Department of Bioscience & Bioengineering

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IIT Jodhpur

We introduce PULSEDYN, a particle dynamics program written in C++, to solve the equations of motion of many-body nonlinear systems in one dimension. PULSEDYN contains a suite of commonly used potentials (Fermi–Pasta–Ulam–Tsingou, Toda, Morse and Lennard-Jones) and solvers (velocity-Verlet and Gear 5th order predictor–corrector) for particle dynamics. PULSEDYN is designed to perform scientifically accurate simulations using these calculations. For accessing the built-in features of PULSEDYN, no knowledge of programming is expected, apart from the creation of a parameter file using predefined commands for running the executable. Therefore, simulations for research projects can be performed with minimal code writing using PULSEDYN. PULSEDYN is distributed under the GNU GPL v3 license and the source code and the executable are available on Github. The writing style emphasizes organization and legibility. Therefore, we anticipate that it would serve as a good template for users who may wish to adapt the code to their specific needs. In this manuscript, we first discuss PULSEDYN and its features in detail. Then, we show results reproduced from literature using PULSEDYN for the following cases (i) Soliton propagation and collisions in the (integrable) Toda lattice (ii) Recurrence phenomena, decay of localized excitations and solitary wave collision in the Fermi–Pasta–Ulam–Tsingou lattice and (iii) Solitary wave propagation in the Morse and Lennard-Jones lattices. Finally, we present a new result on a problem of fundamental historical importance using PULSEDYN. We show by means of explicit specific heat calculations, that in the limit of strong nonlinearity, the quartic Fermi–Pasta–Ulam–Tsingou system approaches equipartition at late times. Program summary: Program Title: PULSEDYN Program Files doi: http://dx.doi.org/10.17632/fc8483t7jz.1 Licensing provisions: GNU General Public License 3 (GPL) Programming Language: C++ Supplementary Material: user manual, documentation Nature of problem: We solve a Newtonian particle dynamics problem in one dimension for a variety of commonly used nonlinear manybody systems. The goal is that the user should be able to run scientifically accurate simulations with minimal effort. Benchmarking should also be easy to perform by different users running simulations across different platforms. Solution method: The code uses a parameter file interface with a set of commands for a range of pre-built functionalities. By providing the code and the needed parameter file to the user we hope to make scientifically accurate simulations easier to perform. We provide the Gear 5th order predictor–corrector algorithm as well as the velocity-Verlet algorithm and the following potentials — the Toda potential, Morse Potential, Lennard-Jones Potential and a polynomial potential up to 4th order. To make benchmarking consistent we release the software as open source and free to distribute. © 2019 Elsevier B.V.

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Computer Physics Communications

PULSEDYN—A dynamical simulation tool for studying strongly nonlinear chains

To identify the upstream signaling of aluminum-induced malate secretion through aluminum-activated malate transporter 1 (AtALMT1), a pharmacological assay using inhibitors of human signal transduction pathways was performed. Early aluminum-induced transcription of AtALMT1 and other aluminum-responsive genes was significantly suppressed by phosphatidylinositol 4-kinase (PI4K) and phospholipase C (PLC) inhibitors, indicating that the PI4K-PLC metabolic pathway activates early aluminum signaling. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and PI4K reduced aluminum-activated malate transport by AtALMT1, suggesting that both the PI3K and PI4K metabolic pathways regulate this process. These results were validated using T-DNA insertion mutants of PI4K and PI3K-RNAi lines. A human protein kinase inhibitor, putatively inhibiting homologous calcineurin B-like protein-interacting protein kinase and/or Ca-dependent protein kinase in Arabidopsis, suppressed late-phase aluminum-induced expression of AtALMT1, which was concomitant with the induction of an AtALMT1 repressor, WRKY46, and suppression of an AtALMT1 activator, Calmodulin-binding transcription activator 2 (CAMTA2). In addition, a human deubiquitinase inhibitor suppressed aluminum-activated malate transport, suggesting that deubiquitinases can regulate this process. We also found a reduction of aluminum-induced citrate secretion in tobacco by applying inhibitors of PI3K and PI4K. Taken together, our results indicated that phosphatidylinositol metabolism regulates organic acid secretion in plants under aluminum stress. © The Author(s) 2019.

Journal of Experimental Botany

Involvement of phosphatidylinositol metabolism in aluminum-induced malate secretion in Arabidopsis

Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate. However, directed migration controlled by extrinsically applied electrical signals is poorly understood. Using a novel microfluidic platform, we found that metastatic breast cancer cells sense and respond to the net direction of weak (∼100 µV cm−1), asymmetric, non-contact induced Electric Fields (iEFs). iEFs inhibited EGFR (Epidermal Growth Factor Receptor) activation, prevented formation of actin-rich filopodia, and hindered the motility of EGF-treated breast cancer cells. The directional effects of iEFs were nullified by inhibition of Akt phosphorylation. Moreover, iEFs in combination with Akt inhibitor reduced EGF-promoted motility below the level of untreated controls. These results represent a step towards isolating the coupling mechanism between cell motility and iEFs, provide valuable insights into how iEFs target multiple diverging cancer cell signaling mechanisms, and demonstrate that electrical signals are a fundamental regulator of cancer cell migration. © 2019, The Author(s).

Communications biology

Electromagnetic fields alter the motility of metastatic breast cancer cells

Bioelectronics and Medical Devices: From Materials to Devices-Fabrication, Applications and Reliability reviews the latest research on electronic devices used in the healthcare sector, from materials, to applications, including biosensors, rehabilitation devices, drug delivery devices, and devices based on wireless technology. This information is presented from the unique interdisciplinary perspective of the editors and contributors, all with materials science, biomedical engineering, physics, and chemistry backgrounds. Each applicable chapter includes a discussion of these devices, from materials and fabrication, to reliability and technology applications. Case studies, future research directions and recommendations for additional readings are also included. The book addresses hot topics, such as the latest, state-of the-art biosensing devices that have the ability for early detection of life-threatening diseases, such as tuberculosis, HIV and cancer. It covers rehabilitation devices and advancements, such as the devices that could be utilized by advanced-stage ALS patients to improve their interactions with the environment. In addition, electronic controlled delivery systems are reviewed, including those that are based on artificial intelligences. © 2019 Elsevier Ltd. All rights reserved.

Bioelectronics and Medical Devices: From Materials to Devices - Fabrication, Applications and Reliability

Bioelectronics and medical devices: From materials to devices - fabrication, applications and reliability

Increase in number of people diagnosed with diabetes makes this disease a new health threat in the 21st century. Understanding the etiology of and finding a way to prevent diabetes, especially type 2 diabetes mellitus, is an urgent challenge for the health care community and our society. Pancreatic islet cells are responsible for maintaining normal blood glucose level and if there is any disturbance that leads to the onset of diabetes. Human pancreatic islet cells contain α,β,δ, and PP cells. Understanding the contribution of each type of cell through gene expression in type 2 diabetes mellitus is very important for the development of diagnostic tools. Therefore, gene expression data of α,β,δ and PP cells can be used. Single cell RNA sequencing technology has been found useful to generate expression data for individual cells. The gene expression data is usually used to find genes that are related to clinical outcome. However, in a biological process a set of genes are involved that share functional similarity. Analysing only single type of data may not generate significant type 2 diabetes mellitus genes. In this regard, an integrated approach has been used to analyse single-cell RNA sequencing data of human pancreatic islet cells. The integrated approach is designed by incorporating protein-protein interaction network data and gene expression data to select a set of genes that are highly related to diabetes also they are functionally related among themselves. The effectiveness of the approach is demonstrated over other existing methods. © 2018 IEEE.

Proceedings - 2018 IEEE International Conference on Bioinformatics and Biomedicine, BIBM 2018

Type 2 Diabetes Gene Identification Using an Integrated Approach from Single-Cell RNA Sequencing Data

Different physical methods have been explored to improve the transdermal delivery efficiency of many drugs. Iontophoresis is one of the significant acceptable physical methods for enhancing the penetration of ionic drugs through/into the skin by the application of electric current. Iontophoretic delivery of drugs is dependent on the physicochemical characteristics of the drug and the magnitude of the applied electric field. Due to its noninvasiveness, avoidance of systemic first-pass metabolism, controlling the rate of drug input over a prolonged period of time, and minimization of systemic side effects, iontophoretic drug delivery mechanism has gained significant acceptance in clinical use. In recent years, iontophoretic drug delivery of different drugs has been extensively explored in dermatology, ophthalmology, dentistry, and physical medicine. In the current chapter, historical background, principles and mechanisms, factors, advantages and disadvantages, and applications of iontophoresis in transdermal drug delivery have been comprehensively reviewed. © 2019 Elsevier Ltd. All rights reserved.

Iontophoretic drug delivery systems

Semi-autonomous functioning of mitochondria in eukaryotic cell necessitates coordination with nucleus. Several RNA species fine-tune mitochondrial processes by synchronizing with the nuclear program, however the involved components remain enigmatic. In this study, we identify a widely conserved dually localized protein Myg1, and establish its role as a 3-5 RNA exonuclease. We employ mouse melanoma cells, and knockout of the Myg1 ortholog in Saccharomyces cerevisiae with complementation using human Myg1 to decipher the conserved role of Myg1 in selective RNA processing. Localization of Myg1 to nucleolus and mitochondrial matrix was studied through imaging and confirmed by sub-cellular fractionation studies. We developed Silexoseqencing, a methodology to map the RNAse trail at single-nucleotide resolution, and identified in situ cleavage by Myg1 on specific transcripts in the two organelles. In nucleolus, Myg1 processes pre-ribosomal RNA involved in ribosome assembly and alters cytoplasmic translation. In mitochondrial matrix, Myg1 processes 3-termini of the mito-ribosomal and messenger RNAs and controls translation of mitochondrial proteins. We provide a molecular link to the possible involvement of Myg1 in chronic depigmenting disorder vitiligo. Our study identifies a key component involved in regulating spatially segregated organellar RNA processing and establishes the evolutionarily conserved ribonuclease as a coordinator of nucleo-mitochondrial crosstalk. © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research.

Nucleic Acids Research

Myg1 exonuclease couples the nuclear and mitochondrial translational programs through RNA processing

Vitiligo is the most common skin pigmentation disorder which affects around 1% of the population worldwide. The disease has complex pathogenesis and is of multifactorial etiology, that finally culminates in patchy depigmentation of skin. Genetic contribution to the disease is well studied, however the information about multiple associated genes and contributing variations are scattered across the literature. To address this complex disorder affecting the skin, we systematically cataloged the genes and variations by creating a Locus Specific Database for vitiligo called, “VitiVar”. This comprehensive resource houses manually curated 322 genes and 254 variations, from 202 articles indexed in PubMed. We applied an integrative approach to stratify genes and variations to facilitate dissection of vitiligo pathogenesis by layering it with expression status in specific constituent cell types of skin and in-house vitiligo expression data. Finally, we were able to demonstrate the utility of VitiVar by generating a vitiligo interactome using GeneMANIA and overlaying the vitiligo and cell type specific information. This interaction network yielded 20 new genes (apart from 322 VitiVar genes)of which we were able to prioritize IFI27 and IFI6 for further validation. This, thereby makes VitiVar a comprehensive integrative platform in unravelling disease biology by providing meaningful leads for functional interrogation. VitiVar is freely accessible to the research community for prioritizing and validating the candidate genes and variations (http://vitivar.igib.res.in/). © 2019

Gene: X

VitiVar: A locus specific database of vitiligo associated genes and variations

The role of inflammation in all phases of atherosclerotic process is well established and soluble TREM-like transcript 1 (sTLT1) is reported to be associated with chronic inflammation. Yet, no information is available about the involvement of sTLT1 in atherosclerotic cardiovascular disease. Present study was undertaken to determine the pathophysiological significance of sTLT1 in atherosclerosis by employing an observational study on human subjects (n=117) followed by experiments in human macrophages and atherosclerotic apolipoprotein E (apoE)−/− mice. Plasma level of sTLT1 was found to be significantly (P&lt;0.05) higher in clinical (2342 +− 184 pg/ml) and subclinical cases (1773 +− 118 pg/ml) than healthy controls (461 +− 57 pg/ml). Moreover, statistical analyses further indicated that sTLT1 was not only associated with common risk factors for Coronary Artery Disease (CAD) in both clinical and subclinical groups but also strongly correlated with disease severity. Ex vivo studies on macrophages showed that sTLT1 interacts with Fc receptor I (FcRI) to activate spleen tyrosine kinase (SYK)-mediated downstream MAP kinase signalling cascade to activate nuclear factor-κ B (NF-kB). Activation of NF-kB induces secretion of tumour necrosis factor-α (TNF-α) from macrophage cells that plays pivotal role in governing the persistence of chronic inflammation. Atherosclerotic apoE−/− mice also showed high levels of sTLT1 and TNF-α in nearly occluded aortic stage indicating the contribution of sTLT1 in inflammation. Our results clearly demonstrate that sTLT1 is clinically related to the risk factors of CAD. We also showed that binding of sTLT1 with macrophage membrane receptor, FcR1 initiates inflammatory signals in macrophages suggesting its critical role in thrombus development and atherosclerosis. © 2019 Portland Press Ltd. All rights reserved.

Clinical Science

Elevated level of circulatory sTLT1 induces inflammation through SYK/MEK/ERK signalling in coronary artery disease

The dynamics of cell-cell adhesion are complicated due to complexities in cellular interactions and intra-membrane interactions. In the present work, we have reconstituted a liposome-based model system to mimic the cell-cell adhesion process. Our model liposome system consists of one fluorescein-tagged and one TRITC (tetramethyl-rhodamine isothiocyanate)-tagged liposome, adhered through biotin-neutravidin interaction. We monitored the adhesion process in liposomes using Förster Resonance Energy Transfer (FRET) between fluorescein (donor) and TRITC (acceptor). Occurrence of FRET is confirmed by the decrease in donor lifetime as well as distinct rise time of the acceptor fluorescence. Interestingly, the acceptor's emission exhibits fluctuations in the range of ≈3±1 s. This may be attributed to structural oscillations associated in two adhered liposomes arising from the flexible nature of biotin-neutravidin interaction. We have compared the dynamics in a cell-mimicking liposome system with that in an in vitro live cell system. In the adhered live cell system, we used CPM (7-diethylamino-3-(4-maleimido-phenyl)-4-methylcoumarin, donor) and nile red (acceptor), which are known to stain the membrane of CHO (Chinese Hamster Ovary) cells. The dynamics of the adhered membranes of two live CHO cells were observed through FRET between CPM and nile red. The acceptor fluorescence intensity exhibits an oscillation in the time-scale of ≈1±0.75 s, which is faster compared to the reconstituted liposome system, indicating the contributions and involvement of multiple dynamic protein complexes around the cell membrane. This study offers simple reconstituted model systems to understand the complex membrane dynamics using a FRET-based physical chemistry approach. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim