scholarly journals Mutation in a SARS-CoV-2 Haplotype from Sub-Antarctic Chile Reveals New Insights into the Spike’s Dynamics

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 883
Author(s):  
Jorge González-Puelma ◽  
Jacqueline Aldridge ◽  
Marco Montes de de Oca ◽  
Mónica Pinto ◽  
Roberto Uribe-Paredes ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Incidence Rates ◽  
Coarse Grained ◽  
Receptor Binding Domain ◽  
Southern Chile ◽  
Dynamic Simulations ◽  
Double Mutation ◽  
Short Period ◽  
Dynamic Domain ◽  
New Mutations

The emergence of SARS-CoV-2 variants, as observed with the D614G spike protein mutant and, more recently, with B.1.1.7 (501Y.V1), B.1.351 (501Y.V2) and B.1.1.28.1 (P.1) lineages, represent a continuous threat and might lead to strains of higher infectivity and/or virulence. We report on the occurrence of a SARS-CoV-2 haplotype with nine mutations including D614G/T307I double-mutation of the spike. This variant expanded and completely replaced previous lineages within a short period in the subantarctic Magallanes Region, southern Chile. The rapid lineage shift was accompanied by a significant increase of cases, resulting in one of the highest incidence rates worldwide. Comparative coarse-grained molecular dynamic simulations indicated that T307I and D614G belong to a previously unrecognized dynamic domain, interfering with the mobility of the receptor binding domain of the spike. The T307I mutation showed a synergistic effect with the D614G. Continuous surveillance of new mutations and molecular analyses of such variations are important tools to understand the molecular mechanisms defining infectivity and virulence of current and future SARS-CoV-2 strains.

scholarly journals Functional alterations caused by mutations reflect evolutionary trends of SARS-CoV-2

2021 ◽  
Author(s):  
Liang Cheng ◽  
Xudong Han ◽  
Zijun Zhu ◽  
Changlu Qi ◽  
Ping Wang ◽  
...  
Keyword(s):  
Reference Genome ◽  
Sequence Data ◽  
Purifying Selection ◽  
Virus Genome ◽  
Receptor Binding Domain ◽  
Evolutionary Trends ◽  
Synonymous Mutations ◽  
Almost All ◽  
Virus Strains ◽  
New Mutations

Abstract Since the first report of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the COVID-19 pandemic has spread rapidly worldwide. Due to the limited virus strains, few key mutations that would be very important with the evolutionary trends of virus genome were observed in early studies. Here, we downloaded 1809 sequence data of SARS-CoV-2 strains from GISAID before April 2020 to identify mutations and functional alterations caused by these mutations. Totally, we identified 1017 nonsynonymous and 512 synonymous mutations with alignment to reference genome NC_045512, none of which were observed in the receptor-binding domain (RBD) of the spike protein. On average, each of the strains could have about 1.75 new mutations each month. The current mutations may have few impacts on antibodies. Although it shows the purifying selection in whole-genome, ORF3a, ORF8 and ORF10 were under positive selection. Only 36 mutations occurred in 1% and more virus strains were further analyzed to reveal linkage disequilibrium (LD) variants and dominant mutations. As a result, we observed five dominant mutations involving three nonsynonymous mutations C28144T, C14408T and A23403G and two synonymous mutations T8782C, and C3037T. These five mutations occurred in almost all strains in April 2020. Besides, we also observed two potential dominant nonsynonymous mutations C1059T and G25563T, which occurred in most of the strains in April 2020. Further functional analysis shows that these mutations decreased protein stability largely, which could lead to a significant reduction of virus virulence. In addition, the A23403G mutation increases the spike-ACE2 interaction and finally leads to the enhancement of its infectivity. All of these proved that the evolution of SARS-CoV-2 is toward the enhancement of infectivity and reduction of virulence.

scholarly journals Unveiling the Dynamics of KRAS4b on Lipid Model Membranes

2021 ◽  
Author(s):  
Cesar A. López ◽  
Animesh Agarwal ◽  
Que N. Van ◽  
Andrew G. Stephen ◽  
S. Gnanakaran
Keyword(s):  
Molecular Mechanisms ◽  
Hypervariable Region ◽  
Small Gtpase ◽  
Model Systems ◽  
Coarse Grained ◽  
Regulatory Function ◽  
Limited Information ◽  
Long Time ◽  
Cell Growth And Differentiation ◽  
State Models

AbstractSmall GTPase proteins are ubiquitous and responsible for regulating several processes related to cell growth and differentiation. Mutations that stabilize their active state can lead to uncontrolled cell proliferation and cancer. Although these proteins are well characterized at the cellular scale, the molecular mechanisms governing their functions are still poorly understood. In addition, there is limited information about the regulatory function of the cell membrane which supports their activity. Thus, we have studied the dynamics and conformations of the farnesylated KRAS4b in various membrane model systems, ranging from binary fluid mixtures to heterogeneous raft mimics. Our approach combines long time-scale coarse-grained (CG) simulations and Markov state models to dissect the membrane-supported dynamics of KRAS4b. Our simulations reveal that protein dynamics is mainly modulated by the presence of anionic lipids and to some extent by the nucleotide state (activation) of the protein. In addition, our results suggest that both the farnesyl and the polybasic hypervariable region (HVR) are responsible for its preferential partitioning within the liquid-disordered (Ld) domains in membranes, potentially enhancing the formation of membrane-driven signaling platforms. Graphic Abstract

scholarly journals Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 862
Author(s):  
Yueh-Te Lin ◽  
Long-Bin Jeng ◽  
Wen-Ling Chan ◽  
Ih-Jen Su ◽  
Chiao-Fang Teng
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Molecular Mechanisms ◽  
Incidence Rates ◽  
Gene Deletions ◽  
S Gene ◽  
B Virus ◽  
Potential Applications ◽  
Prevention And Therapy

Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy.

scholarly journals GEOLOGICAL ASSISTED ON WATER RESOURCES PLANNING IN MOUNTAINOUS CATCHMENTS IN KUNDASANG, SABAH, MALAYSIA

2020 ◽  
Vol 4 (1) ◽  
pp. 26-31
Author(s):  
Rodeano Roslee
Keyword(s):  
Water Resources ◽  
Geological Mapping ◽  
Coarse Grained ◽  
Water Resources Planning ◽  
Groundwater Levels ◽  
Deep Aquifers ◽  
Short Period ◽  
Catchment Areas ◽  
Sand And Gravel ◽  
Resources Planning

Based on geological mapping and geohydrologic data, water resources planning in mountainous catchment areas in Kundasang are outlined. The area is underlain by thick Paleogene clastic sediment and old Quaternary gravels. These rock units are carved by numerous lineaments with complex structural styles developed during series of regional Tertiary tectonic activities. The tectonic complexities reduced the physical and mechanical properties of the rock units and produced intensive displacements and discontinuities among the strata, resulting in high degree of weathering process and instability. The weathered materials are unstable and may cause subsidence and sliding induced by high pore pressure subjected by both shallow and deep hydrodynamic processes. Evaluation of 60 boreholes data in the study area reveals that the depth of the groundwater table ranges from 1.90 m (6 feet) to 11.20 m (35 feet) deep. The groundwater level in the study area fluctuates even within a short period of any instability of climatic change. The Quaternary sand and gravel layers with variable thickness defined the major shallow aquifers within the underlying weathered materials while the highly fractured sedimentary rocks defined the major deep aquifers. Most of the aquifers within the top unconsolidated weathered clastic material are under unconfined condition. The sedimentary formations are coarse-grained clastic materials generally contain fractured porosity and exhibit higher permeability. However, below subsurface, much of the groundwater is partially confined. Movements of groundwater are sufficiently restricted area to cause slightly different in head depth zones during periods of heavy pumping. During periods of less draught, the various groundwater levels will be recovered to their respective original level. This condition resulted from discontinuous nature of sediments where zones of permeable sand and gravel are layered between less permeable beds of silt and clay. Aquifer characterization and geological data are given to assist the local agencies on the water resources planning of the study area.

Exploiting Laboratory Insights to Improve Outcomes of Pediatric Central Nervous System Tumors

2016 ◽  
pp. e540-e546 ◽  
Author(s):  
Giles W. Robinson ◽  
Hendrik Witt ◽  
Adam Resnick
Keyword(s):  
Brain Tumor ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Pediatric Brain Tumor ◽  
Pediatric Brain Tumors ◽  
Low Grade ◽  
Short Period ◽  
Tumor Management ◽  
The Impact ◽  
Pediatric Brain

Over a relatively short period of time, owing to improvements in biotechnology, our ability to identify the molecular mechanisms within pediatric brain tumors has dramatically increased. These findings have reshaped the way that we describe these diseases and have provided insights into how to better treat these often devastating diseases. Although still far from reaching the full therapeutic potential these advancements hold, the impact of these findings is steadily taking hold of pediatric brain tumor management. In this article, we summarize the major discoveries within three common pediatric brain tumor categories; medulloblastoma, ependymoma, and low-grade glioma. We discuss the current impact of these findings on treatment and the direction these findings may take the field of pediatric neuro-oncology.

scholarly journals Mechanistic basis of neonatal heart regeneration revealed by transcriptome and histone modification profiling

2019 ◽  
Vol 116 (37) ◽  
pp. 18455-18465 ◽  
Author(s):  
Zhaoning Wang ◽  
Miao Cui ◽  
Akansha M. Shah ◽  
Wenduo Ye ◽  
Wei Tan ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Rna Binding ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Cardiac Regeneration ◽  
Later Life ◽  
Heart Regeneration ◽  
Cardiomyocyte Proliferation ◽  
Neonatal Heart ◽  
Short Period

The adult mammalian heart has limited capacity for regeneration following injury, whereas the neonatal heart can readily regenerate within a short period after birth. To uncover the molecular mechanisms underlying neonatal heart regeneration, we compared the transcriptomes and epigenomes of regenerative and nonregenerative mouse hearts over a 7-d time period following myocardial infarction injury. By integrating gene expression profiles with histone marks associated with active or repressed chromatin, we identified transcriptional programs underlying neonatal heart regeneration, and the blockade to regeneration in later life. Our results reveal a unique immune response in regenerative hearts and a retained embryonic cardiogenic gene program that is active during neonatal heart regeneration. Among the unique immune factors and embryonic genes associated with cardiac regeneration, we identified Ccl24, which encodes a cytokine, and Igf2bp3, which encodes an RNA-binding protein, as previously unrecognized regulators of cardiomyocyte proliferation. Our data provide insights into the molecular basis of neonatal heart regeneration and identify genes that can be modulated to promote heart regeneration.

scholarly journals Coarse-grained dynamic RNA titration simulations

2019 ◽  
Vol 9 (3) ◽  
pp. 20180066 ◽  
Author(s):  
S. Pasquali ◽  
E. Frezza ◽  
F. L. Barroso da Silva
Keyword(s):  
Electrostatic Interactions ◽  
Molecular Organization ◽  
Coarse Grained ◽  
Solution Ph ◽  
Dynamic Simulations ◽  
Rna Molecules ◽  
Coarse Grained Model ◽  
Constant Ph ◽  
Conformational Plasticity ◽  
And Function

Electrostatic interactions play a pivotal role in many biomolecular processes. The molecular organization and function in biological systems are largely determined by these interactions. Owing to the highly negative charge of RNA, the effect is expected to be more pronounced in this system. Moreover, RNA base pairing is dependent on the charge of the base, giving rise to alternative secondary and tertiary structures. The equilibrium between uncharged and charged bases is regulated by the solution pH, which is therefore a key environmental condition influencing the molecule’s structure and behaviour. By means of constant-pH Monte Carlo simulations based on a fast proton titration scheme, coupled with the coarse-grained model HiRE-RNA, molecular dynamic simulations of RNA molecules at constant pH enable us to explore the RNA conformational plasticity at different pH values as well as to compute electrostatic properties as local p K a values for each nucleotide.

scholarly journals Solvent-induced depletion interactions in multiparticle collision dynamic simulations

2019 ◽  
Vol 30 (10) ◽  
pp. 1941008 ◽  
Author(s):  
Martin Wagner ◽  
Marisol Ripoll
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Coarse Grained ◽  
Simulation Methods ◽  
Mesoscale Simulation ◽  
Dynamic Simulations ◽  
Collision Dynamic ◽  
Versatile Tool ◽  
Depletion Interactions

Molecular-dynamics-coupled multiparticle collision dynamic (MPC-MD) simulations have emerged to be an efficient and versatile tool in the description of mesoscale colloidal dynamics. However, the compressibility of the coarse-grained fluid leads to this method being prone to spurious depletion interactions that may dominate the colloidal dynamics. In this paper, we review the existing methodology to deal with these interactions, establish and report depletion measurements, and present a method to avoid artificial depletion in mesoscale simulation methods.

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