scholarly journals Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7425 ◽  
Author(s):  
Garima Singh ◽  
Sri Krishna jayadev Magani ◽  
Rinku Sharma ◽  
Basharat Bhat ◽  
Ashish Shrivastava ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cathepsin B ◽  
Alcoholic Pancreatitis ◽  
Potential Candidate ◽  
Juvenile Form ◽  
Functional Changes ◽  
Lysosomal Protease ◽  
Tropical Calcific Pancreatitis ◽  
The Impact ◽  
Calcific Pancreatitis

Tropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic non-alcoholic pancreatitis. Cathepsin B (CTSB), a lysosomal protease involved in the cellular degradation process, has recently been studied as a potential candidate gene in the pathogenesis of TCP. According to the Cathepsin B hypothesis, mutated CTSB can lead to premature intracellular activation of trypsinogen, a key regulatory mechanism in pancreatitis. So far, CTSB mutations have been studied in pancreatitis and neurodegenerative disorders, but little is known about the structural and functional effect of variants in CTSB. In this study, we investigated the effect of single nucleotide variants (SNVs) specifically associated with TCP, using molecular dynamics and simulation algorithms. There were two non-synonymous variants (L26V and S53G) of CTSB, located in the propeptide region. We tried to predict the effect of these variants on structure and function using multiple algorithms: SIFT, Polyphen2, PANTHER, SDM sever, i-Mutant2.0 suite, mCSM algorithm, and Vadar. Further, using databases like miRdbSNP, PolymiRTS, and miRNASNP, two SNPs in the 3′UTR region were predicted to affect the miRNA binding sites. Structural mutated models of nsSNP mutants (L26V and S53G) were prepared by MODELLER v9.15 and evaluated using TM-Align, Verify 3D, ProSA and Ramachandran plot. The 3D mutated structures were simulated using GROMACS 5.0 to predict the impact of these SNPs on protein stability. The results from in silico analysis and molecular dynamics simulations suggested that these variants in the propeptide region of Cathepsin B could lead to structural and functional changes in the protein and thus could be pathogenic. Hence, the structural and functional analysis results have given interim conclusions that these variants can have a deleterious effect in TCP pathogenesis, either uniquely or in combination with other mutations. Thus, it could be extrapolated that Cathepsin B gene can be screened in samples from all TCP patients in future, to decipher the distribution of variants in patients.

scholarly journals Structural, functional and molecular dynamics analysis of cathepsin B gene SNPs associated with tropical calcific pancreatitis, a rare disease of tropics

2018 ◽  
Author(s):  
Garima Singh ◽  
MSK Jayadev ◽  
Rinku Sharma ◽  
Basharat Bhat ◽  
CH Madhusudhan ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Cathepsin B ◽  
Alcoholic Pancreatitis ◽  
Potential Candidate ◽  
Single Nucleotide Variants ◽  
Juvenile Form ◽  
Functional Changes ◽  
Tropical Calcific Pancreatitis ◽  
The Impact ◽  
Calcific Pancreatitis

AbstractTropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic non-alcoholic pancreatitis. Cathepsin B (CTSB), a lysososmal protease involved in cellular degradation process, is recently been studied as a potential candidate gene in the pathogenesis of TCP. According to cathepsin B hypothesis, mutated CTSB can lead to premature intracellular activation of trypsinogen, which is a key regulatory mechanism in pancreatitis. So far, CTSB mutations have been studied in pancreatitis and neurodegenerative disorders but little is known about the structural and functional effect of variants in CTSB. In this study, we investigated the effect of single nucleotide variants (SNVs) associated with TCP, using molecular dynamics and simulation algorithms. There were two non-synonymous variants in the coding region (L26V and S53G) of CTSB, located in the propeptide region. We tried to predict the effect of these variants on structure and function using multiple algorithms: SIFT, Polyphen2, Panther, SDM sever, i-Mutant2.0 suite, mCSM algorithm and Vadar. Further, using databases like miRdbSNP, PolymiRTS and miRNASNP, two SNPs in 3’UTR region were predicted to affect the miRNA binding sites. Structural mutated models of nsSNP mutants (L26V and S53G) were prepared by MODELLER v9.15 and evaluated using TM-Align, Verify 3D, ProSA and Ramachandran plot. The results showed that the models (L26V and S53G) were of high accuracy. The 3D mutated structures were simulated using GROMACS 5.0 to predict the impact of these SNPs on protein stability. The results from in silico analysis and molecular dynamics simulations suggested that these variants in the propeptide region of cathepsin B could lead to structural and functional changes in the protein. Hence, the structural and functional analysis results have given interim conclusions that these variants can have deleterious effect in TCP and thus should be screen in samples from all TCP patients to decipher its distribution in patient population.

scholarly journals The Impact of the Electric Field on Surface Condensation of Water Vapor: Insight from Molecular Dynamics Simulation

Nanomaterials ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 64 ◽  
Author(s):  
Qin Wang ◽  
Hui Xie ◽  
Zhiming Hu ◽  
Chao Liu
Keyword(s):  
Molecular Dynamics ◽  
Water Vapor ◽  
Electric Field ◽  
Intermolecular Forces ◽  
Dynamics Simulation ◽  
Water Molecules ◽  
Attraction Force ◽  
Condensation Rate ◽  
Shape Transformation ◽  
The Impact

In this study, molecular dynamics simulations were carried out to study the coupling effect of electric field strength and surface wettability on the condensation process of water vapor. Our results show that an electric field can rotate water molecules upward and restrict condensation. Formed clusters are stretched to become columns above the threshold strength of the field, causing the condensation rate to drop quickly. The enhancement of surface attraction force boosts the rearrangement of water molecules adjacent to the surface and exaggerates the threshold value for shape transformation. In addition, the contact area between clusters and the surface increases with increasing amounts of surface attraction force, which raises the condensation efficiency. Thus, the condensation rate of water vapor on a surface under an electric field is determined by competition between intermolecular forces from the electric field and the surface.

scholarly journals Dopamine Transporter Genetic Reduction Induces Morpho-Functional Changes in the Enteric Nervous System

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 465
Author(s):  
Silvia Cerantola ◽  
Valentina Caputi ◽  
Gabriella Contarini ◽  
Maddalena Mereu ◽  
Antonella Bertazzo ◽  
...  
Keyword(s):  
Nervous System ◽  
Small Intestine ◽  
Enteric Nervous System ◽  
Dopamine Transporter ◽  
Myenteric Plexus ◽  
Receptor Activation ◽  
D1 Receptor ◽  
Functional Changes ◽  
Neurochemical Coding ◽  
The Impact

Antidopaminergic gastrointestinal prokinetics are indeed commonly used to treat gastrointestinal motility disorders, although the precise role of dopaminergic transmission in the gut is still unclear. Since dopamine transporter (DAT) is involved in several brain disorders by modulating extracellular dopamine in the central nervous system, this study evaluated the impact of DAT genetic reduction on the morpho-functional integrity of mouse small intestine enteric nervous system (ENS). In DAT heterozygous (DAT+/−) and wild-type (DAT+/+) mice (14 ± 2 weeks) alterations in small intestinal contractility were evaluated by isometrical assessment of neuromuscular responses to receptor and non-receptor-mediated stimuli. Changes in ENS integrity were studied by real-time PCR and confocal immunofluorescence microscopy in longitudinal muscle-myenteric plexus whole-mount preparations (). DAT genetic reduction resulted in a significant increase in dopamine-mediated effects, primarily via D1 receptor activation, as well as in reduced cholinergic response, sustained by tachykininergic and glutamatergic neurotransmission via NMDA receptors. These functional anomalies were associated to architectural changes in the neurochemical coding and S100β immunoreactivity in small intestine myenteric plexus. Our study provides evidence that genetic-driven DAT defective activity determines anomalies in ENS architecture and neurochemical coding together with ileal dysmotility, highlighting the involvement of dopaminergic system in gut disorders, often associated to neurological conditions.

Evaluation of Triticum durum–Aegilops tauschii derived primary synthetics as potential sources of heat stress tolerance for wheat improvement

2021 ◽  
Vol 19 (1) ◽  
pp. 74-89
Author(s):  
Amandeep Kaur ◽  
Parveen Chhuneja ◽  
Puja Srivastava ◽  
Kuldeep Singh ◽  
Satinder Kaur
Keyword(s):  
Heat Stress ◽  
Stress Tolerance ◽  
Hexaploid Wheat ◽  
Aegilops Tauschii ◽  
Grain Filling ◽  
World Population ◽  
Potential Candidate ◽  
Terminal Heat Stress ◽  
Heat Stress Tolerance ◽  
The Impact

AbstractAddressing the impact of heat stress during flowering and grain filling is critical to sustaining wheat productivity to meet a steadily increasing demand from a rapidly growing world population. Crop wild progenitor species of wheat possess a wealth of genetic diversity for several biotic and abiotic stresses, and morphological traits and can serve as valuable donors. The transfer of useful variation from the diploid progenitor, Aegilops tauschii, to hexaploid wheat can be done through the generation of synthetic hexaploid wheat (SHW). The present study targeted the identification of potential primary SHWs to introduce new genetic variability for heat stress tolerance. Selected SHWs were screened for different yield-associated traits along with three advanced breeding lines and durum parents as checks for assessing terminal heat stress tolerance under timely and late sown conditions for two consecutive seasons. Heat tolerance index based on the number of productive tillers and thousand grain weight indicated that three synthetics, syn9809 (64.32, 78.80), syn14128 (50.30, 78.28) and syn14135 (58.16, 76.03), were able to endure terminal heat stress better than other SHWs as well as checks. One of these synthetics, syn14128, recorded a minimum reduction in thousand kernel weight (21%), chlorophyll content (2.56%), grain width (1.07%) despite minimum grain-filling duration (36.15 d) and has been selected as a potential candidate for introducing the terminal heat stress tolerance in wheat breeding programmes. Breeding efforts using these candidate donors will help develop lines with a higher potential to express the desired heat stress-tolerant phenotype under field conditions.

scholarly journals The Impact of Oxidative Stress on Blood-Retinal Barrier Physiology in Age-Related Macular Degeneration

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 64
Author(s):  
Annamaria Tisi ◽  
Marco Feligioni ◽  
Maurizio Passacantando ◽  
Marco Ciancaglini ◽  
Rita Maccarone
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Blood Retinal Barrier ◽  
Functional Changes ◽  
Beneficial Effects ◽  
Age Related ◽  
The Impact

The blood retinal barrier (BRB) is a fundamental eye component, whose function is to select the flow of molecules from the blood to the retina and vice-versa, and its integrity allows the maintenance of a finely regulated microenvironment. The outer BRB, composed by the choriocapillaris, the Bruch’s membrane, and the retinal pigment epithelium, undergoes structural and functional changes in age-related macular degeneration (AMD), the leading cause of blindness worldwide. BRB alterations lead to retinal dysfunction and neurodegeneration. Several risk factors have been associated with AMD onset in the past decades and oxidative stress is widely recognized as a key factor, even if the exact AMD pathophysiology has not been exactly elucidated yet. The present review describes the BRB physiology, the BRB changes occurring in AMD, the role of oxidative stress in AMD with a focus on the outer BRB structures. Moreover, we propose the use of cerium oxide nanoparticles as a new powerful anti-oxidant agent to combat AMD, based on the relevant existing data which demonstrated their beneficial effects in protecting the outer BRB in animal models of AMD.

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