scholarly journals Spontaneous driving forces give rise to protein−RNA condensates with coexisting phases and complex material properties

2019 ◽  
Vol 116 (16) ◽  
pp. 7889-7898 ◽  
Author(s):  
Steven Boeynaems ◽  
Alex S. Holehouse ◽  
Venera Weinhardt ◽  
Denes Kovacs ◽  
Joris Van Lindt ◽  
...  
Keyword(s):  
Material Properties ◽  
Driving Forces ◽  
Coarse Grained ◽  
Multilayered Structures ◽  
Biologically Relevant ◽  
Rna Molecules ◽  
Coexisting Phases ◽  
Heterotypic Interactions ◽  
Collective Interactions

Phase separation of multivalent protein and RNA molecules underlies the biogenesis of biomolecular condensates such as membraneless organelles. In vivo, these condensates encompass hundreds of distinct types of molecules that typically organize into multilayered structures supporting the differential partitioning of molecules into distinct regions with distinct material properties. The interplay between driven (active) versus spontaneous (passive) processes that are required for enabling the formation of condensates with coexisting layers of distinct material properties remains unclear. Here, we deploy systematic experiments and simulations based on coarse-grained models to show that the collective interactions among the simplest, biologically relevant proteins and archetypal RNA molecules are sufficient for driving the spontaneous emergence of multilayered condensates with distinct material properties. These studies yield a set of rules regarding homotypic and heterotypic interactions that are likely to be relevant for understanding the interplay between active and passive processes that control the formation of functional biomolecular condensates.

scholarly journals Spontaneous driving forces give rise to protein-RNA condensates with coexisting phases and complex material properties

2018 ◽  
Author(s):  
Steven Boeynaems ◽  
Alex S Holehouse ◽  
Venera Weinhardt ◽  
Denes Kovacs ◽  
Joris Van Lindt ◽  
...  
Keyword(s):  
Material Properties ◽  
Driving Forces ◽  
Coarse Grained ◽  
Biologically Relevant ◽  
Rna Molecules ◽  
Heterotypic Interactions ◽  
Collective Interactions

Collective phase transitions, including phase separation and gelation of multivalent protein and RNA molecules appears to underlie the biogenesis of biomolecular condensates such as membraneless organelles. In vivo, these condensates encompass hundreds of distinct types of molecules that are often organized into multi-layered structures supporting the differential partitioning of molecules into distinct regions with distinct material properties. The interplay between driven (active) versus spontaneous (passive) processes that are required for enabling the formation of condensates with coexisting layers of distinct material properties remains unclear. Here, we investigate the role of spontaneous driving forces as determinants of protein-RNA condensates with complex morphologies and distinct material properties. Through the use of systematic in vitro experiments and simulations based on coarse-grained models we find that that the collective interactions among the simplest, biologically relevant proteins and archetypal RNA molecules are sufficient for driving the spontaneous emergence of multi-layered condensates with distinct material properties. Our results demonstrate that key properties of protein-RNA condensates such as their overall morphologies, internal dynamics, and the selective partitioning of substrates are governed specific amino acid chemistries as well as RNA sequence and secondary structure. Our findings yield a clear set of heuristics regarding homo- and heterotypic interactions that are likely to be relevant for understanding the interplay between active and passive processes that control the formation of functional biomolecular condensates.

scholarly journals Evidence of transfer of miRNAs from the diet to the blood still inconclusive

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9567
Author(s):  
Fermín Mar-Aguilar ◽  
Alejandra Arreola-Triana ◽  
Daniela Mata-Cardona ◽  
Vianey Gonzalez-Villasana ◽  
Cristina Rodríguez-Padilla ◽  
...  
Keyword(s):  
Gene Expression ◽  
Model Organism ◽  
Food Sources ◽  
Plant Mirnas ◽  
Biologically Relevant ◽  
Rna Molecules ◽  
Cooking Process ◽  
Caste Development ◽  
Harsh Conditions

MicroRNAs (miRNAs) are short, non-coding, single-strand RNA molecules that act as regulators of gene expression in plants and animals. In 2012, the first evidence was found that plant miRNAs could enter the bloodstream through the digestive tract. Since then, there has been an ongoing discussion about whether miRNAs from the diet are transferred to blood, accumulate in tissues, and regulate gene expression. Different research groups have tried to replicate these findings, using both plant and animal sources. Here, we review the evidence for and against the transfer of diet-derived miRNAs from plants, meat, milk and exosome and their assimilation and putative molecular regulation role in the consuming organism. Some groups using both miRNAs from plant and animal sources have claimed success, whereas others have not shown transfer. In spite of the biological barriers that may limit miRNA transference, several diet-derived miRNAs can transfer into the circulating system and targets genes for transcription regulation, which adds arguments that miRNAs can be absorbed from the diet and target specific genes by regulating their expression. However, many other studies show that cross-kingdom transfer of exogenous miRNAs appears to be insignificant and not biologically relevant. The main source of controversy in plant studies is the lack of reproducibility of the findings. For meat-derived miRNAs, studies concluded that the miRNAs can survive the cooking process; nevertheless, our evidence shows that the bovine miRNAs are not transferred to human bloodstream. The most important contributions and promising evidence in this controversial field is the transference of milk miRNAs in exosomes and the finding that plant miRNAs in beebread regulate honeybee caste development, and cause similar changes when fed to Drosophila. MiRNAs encapsulated in exosomes ensure their stability and resistance in the harsh conditions presented in milk, bloodstream, and gastrointestinaltract to reinforce the idea of transference. Regardless of the model organism, the idea of source of miRNAs, or the approach—bioinformatics or in vivo—the issue of transfer of miRNAs from the diet remains in doubt. Our understanding of the cross-kingdom talk of miRNAs needs more research to study the transfer of “xenomiRs” from different food sources to complement and expand what we know so far regarding the interspecies transfer of miRNAs.

Simulation studies of the interactions between membrane proteins and detergents

2005 ◽  
Vol 33 (5) ◽  
pp. 910-912 ◽  
Author(s):  
P.J. Bond ◽  
J. Cuthbertson ◽  
M.S.P. Sansom
Keyword(s):  
Membrane Proteins ◽  
Membrane Protein ◽  
Self Assembly ◽  
Kinetic Mechanism ◽  
Coarse Grained ◽  
Simulation Studies ◽  
High Resolution Data ◽  
Biologically Relevant ◽  
Structure And Dynamics ◽  
Detergent Interactions

Interactions between membrane proteins and detergents are important in biophysical and structural studies and are also biologically relevant in the context of folding and transport. Despite a paucity of high-resolution data on protein–detergent interactions, novel methods and increased computational power enable simulations to provide a means of understanding such interactions in detail. Simulations have been used to compare the effect of lipid or detergent on the structure and dynamics of membrane proteins. Moreover, some of the longest and most complex simulations to date have been used to observe the spontaneous formation of membrane protein–detergent micelles. Common mechanistic steps in the micelle self-assembly process were identified for both α-helical and β-barrel membrane proteins, and a simple kinetic mechanism was proposed. Recently, simplified (i.e. coarse-grained) models have been utilized to follow long timescale transitions in membrane protein–detergent assemblies.

scholarly journals Aptamer Applications in Emerging Viral Diseases

2021 ◽  
Vol 14 (7) ◽  
pp. 622
Author(s):  
Arne Krüger ◽  
Ana Paula de Jesus Santos ◽  
Vanessa de Sá ◽  
Henning Ulrich ◽  
Carsten Wrenger
Keyword(s):  
Virus Assembly ◽  
Viral Diseases ◽  
Tissue Penetration ◽  
Rna Molecules ◽  
Viral Particles ◽  
Pharmacokinetic Properties ◽  
Oligonucleotide Library ◽  
In Vivo Diagnosis ◽  
Emerging Viral Diseases

Aptamers are single-stranded DNA or RNA molecules which are submitted to a process denominated SELEX. SELEX uses reiterative screening of a random oligonucleotide library to identify high-affinity binders to a chosen target, which may be a peptide, protein, or entire cells or viral particles. Aptamers can rival antibodies in target recognition, and benefit from their non-proteic nature, ease of modification, increased stability, and pharmacokinetic properties. This turns them into ideal candidates for diagnostic as well as therapeutic applications. Here, we review the recent accomplishments in the development of aptamers targeting emerging viral diseases, with emphasis on recent findings of aptamers binding to coronaviruses. We focus on aptamer development for diagnosis, including biosensors, in addition to aptamer modifications for stabilization in body fluids and tissue penetration. Such aptamers are aimed at in vivo diagnosis and treatment, such as quantification of viral load and blocking host cell invasion, virus assembly, or replication, respectively. Although there are currently no in vivo applications of aptamers in combating viral diseases, such strategies are promising for therapy development in the future.

scholarly journals 1,2,3-Triazoles as Biomimetics in Peptide Science

Molecules ◽  
2021 ◽  
Vol 26 (10) ◽  
pp. 2937
Author(s):  
Naima Agouram ◽  
El Mestafa El Hadrami ◽  
Abdeslem Bentama
Keyword(s):  
Enzymatic Degradation ◽  
Triazole Ring ◽  
Biologically Active ◽  
Amide Bond ◽  
Biologically Relevant ◽  
Amide Bonds ◽  
Natural Peptides ◽  
Mimicking Peptides ◽  
Chemical Mediators

Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

Dependence of Mechanical Behavior of the Murine Tail Disc on Regional Material Properties: A Parametric Finite Element Study

2005 ◽  
Vol 127 (7) ◽  
pp. 1158-1167 ◽  
Author(s):  
Adam H. Hsieh ◽  
Diane R. Wagner ◽  
Louis Y. Cheng ◽  
Jeffrey C. Lotz
Keyword(s):  
Finite Element ◽  
Mechanical Behavior ◽  
Nucleus Pulposus ◽  
Material Properties ◽  
Mechanical Response ◽  
Swelling Pressure ◽  
Transient Behavior ◽  
Sensitivity Analyses ◽  
Intact Mouse

In vivo rodent tail models are becoming more widely used for exploring the role of mechanical loading on the initiation and progression of intervertebral disc degeneration. Historically, finite element models (FEMs) have been useful for predicting disc mechanics in humans. However, differences in geometry and tissue properties may limit the predictive utility of these models for rodent discs. Clearly, models that are specific for rodent tail discs and accurately simulate the disc’s transient mechanical behavior would serve as important tools for clarifying disc mechanics in these animal models. An FEM was developed based on the structure, geometry, and scale of the mouse tail disc. Importantly, two sources of time-dependent mechanical behavior were incorporated: viscoelasticity of the matrix, and fluid permeation. In addition, a novel strain-dependent swelling pressure was implemented through the introduction of a dilatational stress in nuclear elements. The model was then validated against data from quasi-static tension-compression and compressive creep experiments performed previously using mouse tail discs. Finally, sensitivity analyses were performed in which material parameters of each disc subregion were individually varied. During disc compression, matrix consolidation was observed to occur preferentially at the periphery of the nucleus pulposus. Sensitivity analyses revealed that disc mechanics was greatly influenced by changes in nucleus pulposus material properties, but rather insensitive to variations in any of the endplate properties. Moreover, three key features of the model—nuclear swelling pressure, lamellar collagen viscoelasticity, and interstitial fluid permeation—were found to be critical for accurate simulation of disc mechanics. In particular, collagen viscoelasticity dominated the transient behavior of the disc during the initial 2200s of creep loading, while fluid permeation governed disc deformation thereafter. The FEM developed in this study exhibited excellent agreement with transient creep behavior of intact mouse tail motion segments. Notably, the model was able to produce spatial variations in nucleus pulposus matrix consolidation that are consistent with previous observations in nuclear cell morphology made in mouse discs using confocal microscopy. Results of this study emphasize the need for including nucleus swelling pressure, collagen viscoelasticity, and fluid permeation when simulating transient changes in matrix and fluid stress/strain. Sensitivity analyses suggest that further characterization of nucleus pulposus material properties should be pursued, due to its significance in steady-state and transient disc mechanical response.

siRNA, miRNA, and shRNA: in vivo Applications

2008 ◽  
Vol 87 (11) ◽  
pp. 992-1003 ◽  
Author(s):  
P.N. Pushparaj ◽  
J.J. Aarthi ◽  
J. Manikandan ◽  
S.D. Kumar
Keyword(s):  
Metabolic Diseases ◽  
Small Interfering Rnas ◽  
Base Pairs ◽  
Rna Molecules ◽  
Rna Activation ◽  
Research Findings ◽  
Dental Diseases ◽  
Short Hairpin Rnas ◽  
Clinical Potential

RNA interference (RNAi), an accurate and potent gene-silencing method, was first experimentally documented in 1998 in Caenorhabditis elegans by Fire et al., who subsequently were awarded the 2006 Nobel Prize in Physiology/Medicine. Subsequent RNAi studies have demonstrated the clinical potential of synthetic small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) in dental diseases, eye diseases, cancer, metabolic diseases, neurodegenerative disorders, and other illnesses. siRNAs are generally from 21 to 25 base-pairs (bp) in length and have sequence-homology-driven gene-knockdown capability. RNAi offers researchers an effortless tool for investigating biological systems by selectively silencing genes. Key technical aspects—such as optimization of selectivity, stability, in vivo delivery, efficacy, and safety—need to be investigated before RNAi can become a successful therapeutic strategy. Nevertheless, this area shows a huge potential for the pharmaceutical industry around the globe. Interestingly, recent studies have shown that the small RNA molecules, either indigenously produced as microRNAs (miRNAs) or exogenously administered synthetic dsRNAs, could effectively activate a particular gene in a sequence-specific manner instead of silencing it. This novel, but still uncharacterized, phenomenon has been termed ‘RNA activation’ (RNAa). In this review, we analyze these research findings and discussed the in vivo applications of siRNAs, miRNAs, and shRNAs.

Abstract 562: Human Carotid Atherosclerosis Plaque Progression and Vessel Material Stiffness at Follow Up Had Positive Correlation: An in vivo Vessel Stiffness MRI Follow Up Study

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Qingyu Wang ◽  
Dalin Tang ◽  
Gador Canton ◽  
Jian Guo ◽  
Xiaoya Guo ◽  
...  
Keyword(s):  
Negative Correlation ◽  
Material Properties ◽  
Stretch Ratio ◽  
Patient Specific ◽  
Plaque Progression ◽  
Material Stiffness ◽  
Variation Rate ◽  
Vessel Material

It is hypothesized that artery stiffness may be associated with plaque progression. However, in vivo vessel material stiffness follow-up data is lacking in the literature. In vivo 3D multi-contrast and Cine magnetic resonance imaging (MRI) carotid plaque data were acquired from 8 patients with follow-up (18 months) with written informed consent obtained. Cine MRI and 3D thin-layer models were used to determine parameter values of the Mooney-Rivlin models for the 81slices from 16 plaques (2 scans/patient) using our established iterative procedures. Effective Young’s Modulus (YM) values for stretch ratio [1.0,1.3] were calculated for each slice for analysis. Stress-stretch ratio curves from Mooney-Rivlin models for the 16 plaques and 81 slices are given in Fig. 1. Average YM value of the 81 slices was 411kPa. Slice YM values varied from 70 kPa (softest) to 1284 kPa (stiffest), a 1734% difference. Average slice YM values by vessel varied from 109 kPa (softest) to 922 kPa (stiffest), a 746% difference. Location-wise, the maximum slice YM variation rate within a vessel was 306% (139 kPa vs. 564 kPa). Average slice YM variation rate within a vessel for the 16 vessels was 134%. Average variation of YM values from baseline (T1) to follow up (T2) for all patients was 61.0%. The range of the variation of YM values was [-28.4%, 215%]. For progression study, YM increase (YMI=YM T2 -TM T1 ) showed negative correlation with plaque progression measured by wall thickness increase (WTI), (r= -0.6802, p=0.0634). YM T2 showed strong negative correlation with WTI (r= -0.7764, p=0.0235). Correlation between YM T1 and WTI was not significant (r= -0.4353, p= 0.2811). Conclusion In vivo carotid vessel material properties have large variations from patient to patient, along the vessel segment within a patient, and from baseline to follow up. Use of patient-specific, location specific and time-specific material properties could potentially improve the accuracy of model stress/strain calculations.

scholarly journals Asymmetric and Regiospecific Synthesis of Isotopically Labelled Cyclopropane Fatty Acid (9R,10S)-Dihydrosterculic Acid: Overcoming Spontaneous Protonation During Lithium-Sulfoxide Exchange­

SynOpen ◽  
2018 ◽  
Vol 02 (02) ◽  
pp. 0168-0175
Author(s):  
Samuel Shields ◽  
Peter Buist ◽  
Jeffrey Manthorpe
Keyword(s):  
Fatty Acid ◽  
Total Synthesis ◽  
Cyclopropane Ring ◽  
Rapid Quenching ◽  
Cyclopropane Fatty Acid ◽  
Deuterium Incorporation ◽  
Biologically Relevant ◽  
Dihydrosterculic Acid

The total synthesis of isotopically labelled (9R,10S)-dihydro­sterculic acid, a usual cyclopropane fatty acid with biologically relevant toxicity upon desaturation in vivo, is reported. A diastereoselective Corey­–Chaykovsky reaction was employed to form the cyclopropane ring. Rapid quenching of a lithium-sulfoxide exchange was required to achieve the requisite high levels of deuterium incorporation.

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