Browsing by Author "Ashutosh Singh"

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A novel inhibitor L755507 efficiently blocks c-Myc–MAX heterodimerization and induces apoptosis in cancer cells
(American Society for Biochemistry and Molecular Biology Inc., 2021) Ashutosh Singh; Ankur Kumar; Prateek Kumar; Namyashree Nayak; Taniya Bhardwaj; Rajanish Giri; Neha Garg
c-Myc is a transcription factor that plays a crucial role in cellular homeostasis, and its deregulation is associated with highly aggressive and chemotherapy-resistant cancers. After binding with partner MAX, the c-Myc–MAX heterodimer regulates the expression of several genes, leading to an oncogenic phenotype. Although considered a crucial therapeutic target, no clinically approved c-Myc-targeted therapy has yet been discovered. Here, we report the discovery via computer-aided drug discovery of a small molecule, L755507, which functions as a c-Myc inhibitor to efficiently restrict the growth of diverse Myc-expressing cells with low micromolar IC50 values. L755507 successfully disrupts the c-Myc–MAX heterodimer, resulting in decreased expression of c-Myc target genes. Spectroscopic and computational experiments demonstrated that L755507 binds to the c-Myc peptide and thereby stabilizes the helix–loop–helix conformation of the c-Myc transcription factor. Taken together, this study suggests that L755507 effectively inhibits the c-Myc–MAX heterodimerization and may be used for further optimization to develop a c-Myc-targeted antineoplastic drug. © 2021 THE AUTHORS.
Anticancer SAR establishment and α/β-tubulin isoform specific targeting: a detailed insight of the anticancer potential of 4H-chromene derivatives
(Royal Society of Chemistry, 2023) None Mayank; Ashutosh Singh; Kumar Udit Saumya; Mayank Joshi; Navneet Kaur; Neha Garg; Narinder Singh
4H-Chromene derivatives are promising anticancer compounds known to bind within the colchicine binding site of the tubulin protein. Among these, the 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile-based 4H-chromenes scaffold is known to produce a significant impact on tubulin proteins. Other molecules with similar pharmacophores are also known for their colchicine binding site targeting abilities. However, tubulin is not a single protein; multiple isoforms have been reported, and some are comparatively more important under malignant conditions. Therefore, the research findings presented herein include a detailed understanding of the interaction pattern of the 2-amino-4-phenyl-4H-benzo[h]chromene-3-carbonitrile series for their colchicine binding ability against various tubulin isoforms proteins. We have established the current series anticancer potential and structural activity relationship. The series revealed promising anticancer potential, and MNC-1 was the best among all. However, a serious side effect of this scaffold is a major problem, as these derivatives indiscriminately bind to the tubulin of malignant and normal cells. However, the expression profile of tubulin isoforms was found to be different in normal and malignant cell types. Therefore, selective killing of the malignant cell seems possible by designing a 4H-chromenes derivative selective against particular tubulin isoforms. The insights provided herein clearly indicate the differences in the binding pattern of different 4H-chromenes derivatives against different tubulin isoforms. Therefore, with precise structural modification, these molecules’ selective targeting against cancer cells seems quite possible. © 2023 The Royal Society of Chemistry.
Aspects of nonflat FRW bouncing models with quadratic equation of state
(World Scientific Publishing Co. Pte Ltd, 2018) Ashutosh Singh; Rakesh Raushan; R. Chaubey; T. Singh
In this paper, we investigate the possibility of a nonsingular model of universe in the framework of general relativity in nonflat FRW geometries with quadratic equation of state and bulk viscosity. We study whether a nonsingular bounce requires violation of energy conditions. We discuss the thermodynamical aspects of the resulting models with equilibrium description. In particular, we discuss the validity of the generalized second law of thermodynamics for resulting cosmologies. © 2018 World Scientific Publishing Company.
Beam-wave interaction behavior of a 35 GHz metal PBG cavity gyrotron
(American Institute of Physics Inc., 2014) Ashutosh Singh; P.K. Jain
The RF behavior of a 35GHz photonic band gap (PBG) cavity gyrotron operating in TE041-like mode has been presented to demonstrate its single mode operation capability. In this PBG cavity gyrotron, the conventional tapered cylindrical cavity is replaced by a metal PBG cavity as its RF interaction structure. The beam-wave interaction behavior has been explored using time dependent multimode nonlinear analysis as well as through 3D PIC simulation. Metal PBG cavity is treated here similar to that of a conventional cylindrical cavity for the desired mode confinement. The applied DC magnetic field profile has been considered uniform along the PBG cavity length both in analysis as well as in simulation. Electrons energy and phase along the interaction length of the PBG cavity facilitates bunching mechanism as well as energy transfer phenomena from the electron beam to the RF field. The RF output power for the TE041-like design mode as well as nearby competing modes have been estimated and found above to 100kW in TE041-like mode with ∼15% efficiency. Results obtained from the analysis and the PIC simulation are found in agreement within 8% variation, and also it supports the single mode operation, as the PBG cavity does not switch into other parasitic modes in considerably large range of varying DC magnetic field, contrary to the conventional cylindrical cavity interaction structure. © 2014 AIP Publishing LLC.
Bounce conditions for FRW models in modified gravity theories
(Springer Verlag, 2015) T. Singh; R. Chaubey; Ashutosh Singh
In this paper, we have derived the minimal conditions for a bounce to occur in FRW cosmologies for the theories like Hoyle-Narlikar creation field theory, Lyra geometry, Brans-Dicke theory, general class of Scalar-Tensor theories, Einstein’s theory with variable cosmological term, with bulk viscosity and Finslerian cosmology. We derive the model-independent minimal necessary conditions for non-singular bounce and show that there is an open temporal region surrounding the bounce over which the strong energy condition (SEC) must be violated. Null energy condition is also violated in some of the modified gravity theories. © 2015, Società Italiana di Fisica and Springer-Verlag Berlin Heidelberg.
Bounce conditions in Kantowski-Sachs and Bianchi cosmologies in modified gravity theories
(World Scientific Publishing Co. Pte Ltd, 2015) T. Singh; R. Chaubey; Ashutosh Singh
Many cosmological scenarios envisage either a bounce of the universe at early times, or a collapse locally to form a black hole which re-expands into a new expanding universe region. Energy conditions preclude this phenomena for ordinary matter in general relativistic universe, but scalar or other types of fields can violate some of these conditions, and so can, possibly, provide conditions for a bouncing universe. In this paper, we have investigated the necessary conditions for a bounce in Kantowski-Sachs (KS) and Bianchi type models in some modified theories of gravity like Hoyle-Narlikar creation field theory, Lyra geometry, general class of scalar-tensor theories, Einstein's theory with variable cosmological term. © 2015 World Scientific Publishing Company.
Bouncing cosmologies in Brans-Dicke theory
(Canadian Science Publishing, 2016) T. Singh; R. Chaubey; Ashutosh Singh
In this paper it is shown that in Brans-Dicke theory, if one considers a non-minimal coupling between the matter and scalar field, can give rise to a bouncing universe (i.e., an expanding universe preceded by a contracting universe). Two examples of such universes have been considered in a spatially flat Friedmann-Robertson-Walker universe and their physical properties have been studied. © 2016 Published by NRC Research Press.
Bouncing cosmologies with viscous fluids
(Springer Netherlands, 2016) T. Singh; R. Chaubey; Ashutosh Singh
The bounce in viscous fluid cosmology with inhomogeneous viscous fluids in Friedman-Robertson-Walker (FRW) space-time has been investigated. Different forms for the scale factor have been considered. The general features of the fluids which realize them and the possibility to have an acceleration after the bounce have been discussed. © 2016, Springer Science+Business Media Dordrecht.
Carotenoids and pH of the culture medium play an important role in displaying metal stress in batch and semi-continuous cultures of Anabaena doliolum
(2009) Bhumi Nath Tripathi; Rohini Kasana; Vijeta Singh; Indu Bhatt; Ashutosh Singh; Vinay Sharma; Jai Prakash Gaur
We analysed the responses of Anabaena doliolum to elevated levels of copper and zinc in batch and semi-continuous cultures. Approximately 10, 4 and 8 and 5-times greater inhibition in final yield of A. doliolum occurred at 1, 2 μM Cu and 2.5 and 5 μM of Zn, respectively, in semi-continuous culture in comparison to batch culture. Protein, chlorophyl a and carotenoid contents of A. doliolum showed significantly (P<0.05) higher inhibition by test metals in semi-continuous culture than in batch culture. The greater sensitivity of different parameters of the test organism was related to the high metal content of the cells grown in semi-continuous system. Moreover, enhancement of pH of the culture suspension in batch culture showed a negative relationship with metal accumulation, and therefore with toxicity. This was due to decrease in free ionic concentrations of test metals. Carotenoids acted as a metal detoxifying agent by minimizing metal-induced inhibition in batch culture as was evident from its negative relationship with metal toxicity. © EDP Sciences, 2009.
Cellular experiments to study the inhibition of c-Myc/MAX heterodimerization
(Academic Press Inc., 2022) Ashutosh Singh; Shilpa Sharma; Praveen Kumar; Neha Garg
The c-Myc oncogene is a master regulator of cancer cell metabolism, which controls a variety of pathways, including cell proliferation, cell cycle, apoptosis, and epigenetics. Belonging to the bHLH family of transcription factors, c-Myc forms a heterodimeric complex with another bHLH family protein MAX. c-Myc deregulation is reported in most cancers. This heterodimeric complex is a potent transcription factor that controls the expression of the target gene by binding to the E-box sequence and thereby controlling cancer cell proliferation. c-Myc in isolation has a partially folded structure and cannot carry the transcription. However, its heterodimerization provides the ability to bind DNA and carry out the regulatory function. Therefore, heterodimerization of c-Myc and Max is of great interest for cancers, and it has always been considered a target for cancer therapy. This book chapter will present a detailed protocol of cellular experiments employed to validate the in vitro potency of c-Myc inhibitor candidates to search for a novel c-Myc-targeted neoplastic drug. © 2022 Elsevier Inc.
Chameleon scalar field in LRS Bianchi type I cosmological model
(Maik Nauka Publishing / Springer SBM, 2016) R. Chaubey; Ashutosh Singh; Rakesh Raushan
We consider an anisotropic cosmological model with cold dark matter and a scalar field, where one component of the scale factor is taken in the framework of (i) a logamediate scenario (ii) an intermediate scenario, and (iii) an emergent scenario. In all cases we find expressions for the Chameleon field, Chameleon potential, the statefinder diagnostic pair, i.e., the {r, s} parameters, and the slow-roll parameters. All physical parameters are calculated and discussed in all three cases. It is also shown how the Chameleon field is directly affected by the role of curvature of space time. At large times (t→∞) the models tend asymptotically to an isotropic Friedmann–Robertson–Walker cosmological model. © 2016, Pleiades Publishing, Ltd.
Direct transport theory: From the nose to the brain
(Elsevier, 2021) Namdev Dhas; Dattatray Yadav; Ashutosh Singh; Atul Garkal; Ritu Kudarha; Priyanka Bangar; Jignasa Savjani; Chandrakantsing V. Pardeshi; Neha Garg; Tejal Mehta
The delivery of drugs to CNS has been constrained due to the presence of blood-brain barrier (BBB). The intranasal route involving several pathways (viz., olfactory, trigeminal, and rostral migratory stream-based pathway) has emerged as potential route to bypass the BBB and transport drug directly to the brain. In another terms, intranasal route involves two distinct mechanistic transportation pathways, viz., extracellular and intracellular. Extracellular pathway is responsible for the transportation of drug directly to cerebrospinal fluid (CSF) by passing through paracellular space across the nasal epithelium, then through the perineuronal space to the subarachnoid space of the brain. However, intracellular pathways start with olfactory sensory cell-based endocytosis, followed by axonal transportation to their synaptic clefts in the olfactory bulb where the therapeutic moiety is exocytosed. This chapter inculcates various pathways and transport mechanisms involved in the direct transportation of drugs to the brain. The several case studies involving pharmacokinetics of nanoparticle-based delivery systems when administered intranasally have also been explained in this chapter. © 2021 Elsevier Inc.
Drug Screening Assays on Medulloblastoma Stem Cells Using Compound Libraries
(Humana Press Inc., 2022) Ashutosh Singh; Neha Garg
Conventional chemotherapies for medulloblastoma are restricted to only proliferative population leaving the cancer stem cells unscathed. This shortcoming of the traditional therapies is attributed to the relapse and metastasis of the cancer. The current research is entirely focused on the screening of therapeutic agents that can restrict and target the self-renewal potential of the cancer stem cells. The advances in drug screening strategies have led to high-throughput screening which provide a robust and expeditious platform to screen potential compounds against cancer stem cells. In this book chapter, we describe two in vitro assays that are routinely used to measure the cell killing and anti–self-renewal activity of the compounds against the cancer stem cells. Combining these assays with high-throughput screening offers a rapid, reliable, and inexpensive approach to screen potential compounds against cancer stem cells and to overcome the limitation of conventional chemotherapeutic agents. © 2022, The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.
Excited-State Intramolecular Hydrogen-Bonding-Assisted Restricted Rotation: A Mechanism for Monitoring Intracellular Viscosity and Distinguishing Malignant, Differentiating, and Apoptotic Cancer Cells
(American Chemical Society, 2021) Mayank; Jayant Sindhu; Ashutosh Singh; Namyashree Nayak; Neha Garg; Navneet Kaur; Narinder Singh
We have successfully developed a sensor (IP1) that utilizes a confocal-based live-cell imaging technique for distinguishing malignant, differentiating, and under-apoptosis cancer cells. The intracellular viscosity (IVis) is minimum in the cancer cell, intermediate in differentiating cells, and maximum in the apoptotic cells. Therefore, we have developed a molecular rotor (IP1) that can sense the changes in intracellular viscosity. IP1 works on the viscosity-assisted restricted-rotation mechanism and is facilitated by the excited-state intramolecular hydrogen-bonding phenomenon (ESIHB). The use of ESIHB has fine-tuned the viscosity-sensing properties of IP1, which in turn has greatly helped in our quest of distinguishing the malignant, differentiating, and apoptotic cancer cells by the IP1 probe. It was very effective in monitoring apoptosis by increased fluorescence intensity by the confocal live-cell imaging technique. The noncytotoxic behavior, even at 10 μg/mL concentration, is a charming feature of the developed probe. To the best of our knowledge, this is the first report for the ESIHB-based fluorescence probe that can distinguish malignant, differentiating, and apoptotic cancer cells by the use of live-cell imaging techniques. © 2021 American Chemical Society.
Exploring cosmic dynamics in Finsler–Randers model: Observational and dynamical system analysis
(World Scientific, 2025) Ashutosh Singh; Rakesh Raushan; Raghavendra Chaubey; Sajal Mandal
In this study, we consider the Finsler–Randers geometry model composed of standard matter, radiation and the cosmological constant-like dark energy. We explore the cosmic dynamics by using the dynamical system approach. This analysis reveals that the universe evolution composed of the decelerating and accelerating era will be explained in the model. In particular, the fixed points for the matter, radiation and the de Sitter era will exist in the model along with an additional fixed point for which the universe will evolve with ρ ∝ (1 + z)½. The observational estimation of model parameters involves the Bayesian analysis approach using the Markov Chain Monte Carlo method. The observational analysis highlight that the Finsler and ΛCDM models may be indistinguishable from each other for Ωϕ = 10−3. Although, for higher order values of Ωϕ, the universe in the Finsler and ΛCDM model may evolve differently. © 2025 World Scientific Publishing Company.
Functional inhibition of c-Myc using novel inhibitors identified through “hot spot” targeting
(American Society for Biochemistry and Molecular Biology Inc., 2022) Ashutosh Singh; Prateek Kumar; Sailu Sarvagalla; Taniya Bharadwaj; Namyashree Nayak; Mohane Selvaraj Coumar; Rajanish Giri; Neha Garg
Protein–protein interactions drive various biological processes in healthy as well as disease states. The transcription factor c-Myc plays a crucial role in maintaining cellular homeostasis, and its deregulated expression is linked to various human cancers; therefore, it can be considered a viable target for cancer therapeutics. However, the structural heterogeneity of c-Myc due to its disordered nature poses a major challenge to drug discovery. In the present study, we used an in silico alanine scanning mutagenesis approach to identify “hot spot” residues within the c-Myc/Myc-associated factor X interface, which is highly disordered and has not yet been systematically analyzed for potential small molecule binding sites. We then used the information gained from this analysis to screen potential inhibitors using a conformation ensemble approach. The fluorescence-based biophysical experiments showed that the identified hit molecules displayed noncovalent interactions with these hot spot residues, and further cell-based experiments showed substantial in vitro potency against diverse c-Myc-expressing cancer/stem cells by deregulating c-Myc activity. These biophysical and computational studies demonstrated stable binding of the hit compounds with the disordered c-Myc protein. Collectively, our data indicated effective drug targeting of the disordered c-Myc protein via the determination of hot spot residues in the c-Myc/Myc-associated factor X heterodimer. © 2022 THE AUTHORS.
General class of Bianchi cosmological models with Λ in creation-field cosmology
(Kluwer Academic Publishers, 2014) R. Chaubey; A.K. Shukla; Ashutosh Singh; T. Singh
The solutions of Einstein's equations with cosmological constant (Λ) in the presence of a creation field have been obtained for general class of anisotropic cosmological models. We have obtained the cosmological solutions for two different scenarios of average scale factor. In first case, we have discussed three different types of physically viable cosmological solutions of average scale factor for the general class of Bianchi cosmological models by using a special law for deceleration parameter which is linear in time with a negative slope. In second case, we have discussed another three different forms of cosmological solutions by using the average scale factor in three different scenarios like Intermediate scenario, Logamediate scenario and Emergent scenario. All physical parameters are calculated and discussed in each physical viable cosmological model. We examine the nature of creation field and cosmological constant is dominated the early Universe but they do not survive for long time and finally tends to zero for large cosmic time t. We have also discussed the all energy conditions in each cases. © 2014 Springer Science+Business Media Dordrecht.
Interacting dark energy models within the context of the particle creation framework: A dynamical systems study
(Elsevier B.V., 2025) Aman K. Shukla; Ashutosh Singh; Raghavendra Chaubey
In this paper, we employ the dynamical system method to probe the cosmological evolution in a matter creation model admitting interacting dark energy behavior. The set of dynamical variables in this framework allows one to trace the cosmic evolution in comparison to the Λ cold dark matter (ΛCDM) model. The critical points in cosmological phase space are analyzed for their stability nature. The numerical integrations of the autonomous system are used to extract the evolution of cosmological quantities of the model, subjected to the initial condition compatible with observational data. The resulting cosmological behavior observed from the dynamical variables, cosmographic parameters and statefinder analysis illustrate the similarity as well as deviations from the ΛCDM model during different cosmic expansion phases. The autonomous systems are also used to study the classical stability of models under consideration. The interacting dark energy scenario in the matter creation mechanism leads to the universe evolution, which traces their journey from the decelerating phase (composed of radiation and matter phase) into accelerating phase dominated by a negative pressure component, which is directly consistent with observations. © 2025
K-essence cosmologies in Kantowski-Sachs and Bianchi space-times
(Canadian Science Publishing, 2015) T. Singh; R. Chaubey; Ashutosh Singh
We investigate Kantowski-Sachs, locally rotationally symmetric Bianchi-I and Bianchi-III cosmology with k-essence and found a set of models that dissipate the initial anisotropy. We obtain the conditions leading to a regular bounce of the average geometry. We show that the linear k-field and polynomial kinetic function models evolve asymptotically to Friedmann-Robertson-Walker cosmologies. For linear k-essence we find the general solution in these cosmologies, when the k-field is driven by an inverse scalar potential. © 2015 Published by NRC Research Press.
Kantowski-Sachs and Bianchi type models with a general non-canonical scalar field
(Maik Nauka Publishing / Springer SBM, 2017) T. Singh; R. Chaubey; Ashutosh Singh
The paper deals with spatially homogeneous and anisotropic Kantowski-Sachs and Bianchi universes with a general non-canonical scalar field with the Lagrangian L = F(X) − Ω(ϕ), where X=12ϕiϕi. We discuss a general non-canonical scalar field in three different cosmologies: (i) cosmology with a constant potential, Ω(ϕ) = Ω0 = const, (ii) cosmology with a constant equation-of-state parameter, i.e., γϕ = const, and (iii) cosmology with a constant speed of sound, i.e., cs 2 = const. For a constant potential, we have shown that the k-essence Lagrangian and the Lagrangian of the present model are equivalent. Dissipation of anisotropy, when the universe is filled with a general non-canonical scalar field, is investigated. The existence of an average bounce in Kantowski-Sachs and locally rotationally symmetric Bianchi-I and Bianchi-III models is discussed in detail. © 2017, Pleiades Publishing, Ltd.