
Beta Secretase ◽  
Life Threatening ◽  
Amyloid Fiber Formation

AbstractHereditary transthyretin (TTR) amyloidosis (hATTR) is a rare life-threatening disorder caused by amyloidogenic coding mutations located in TTR gene. To understand the high phenotypic variability observed among carriers of TTR disease-causing mutations, we conducted an epigenome-wide association study (EWAS) assessing more than 700,000 methylation sites and testing epigenetic difference of TTR coding mutation carriers vs. non-carriers. We observed a significant methylation change at cg09097335 site located in Beta-secretase 2 (BACE2) gene (standardized regression coefficient = −0.60, p = 6.26 × 10–8). This gene is involved in a protein interaction network enriched for biological processes and molecular pathways related to amyloid-beta metabolism (Gene Ontology: 0050435, q = 0.007), amyloid fiber formation (Reactome HSA-977225, q = 0.008), and Alzheimer’s disease (KEGG hsa05010, q = 2.2 × 10–4). Additionally, TTR and BACE2 share APP (amyloid-beta precursor protein) as a validated protein interactor. Within TTR gene region, we observed that Val30Met disrupts a methylation site, cg13139646, causing a drastic hypomethylation in carriers of this amyloidogenic mutation (standardized regression coefficient = −2.18, p = 3.34 × 10–11). Cg13139646 showed co-methylation with cg19203115 (Pearson’s r2 = 0.32), which showed significant epigenetic differences between symptomatic and asymptomatic carriers of amyloidogenic mutations (standardized regression coefficient = −0.56, p = 8.6 × 10–4). In conclusion, we provide novel insights related to the molecular mechanisms involved in the complex heterogeneity of hATTR, highlighting the role of epigenetic regulation in this rare disorder.

Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa

2011 ◽  
Vol 48 (7) ◽  
pp. 450-457 ◽  
Author(s):  
D. Kiritsi ◽  
J. S. Kern ◽  
H. Schumann ◽  
J. Kohlhase ◽  
C. Has ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Molecular Mechanisms ◽  
Phenotypic Variability ◽  
Junctional Epidermolysis Bullosa

scholarly journals Effects on phenotypic variability of directional selection arising through genetic differences in residual variability

2004 ◽  
Vol 83 (2) ◽  
pp. 121-132 ◽  
Author(s):  
WILLIAM G. HILL ◽  
XU-SHENG ZHANG
Keyword(s):  
Genetic Variance ◽  
Environmental Variability ◽  
Phenotypic Variability ◽  
Additive Genetic Variance ◽  
Directional Selection ◽  
Frequency Change ◽  
Phenotypic Variance ◽  
Additive Effects ◽  
Genetic Covariance ◽  
Mean And Variance

In standard models of quantitative traits, genotypes are assumed to differ in mean but not variance of the trait. Here we consider directional selection for a quantitative trait for which genotypes also confer differences in variability, viewed either as differences in residual phenotypic variance when individual loci are concerned or as differences in environmental variability when the whole genome is considered. At an individual locus with additive effects, the selective value of the increasing allele is given by ia/σ+½ixb/σ2, where i is the selection intensity, x is the standardized truncation point, σ2 is the phenotypic variance, and a/σ and b/σ2 are the standardized differences in mean and variance respectively between genotypes at the locus. Assuming additive effects on mean and variance across loci, the response to selection on phenotype in mean is iσAm2/σ+½ixcovAmv/σ2 and in variance is icovAmv/σ+½ixσ2Av/σ2, where σAm2 is the (usual) additive genetic variance of effects of genes on the mean, σ2Av is the corresponding additive genetic variance of their effects on the variance, and covAmv is the additive genetic covariance of their effects. Changes in variance also have to be corrected for any changes due to gene frequency change and for the Bulmer effect, and relevant formulae are given. It is shown that effects on variance are likely to be greatest when selection is intense and when selection is on individual phenotype or within family deviation rather than on family mean performance. The evidence for and implications of such variability in variance are discussed.

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