<p>Shiv Nadar University is a comprehensive, multidisciplinary, research-focused, and student-centric University offering a full range of academic programs at the undergraduate, postgraduate and doctoral level. With state-of-the-art infrastructure, the University comprises of academic wings, sophisticated labs, international standard sports facilities, amphitheaters, auditorium, conference rooms and smart classrooms. The University&rsquo;s goal is to become internationally recognized for the quality of its research and creative endeavors and their applicability to improving quality of life, generating new insights and expanding the boundaries of human knowledge creativity. Committed to excellence in teaching, research and service, the University aims to serve the higher education needs of India and the world beyond.</p>

Shiv Nadar University

(SoNS) School of Natural Sciences

Despite the existing therapies and lack of receptors such as HER-2, estrogen receptor and progesterone receptor, triple-negative breast cancer is one of the most aggressive subtypes of breast cancer. TNBCs are known for their highly aggressive metastatic behavior and typically migrate to brain and bone for secondary site propagation. Many diseases share similar molecular pathology exposing new avenues in molecular signaling for engendering innovative therapies. Generation of newer therapies and novel drugs are time consuming associated with very high resources. In order to provide personalized or precision medicine, drug repositioning will contribute in a cost-effective manner. In our study, we have repurposed and used a neoteric combination of two drug molecules namely, fluvoxamine and tivozanib, to target triple-negative breast cancer growth and progression. Our combination regime significantly targets two diverse but significant pathways in TNBCs. Subsequent analysis on migratory, invasive, and angiogenic properties showed the significance of our repurposed drug combination. Molecular array data resulted in identifying the specific and key players participating in cancer progression when the drug combination was used. The innovative combination of fluvoxamine and tivozanib reiterates the use of drug repositioning for precision medicine and subsequent companion diagnostic development. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

World University root node

Life Sciences

Molecular and Cellular Biochemistry

Intuitive repositioning of an anti-depressant drug in combination with tivozanib: precision medicine for breast cancer therapy

Hijacking of host metabolic status by a pathogen for its regulated dissemination from the host is prerequisite for the propagation of infection. M. tuberculosis secretes an NAD+-glycohydrolase, TNT, to induce host necroptosis by hydrolyzing Nicotinamide adenine dinucleotide (NAD+). Herein, we expressed TNT in macrophages and erythrocytes; the host cells for M. tuberculosis and the malaria parasite respectively, and found that it reduced the NAD+ levels and thereby induced necroptosis and eryptosis resulting in premature dissemination of pathogen. Targeting TNT in M. tuberculosis or induced eryptosis in malaria parasite interferes with pathogen dissemination and reduction in the propagation of infection. Building upon our discovery that inhibition of pathogen-mediated host NAD+ modulation is a way forward for regulation of infection, we synthesized and screened some novel compounds that showed inhibition of NAD+-glycohydrolase activity and pathogen infection in the nanomolar range. Overall this study highlights the fundamental importance of pathogen-mediated modulation of host NAD+ homeostasis for its infection propagation and novel inhibitors as leads for host-targeted therapeutics. © 2021, The Author(s).

Fulltext

Cell Death Discovery

Pathogen induced subversion of NAD+ metabolism mediating host cell death: a target for development of chemotherapeutics

Studies over the past four decades have elucidated the role of Wnt/β-catenin mediated regulation in cell proliferation, differentiation and migration. These processes are fundamental to embryonic development, regeneration potential of tissues, as well as cancer initiation and progression. In this review, we focus on the epigenetic players which influence the Wnt/β-catenin pathway via modulation of its components and coordinated regulation of the Wnt target genes. The role played by crosstalk with other signaling pathways mediating tumorigenesis is also elaborated. The Hippo/YAP pathway is particularly emphasized due to its extensive crosstalk via the Wnt destruction complex. Further, we highlight the recent advances in developing potential therapeutic interventions targeting the epigenetic machinery based on the characterization of these regulatory networks for effective treatment of various cancers and also for regenerative therapies. © Copyright © 2021 Sharma, Mir and Galande.

Frontiers in Genetics

Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer

The article describes the non-genetic roles of DNA molecule and its applications in diagnostic and therapeutic fields such as in biosensors, barcodes, nanomachines, biochips, probes, and DNA scaffolds. © 2021, Indian Academy of Sciences.

Resonance

DNA: More Than Just a Genetic Material

The current theoretical perception of enzymatic activity is highly reliant on the determination of the activation energy of the reactions{,} which is often calculated using computationally demanding quantum mechanical calculations. With the ever-increasing use of bioengineering techniques that produce too many variants of the same enzyme{,} a fast and accurate way to study the relative efficiency of enzymes is currently in high demand. Here{,} we propose the local electric field (LEF) of the enzyme along the reaction axis as a descriptor for the enzymatic activity using the example of chorismate mutase in its native form and several variants (R90A{,} R90G{,} and R90K/C88S). The study shows a direct correlation between the calculated enzymatic EF and the enzymatic activity for all the complexes. MD simulations of the Michaelis complex and the transition state analog (TSA) show a stabilizing force on the TSA due to the enzymatic EF. QM/MM and QM-only DFT calculations in the presence of an external electric field (EEF) oriented along the reaction axis show that the electric field can interact with the dipole moment of the TS{,} thereby stabilizing it and thus lowering the activation energy.

Chemistry

Phys. Chem. Chem. Phys.

Can the local electric field be a descriptor of catalytic activity? A case study on chorismate mutase

The HisA enzyme catalyzes the first step of histidine biosynthesis via Amadori rearrangement of substrate ProFAR. Since it possesses the most conserved and ancient TIM-barrel fold{,} it provides an ideal framework for bioengineering a new function from ancestral enzymes. In the present study firstly{,} the catalytic mechanism of HisA biosynthesis was elucidated using hybrid Quantum Mechanical/Molecular Mechanical calculations{,} and thereafter{,} key residues contributing towards the promiscuity for TrpF activity were revealed using several MD simulations of wild type enzyme and its variant with the native (ProFAR) and promiscuous (PRA) substrates. Our study reveals that the two loops (βα)1 and (βα)5 on the catalytic site of the HisA enzyme{,} have incredible adaptability for the native and promiscuous substrates. The conformational interplay between these two loops is substrate driven and precise bioengineering targeting these loops is key to the emergence of new functions. Furthermore{,} the study reveals a key role of Arg 15 residue which is close to the catalytic center of the enzyme in the bifunctionality of HisA enzyme by increasing the loop flexibility. Therefore{,} our study provides crucial information for future bioengineering work to use the HisA enzyme as a scaffold for new enzymatic activity.

Org. Biomol. Chem.

Simulations Reveal Key Role of Arg15 for Promiscuous Activity in HisA Enzyme

This chapter describes the use of external-electric fields (EEFs) as effectors of chemical change{,} with the aim of providing a guiding conceptual framework. As such{,} the following text intends to serve as a teaching material for readers{,} on how to conceptualize and design electric-field effects on bonds{,} structures{,} and reactions. Many of these effects can be comprehended in terms of valence bond (VB) concepts as the field-induced stabilization of ionic structures. Thus{,} orienting the field along the “bond axis” will facilitate bond breaking. Similarly{,} orienting the field along the “reaction axis”{,} the direction in which electron pairs transform from reactant-to product-like{,} will lower the reaction barrier. Flipping the field{'}s orientation along the reaction axis will cause inhibition. Orienting the field off-reaction-axis will generally control stereo-selectivity and enantioselectivity{,} and the removal of forbidden-orbital mixing. Three-directional fields will orient the reactants in space and control their reactivity and selectivity patterns. Increasing the field strength for concerted reactions{,} e.g.{,} in Diels–Alder and oxidative addition reactions{,} will cause mechanistic-switchover to stepwise mechanisms with ionic intermediates. Examples of bond breaking and control of reactivity/selectivity and mechanistic crossovers are presented and analysed from the “ionic perspective”. Textboxes and rules summarize the various effects of electric fields.

CHAPTER 2 The Impact of Electric Fields on Chemical Structure and Reactivity

To improve the power conversion efficiency (PCE) of the organic solar cells (OSCs), it is necessary to widen the absorption profile of the active layer. It is possible by using a ternary active layer consisting of either two donors (D) and one acceptor (A) or two acceptors and one donor having complementary absorption and appropriate frontier energy levels for efficient exciton generation and their dissociation into free charge carriers and subsequent charge/energy transfer. Herein, a large bandgap guaiacol-based small molecule (SMD) is used as guest donor in ternary OSCs to improve the PCE and suppress the energy loss. SMD exhibits a lager bandgap and deeper highest occupied molecular orbital (HOMO) energy level compared with conjugated polymer donor (P). Therefore, the HOMO energy level is effectively down-shifted when P is mixed with SMD, which is beneficial for attaining high open circuit voltage (VOC). OSCs based on the optimized ternary blend P:SMD:Y6 (0.8:0.2:1.2, w/w) after solvent vapor annealing attained a higher VOC of 0.85 V and low energy loss of 0.51 eV compared with the binary device P:Y6 (1:1.2, w/w) with VOC of 0.81 V and energy loss of 0.55 eV, delivering an overall PCE of 15.37%. © 2021 Wiley-VCH GmbH.

Solar RRL

Incorporation of a Guaiacol-Based Small Molecule Guest Donor Enables Efficient Nonfullerene Acceptor-Based Ternary Organic Solar Cells

<p>Inducement of high charge carrier density in organic field-effect transistors (OFETs) is a subject of immense interest due to its fundamental and applied impact on device operation. Here, the high performance of imidazolium-based ionic liquid (IL)-gated OFETs is reported. By exploiting the p-doping of poly(3-hexylthiophene-2,5diyl) (P3HT) in the ambient environment and using the IL-gating, high charge carrier density (1016 cm-2) has been induced in P3HT, which has resulted in high hole mobility (20.2 cm2 V-1 s-1). This is a remarkable improvement in field-effect mobility in organic polymer semiconductors. Along with high mobility, low threshold voltage (∼0.6 V), low subthreshold swing (∼100 mV dec-1), and specifically the high transconductance (&gt;1 mS) position this class of devices as a strong candidate for electrical sensor platforms. The compatibility of ILs with biomolecules and the direct access to IL/P3HT interface make these devices suitable for in situ biosensors. The IL components (cation and anion) were varied (one at a time) to investigate the effect on the electrical performance of the OFETs. An increase in the gate-electrode metal work function leads to a systematic decrease in the threshold voltage (by up to 0.6 V). The mobility exhibits a negative power dependence on specific capacitance, a signature of polaronic self-localization in organic semiconductors. The shelf life of the IL-gated OFETs is found to be more than 40 days. ©</p>

Physics

ACS Applied Electronic Materials

High-Performance Organic Field-Effect Transistors Gated by Imidazolium-Based Ionic Liquids

Non-pharmaceutical interventions (NPIs) involving social-isolation strategies such as self-quarantine (SQ) and social-distancing (SD) are useful in controlling the spread of infections that are transmitted through human-to–human contacts, e.g., respiratory diseases such as COVID-19. In the absence of a safe and effective cure or vaccine during the first ten months of the COVID-19 pandemic, countries around the world implemented these social-isolation strategies and other NPIs to reduce COVID-19 transmission. But, individual and public perception play a crucial role in the success of any social-isolation measure. Thus, in spite of governments’ initiatives to use NPIs to combat COVID-19 in many countries around the world, individual choices rendered social-isolation unsuccessful in some of these countries. This resulted in huge outbreaks that imposed a substantial morbidity, mortality, hospitalization, economic, etc., toll on human lives. In particular, human choices pose serious challenges to public health strategic decision-making in controlling the COVID-19 pandemic. To unravel the impact of this behavioral response to social-isolation on the burden of the COVID-19 pandemic, we develop a model framework that integrates COVID-19 transmission dynamics with a multi-strategy evolutionary game approach of individual decision-making. We use this integrated framework to characterize the evolution of human choices in social-isolation as the disease progresses and public health control measures such as mandatory lockdowns are implemented. Analysis of the model illustrates that SD plays a major role in reducing the burden of the disease compared to SQ. Parameter estimation using COVID-19 incidence data, as well as different lockdown data sets from India, and scenario analysis involving a combination of Voluntary-Mandatory implementation of SQ and SD shows that the effectiveness of this approach depends on the type of isolation, and the time and period of implementation of the selected isolation measure during the outbreak. © 2021 Elsevier Ltd