scholarly journals Differences in codon bias and GC content contribute to the balanced expression of TLR7 and TLR9

2016 ◽  
Vol 113 (10) ◽  
pp. E1362-E1371 ◽  
Author(s):  
Zachary R. Newman ◽  
Janet M. Young ◽  
Nicholas T. Ingolia ◽  
Gregory M. Barton
Keyword(s):  
Nucleic Acids ◽  
Codon Bias ◽  
Codon Optimization ◽  
Immune Surveillance ◽  
Gc Content ◽  
Surveillance Strategy ◽  
Protein Levels ◽  
Low Levels ◽  
The Cost ◽  
Control Of Expression

The innate immune system detects diverse microbial species with a limited repertoire of immune receptors that recognize nucleic acids. The cost of this immune surveillance strategy is the potential for inappropriate recognition of self-derived nucleic acids and subsequent autoimmune disease. The relative expression of two closely related receptors, Toll-like receptor (TLR) 7 and TLR9, is balanced to allow recognition of microbial nucleic acids while limiting recognition of self-derived nucleic acids. Situations that tilt this balance toward TLR7 promote inappropriate responses, including autoimmunity; therefore, tight control of expression is critical for proper homeostasis. Here we report that differences in codon bias limit TLR7 expression relative to TLR9. Codon optimization of Tlr7 increases protein levels as well as responses to ligands, but, unexpectedly, these changes only modestly affect translation. Instead, we find that much of the benefit attributed to codon optimization is actually the result of enhanced transcription. Our findings, together with other recent examples, challenge the dogma that codon optimization primarily increases translation. We propose that suboptimal codon bias, which correlates with low guanine-cytosine (GC) content, limits transcription of certain genes. This mechanism may establish low levels of proteins whose overexpression leads to particularly deleterious effects, such as TLR7.

scholarly journals The Evolutionary Basis of Translational Accuracy in Plants

2017 ◽  
Vol 7 (7) ◽  
pp. 2363-2373 ◽  
Author(s):  
Salvatore Camiolo ◽  
Gaurav Sablok ◽  
Andrea Porceddu
Keyword(s):  
Codon Bias ◽  
Synonymous Codon ◽  
Gc Content ◽  
Translational Accuracy ◽  
Wide Range ◽  
Evolutionarily Conserved ◽  
Plant Genes ◽  
Translation Accuracy ◽  
And Function ◽  
The Cost

Abstract Mistranslation errors compromise fitness by wasting resources on nonfunctional proteins. In order to reduce the cost of mistranslations, natural selection chooses the most accurately translated codons at sites that are particularly important for protein structure and function. We investigated the determinants underlying selection for translational accuracy in several species of plants belonging to three clades: Brassicaceae, Fabidae, and Poaceae. Although signatures of translational selection were found in genes from a wide range of species, the underlying factors varied in nature and intensity. Indeed, the degree of synonymous codon bias at evolutionarily conserved sites varied among plant clades while remaining uniform within each clade. This is unlikely to solely reflect the diversity of tRNA pools because there is little correlation between synonymous codon bias and tRNA abundance, so other factors must affect codon choice and translational accuracy in plant genes. Accordingly, synonymous codon choice at a given site was affected not only by the selection pressure at that site, but also its participation in protein domains or mRNA secondary structures. Although these effects were detected in all the species we analyzed, their impact on translation accuracy was distinct in evolutionarily distant plant clades. The domain effect was found to enhance translational accuracy in dicot and monocot genes with a high GC content, but to oppose the selection of more accurate codons in monocot genes with a low GC content.

scholarly journals Primer Based Approach for PCR Amplification of High GC Content Gene: Mycobacterium Gene as a Model

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Arbind Kumar ◽  
Jagdeep Kaur
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Codon Optimization ◽  
Gc Content ◽  
Pcr Amplification ◽  
Pcr Conditions

The genome of Mycobacterium is rich in GC content and poses problem in amplification of some genes, especially those rich in the GC content in terminal regions, by standard/routine PCR procedures. Attempts have been made to amplify three GC rich genes of Mycobacterium sp. (Rv0519c and Rv0774c from M. tuberculosis and ML0314c from M. leprae). Out of these three genes, Rv0774c gene was amplified with normal primers under standard PCR conditions, while no amplification was observed in case of Rv0519c and ML0314c genes. In the present investigation a modified primer based approach was successfully used for amplification of GC rich sequence of Rv0519c through codon optimization without changing the native amino acid sequence. The strategy was successfully confirmed by redesigning the standard primers with similar modifications followed by amplification of ML0314c gene.

Labor Activation, Social Protection and Poverty Reduction: The Case of Russia

2019 ◽  
Vol 4 (3) ◽  
pp. 328-353
Author(s):  
Esuna Dugarova
Keyword(s):  
Labor Market ◽  
Poverty Reduction ◽  
Social Protection ◽  
Decent Work ◽  
Russian Government ◽  
Core Element ◽  
Low Levels ◽  
Demographic Shifts ◽  
Working Poverty ◽  
The Cost

Social protection is an important strategy to protect people from livelihood risks, develop human capital and promote economic growth. Decent work is a core element of social protection and a critical condition for eradicating poverty. Despite high labor force participation and low unemployment, Russia’s labor market shows several negative trends, including working poverty and growing informality. Both are exacerbated by gender disparities and unfavorable demographic shifts. Over the past decade the Russian government has implemented active labor market interventions, and enhanced targeted social protection aimed at promoting employment and reducing poverty. Based on the analysis of key data and programs, the article finds that the country achieved stability in the labor market, but at the cost of deteriorating living standards caused by low levels of productivity and wages.

scholarly journals TYK2: An Upstream Kinase of STATs in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1728 ◽  
Author(s):  
Katharina Wöss ◽  
Natalija Simonović ◽  
Birgit Strobl ◽  
Sabine Macho-Maschler ◽  
Mathias Müller
Keyword(s):  
Protein Tyrosine Kinase ◽  
Inflammatory Responses ◽  
Immune Surveillance ◽  
Pharmacological Intervention ◽  
Cytokine Signaling ◽  
Loss Of Function ◽  
Signal Transducers ◽  
Protein Levels ◽  
Tyrosine Kinase 2 ◽  
Upstream Kinase

In this review we concentrate on the recent findings describing the oncogenic potential of the protein tyrosine kinase 2 (TYK2). The overview on the current understanding of TYK2 functions in cytokine responses and carcinogenesis focusses on the activation of the signal transducers and activators of transcription (STAT) 3 and 5. Insight gained from loss-of-function (LOF) gene-modified mice and human patients homozygous for Tyk2/TYK2-mutated alleles established the central role in immunological and inflammatory responses. For the description of physiological TYK2 structure/function relationships in cytokine signaling and of overarching molecular and pathologic properties in carcinogenesis, we mainly refer to the most recent reviews. Dysregulated TYK2 activation, aberrant TYK2 protein levels, and gain-of-function (GOF) TYK2 mutations are found in various cancers. We discuss the molecular consequences thereof and briefly describe the molecular means to counteract TYK2 activity under (patho-)physiological conditions by cellular effectors and by pharmacological intervention. For the role of TYK2 in tumor immune-surveillance we refer to the recent Special Issue of Cancers “JAK-STAT Signaling Pathway in Cancer”.

scholarly journals Air Pollution Control: Equity Considerations for Rural and Urban America

1973 ◽  
Vol 2 (2) ◽  
pp. 224-234
Author(s):  
Douglas E. Morris
Keyword(s):  
Air Pollution ◽  
Pollution Control ◽  
Air Pollution Control ◽  
Equity Issue ◽  
Great Magnitude ◽  
Urban America ◽  
Rural And Urban ◽  
Low Levels ◽  
The Many ◽  
The Cost

This paper deals with one of the many aspects of controlling air pollution–equity. The equity issue discussed concerns the fact that areas with high and low levels of air pollution are subjected to many of the same controls under current legislation. The equity issue is, of course, only one of several imperative questions that should be addressed and fully researched before society embarks on an abatement program of great magnitude. In fact, comparisons between expected cost outlays by firms and individuals to control air pollution, and the cost of allowing the pollution to continue, indicate that it may be less costly for firms and individuals to do nothing.

scholarly journals Widespread selection for extremely high and low levels of secondary structure in coding sequences across all domains of life

Open Biology ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. 190020 ◽  
Author(s):  
Daniel Gebert ◽  
Julia Jehn ◽  
David Rosenkranz
Keyword(s):  
Secondary Structure ◽  
Gc Content ◽  
Secondary Structures ◽  
Coding Sequences ◽  
Rna Secondary Structures ◽  
Synonymous Mutations ◽  
Codon Composition ◽  
Domains Of Life ◽  
Low Levels ◽  
Selection For

Codon composition, GC content and local RNA secondary structures can have a profound effect on gene expression, and mutations affecting these parameters, even though they do not alter the protein sequence, are not neutral in terms of selection. Although evidence exists that, in some cases, selection favours more stable RNA secondary structures, we currently lack a concrete idea of how many genes are affected within a species, and whether this is a universal phenomenon in nature. We searched for signs of structural selection in a global manner, analysing a set of 1 million coding sequences from 73 species representing all domains of life, as well as viruses, by means of our newly developed software PACKEIS. We show that codon composition and amino acid identity are main determinants of RNA secondary structure. In addition, we show that the arrangement of synonymous codons within coding sequences is non-random, yielding extremely high, but also extremely low, RNA structuredness significantly more often than expected by chance. Taken together, we demonstrate that selection for high and low levels of secondary structure is a widespread phenomenon. Our results provide another line of evidence that synonymous mutations are less neutral than commonly thought, which is of importance for many evolutionary models.

scholarly journals Total Versus Free Placental Growth Factor Levels in the Pathogenesis of Preeclampsia

Hypertension ◽  
2020 ◽  
Vol 76 (3) ◽  
pp. 875-883
Author(s):  
Edouard Lecarpentier ◽  
Zsuzsanna K. Zsengellér ◽  
Saira Salahuddin ◽  
Ambart E. Covarrubias ◽  
Agnes Lo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Ex Vivo ◽  
Quantitative Polymerase Chain Reaction ◽  
Placental Growth Factor ◽  
Protein Levels ◽  
Key Characteristics ◽  
Human Blood Samples ◽  
Polymerase Chain ◽  
Low Levels ◽  
Independent Cohort

Elevated circulating sFLT-1 (soluble fms-like tyrosine kinase) and low levels of its ligand, PlGF (placental growth factor), are key characteristics of preeclampsia. However, it is unclear if the low levels of plasma PlGF noted during preeclampsia are due to decreased placental production of PlGF or due to binding of PlGF by increased circulating sFLT-1. Here, we describe a biochemical procedure to dissociate PlGF-sFLT-1 complex ex vivo and when used in conjunction with an immunoassay platform, demonstrate a method to measure total and free PlGF in human blood samples. Using this method, we noted that plasma free PlGF levels were significantly lower in preeclampsia (N=22) than in nonhypertensive controls (N=24; mean, 314 versus 686 pg/mL, P <0.05), but total PlGF levels were not different (mean, 822 versus 800 pg/mL, P =0.49). In contrast, total sFLT-1 levels were significantly higher in preeclampsia than in nonhypertensive controls (mean, 16 957 versus 3029 pg/mL, P <0.01) and sFLT-1 levels correlated with bound PlGF levels (bound PlGF=total PlGF−free PlGF) in these samples ( r 2 =0.68). We confirmed these findings in an independent cohort of subjects (N=49). Furthermore, we did not detect any difference in PlGF mRNA by quantitative polymerase chain reaction or in PlGF protein expression by immunohistochemistry in preeclamptic placentas when compared with nonhypertensive controls. In contrast, sFLT-1 mRNA and protein levels were upregulated in placentas from women with preeclampsia. Taken together with prior studies, our results provide evidence that decrease in circulating PlGF noted during preeclampsia is largely mediated by excess circulating sFLT-1.

The status and future of bilingual education for remote indigenous students in the Northern Territory

2011 ◽  
Vol 34 (3) ◽  
pp. 260-279 ◽  
Author(s):  
Brian Devlin
Keyword(s):  
Bilingual Education ◽  
Northern Territory ◽  
Student Attendance ◽  
Political Decision ◽  
Educational Approach ◽  
Indigenous Students ◽  
The Status ◽  
Low Levels ◽  
The Cost ◽  
Political Decision Making

This article analyses the status and future of bilingual education programs using Indigenous languages and English in remote Northern Territory schools. It explains why this educational approach is so contested at present, resulting in an unresolved situation which can best be regarded as an uneasy compromise on the ground and a stalemate at higher levels of political decision making. If the bilingual education approach was better understood by the current NT Government, there would a strong impetus now to refine and effectively implement a model of schooling that is appropriate for students in remote areas. Instead, current politicians debunk the bilingual approach, thereby robbing schools and literacy plans of any momentum and distracting attention away from the work that needs to be done. Meanwhile, student attendance rates have fallen away to worryingly low levels (Dickson, 2010). The current regime may well resolve the impasse, but in the absence of any meaningful, open negotiation the future looks uncertain. It is too soon to judge the cost of this uncertainty, but it may well result in further alienation and the emergence of non-government alternatives.

scholarly journals Consequences of Increases in Wild Boar-Vehicle Accidents 2003–2016 in Sweden on Personal Injuries and Costs

Safety ◽  
2018 ◽  
Vol 4 (4) ◽  
pp. 53 ◽  
Author(s):  
Annika Jägerbrand ◽  
Ing-Marie Gren
Keyword(s):  
Wild Boar ◽  
Sus Scrofa ◽  
Temporal Trends ◽  
Vehicle Accidents ◽  
Low Levels ◽  
The Cost

This study examined whether the rising trends of wild boar (Sus scrofa)-vehicle accidents in Sweden are accompanied by a higher amount of personal injuries and costs. Temporal trends in accident frequencies and the number of persons injured in wild boar-vehicle accidents were examined for 2003–2016, and the cost of wild boar-vehicle accidents was calculated. Results show increases in the number of personal injuries, and increased costs, particularly after 2010–2012. The total number of wild boar accidents correlated with the number of injured persons as well as with the number of accidents with personal injuries. Approximately one person (1.13%) is injured per 100 wild boar-vehicle accidents, and approximately one accident per 200 wild boar-vehicle accidents will result in one or more persons with injuries (0.5%). However, most of the persons injured have slighter injuries. Although the number of wild boar-vehicle accidents and the number of persons injured in the accidents have increased, the frequency of accidents resulting in personal injuries is still at low levels in comparison with, for example, frequencies of personal injuries for moose accidents. The cost for wild boar-vehicle accidents has increased between 2003 to 2016 and is currently estimated to vary between approximately EUR 9.66–12.31 million per year.

Environmentally Relevant Level of Aflatoxin B1 Dysregulates Human Dendritic Cells Through Signaling on Key Toll-Like Receptors

2014 ◽  
Vol 33 (3) ◽  
pp. 175-186 ◽  
Author(s):  
Azam Mohammadi ◽  
Jalil Mehrzad ◽  
Mahmoud Mahmoudi ◽  
Marion Schneider
Keyword(s):  
Dendritic Cells ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
Immune Surveillance ◽  
Toll Like Receptors ◽  
Myeloid Dendritic Cells ◽  
Protein Levels ◽  
Tlr4 Mrna ◽  
Relevant Level

Aflatoxins (AFs) are highly hazardous fungal biometabolites usually present in feeds and foods. Aflatoxin B1 (AFB1) is the most toxic and a known carcinogen. Toll-like receptors (TLRs), highly expressed by myeloid dendritic cells (DC), are key innate immune-surveillance molecules. Toll-like receptors not only sense pathogen-associated molecular patterns but also contribute to infections and cancer. To assess AFB1–TLR interactions on human myeloid DC, pure CD11c+ DC were generated from monocytes isolated from healthy individuals and then exposed to relevant level of AFB1 for 2 hours. Both quantitative polymerase chain reaction and flow cytometric assays were used to quantify, respectively, expression of TLR2 and TLR4 at the messenger RNA (mRNA) and protein levels in these DC. Levels of interleukin (IL) 1β, IL-6, and IL-10 were also analyzed in AFB1- and mock-treated DC. Compared to nontreated CD11c+ DC, expression levels of both TLR2 and TLR4 mRNA and proteins were significantly upregulated in AFB1-treated cells. Further, although IL-10 levels in AFB1-treated DC were similar to those in the mock-treated DC, the AFB1-exposed DC secreted higher amounts of IL-1β and IL-6. Dendritic cells are sensitive to environmentally relevant level of AFB1, and TLR2 and TLR4 are involved in sensing AFB1. Considering the broad roles of TLR2, TLR4, and DC in immunity and infections, our novel findings open a new door to understanding the molecular mechanisms and functional consequences of AFB1 in inducing immunodysregulation, immunotoxicity, and thus (non)infectious diseases in humans.

Sign in / Sign up

Export Citation Format

Share Document