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Shiv Nadar University

(SoNS) School of Natural Sciences

Post-translational modifications (PTMs) including phosphorylation and palmitoylation have emerged as crucial biomolecular events that govern many cellular processes including functioning of motility- and invasion-associated proteins during Plasmodium falciparum invasion. However, no study has ever focused on understanding the possibility of a crosstalk between these two molecular events and its direct impact on preinvasion- and invasion-associated protein–protein interaction (PPI) network-based molecular machinery. Here, we used an integrated in silico analysis to enrich two different catalogues of proteins: (i) the first group defines the cumulative pool of phosphorylated and palmitoylated proteins, and (ii) the second group represents a common set of proteins predicted to have both phosphorylation and palmitoylation. Subsequent PPI analysis identified an important protein cluster comprising myosin A tail interacting protein (MTIP) as one of the hub proteins of the glideosome motor complex in P. falciparum, predicted to have dual modification with the possibility of a crosstalk between the same. Our findings suggested that blocking palmitoylation led to reduced phosphorylation and blocking phosphorylation led to abrogated palmitoylation of MTIP. As a result of the crosstalk between these biomolecular events, MTIP’s interaction with myosin A was found to be abrogated. Next, the crosstalk between phosphorylation and palmitoylation was confirmed at a global proteome level by click chemistry and the phenotypic effect of this crosstalk was observed via synergistic inhibition in P. falciparum invasion using checkerboard assay and isobologram method. Overall, our findings revealed, for the first time, an interdependence between two PTM types, their possible crosstalk, and its direct impact on MTIP-mediated invasion via glideosome assembly protein myosin A in P. falciparum. These insights can be exploited for futuristic drug discovery platforms targeting parasite molecular machinery for developing novel antimalarial therapeutics. Copyright © 2022 Anam, Kumari, Mukherjee, Rex, Biswas, Maurya, Ravikumar, Gupta, Kushawaha, Sah, Chaurasiya, Singhal, Singh, Kaushik, Prasad, Pati, Ranganathan and Singh.

World University root node

Life Sciences

Fulltext

Frontiers in Cellular and Infection Microbiology

Complementary crosstalk between palmitoylation and phosphorylation events in MTIP regulates its role during Plasmodium falciparum invasion

Human COVID-19 has affected more than 491 million people worldwide. It has caused over 6.1 million deaths and has especially perpetrated a high number of casualties among the elderly and those with comorbid illnesses. COVID-19 triggers a pro-oxidant response, leading to the production of reactive oxygen species (ROS) as a common innate defense mechanism. However, ROS are regulated by a key enzyme called G6PD via the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), which controls the generation and removal of ROS in a tissue-specific manner. Therefore, a deficiency of G6PD can lead to the dysregulation of ROS, which causes a severe inflammatory response in COVID-19 patients. This report highlights the G6PD dichotomy in the regulation of ROS and inflammatory responses, as well as its deficiency in severity among COVID-19 patients. © 2022 Future Medicine Ltd.

Future Microbiology

G6PD deficiency: imbalance of functional dichotomy contributing to the severity of COVID-19

Hirschsprung's disease (HD) is widely characterized by the absence of ganglion cells in the colon of infants and children resulting in a spectrum of diseases starting from constipation to intestinal obstruction. The disease can have a serious manifestation of Hirschsprung-associated enterocolitis which can lead to significant morbidity and even mortality. Presently the treatment includes surgical excision of the pathological segment of the colon. Identification of the segment requires histopathology and immunohistochemistry which is time-consuming and requires significant expertise of a pathologist. There is a gap in the management of the disease in the form of absence of suitable, sensitive, and efficient technologies to detect the pathological segment of the intestine, which could significantly reduce surgery duration in the operation theatre, as well as associated risks to patients. It, therefore, becomes a matter of extreme importance to develop a point-of-care platform for early and efficient identification of the occurrence of HD in neonates and older children during surgery. The present work reports on the development of an electrochemical enzymatic biosensor using anodized laser-induced graphene (aLIG) conjugated with acetylcholinesterase enzyme (AchE), for detection of HD as a function of acetylcholine – the key biomarker. The developed sensor was initially characterized using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), while the sensor's analytical performance was assessed using CV. The sensor exhibited a limit of detection of 0.26 μM with a shelf life of 1 month, while remaining unperturbed in the presence of common interferants. The performance of the developed sensor was also examined in spiked serum samples and was observed to yield a high degree of linearity. © 2022 Elsevier B.V.

Physics

Diamond and Related Materials

Design and development of an electroanalytical enzymatic sensor using anodized laser induced graphene for the management of Hirschsprung Disease

Modeling approaches and modern simulations to investigate the biomolecular structure and function rely on various methods. Since water molecules play a crucial role in all sorts of chemistry, the accurate modeling of water molecules is vital for such simulations. In cytochrome P450 (CYP450), in particular, water molecules play a key role in forming active oxidant that ultimately performs oxidation and metabolism. In the present study, we have highlighted the behavior of the three most widely used water models TIP3P, SPC/E, and OPC for three different CYP450 enzymes CYP450BM3, CYP450OleT, and CYP450BSβ during MD simulations and QM/MM calculations. We studied the various properties, such as RMSD, RMSF, H-bond, water occupancy, and hydrogen atom transfer (HAT), using QM/MM calculations and compared them for all three water models. Our study shows that the stabilities of the enzyme complexes are well maintained in all three water models. However, the OPC water model performs well for the polar active sites, that is, in CYP450OleT and CYP450BSβ, while the TIP3P water model is superior for the hydrophobic site, such as CYP450BM3. © 2022 American Chemical Society.

Chemistry

Journal of Chemical Information and Modeling

The Performance of Different Water Models on the Structure and Function of Cytochrome P450 Enzymes

Insecticide-treated net (ITN) is the most applicable and cost-effective malaria intervention measure in sub-Saharan Africa and elsewhere. Although ITNs have been widely distributed to malaria-endemic regions in the past, their success has been threatened by misuses (in fishing, agriculture etc.) and decay in ITN efficacy. Decision-making in using the ITNs depends on multiple coevolving factors: malaria prevalence, mosquito density, ITN availability and its efficacy, and other socio-economic determinants. While ITN misuse increases as the efficacy of ITNs declines, high efficacy also impedes proper use due to free-riding. This irrational usage leads to increased malaria prevalence, thereby worsening malaria control efforts. It also remains unclear if the optimum ITN use for malaria elimination can be achieved under such an adaptive social learning process. Here, we incorporate evolutionary game theory into a disease transmission model to demonstrate these behavioural interactions and their impact on malaria prevalence. We show that social optimum usage is a function of transmission potential, ITN efficacy and mosquito demography. Under specific parameter regimes, our model exhibits patterns of ITN usage similar to observed data from parts of Africa. Our study suggests that the provision of financial incentives as prompt feedback to improper ITN use can reduce misuse and contribute positively towards malaria elimination efforts in Africa and elsewhere. © 2022 The Authors.

Mathematics

Royal Society Open Science

An evolutionary game model of individual choices and bed net use: Elucidating key aspect in malaria elimination strategies

Recently, the ternary active-layer-based organic solar cells have shown remarkable increment in the power conversion efficiency (PCE) by utilizing the synergistic effect of complementary absorption, band alignment, and nano-scale morphology enhancement. Non-fullerene acceptors (NFAs) are an important class of functional materials for the improved performance of ternary organic solar cells due to their role in improvising the light absorption and the morphology of the active layer. Here, the non-fullerene (NF) molecule, NAI-FN-NAI (BO), is used as the third component in the bulk heterojunction of PTB7-Th: PC71BM to fabricate the ternary organic solar cell. The magical number of the composition, i.e., 20% by weight of the NF in the ternary active layer resulted in the PCE of 8.1% devices, which is almost 35% higher efficiency than PTB7-Th: PC71BM binary devices having the PCE of 6%. The enhanced efficiency is observed even though the lessened effect of complementary absorption and band alignment factors of the NF. Such an improved efficiency is attributed in ternary devices to the nano-scale morphology enhancement. It could pave the way to realize the best possible bulk heterojunction blend to attain high PCE close to inorganic counterparts. © 2022 Wiley-VCH GmbH.

Physica Status Solidi (A) Applications and Materials Science

Non-Fullerene Acceptor-Based Nanomorphology Enhancement for Efficient Ternary Organic Solar Cells

Inverters are an indispensable component of any digital circuit. We report, for the first time, an organic unipolar inverter with the driver and the load transistors gated by ionic liquids (ILs). We have devised a new design strategy that exploits the considerably low saturation regime channel resistance of the IL-gated organic field-effect transistors. This simple and scalable fabrication methodology eliminates the need for different channel dimensions of the driver and the load transistors, thereby enabling the size reduction of circuits. We have achieved a gain exceeding 10 V V−1, attributable to high transistor transconductance (&gt;5 mS), at operating voltage &lt;1 V for the unipolar organic inverters, fabricated and characterized in the ambient environment. The switching threshold of the inverter has been tuned by up to 40% while maintaining a high gain by exploiting the strong influence of the gate electrode and the IL anion on the transistor behavior. The inverters exhibit an excellent noise margin of up to 60%, the highest noise margin reported for a low-voltage operating unipolar organic inverter. Solution-processable organic semiconductor-based high-performance, ambient-stable, and flexible-compatible inverters and subsequent integration of such devices into complex circuits will facilitate all-organic low-cost, and conformable electronic devices. © 2023 The Royal Society of Chemistry.

Journal of Materials Chemistry C

Ionic liquid gated unipolar inverters with tunable switching voltage and excellent noise margin

Examples of the β-Jacobi ensemble in random matrix theory specify the joint distribution of the transmission eigenvalues in scattering problems. For this application, the trace is of relevance as determining the conductance. Earlier, in the case β=1, the trace statistic was isolated in studies of covariance matrices in multivariate statistics. There, Davis showed that for β=1 the trace statistic could be characterised by (N+1)×(N+1) matrix differential equations, now understood for general β>0 as part of the theory of Selberg correlation integrals. However the characterisation provided was incomplete, as the connection problem of determining the linear combination of Frobenius type solutions that correspond to the statistic was not solved. We solve this connection problem for Jacobi parameters b and Dyson index β non-negative integers. The distribution then has the functional form of a series of piecewise power functions times a polynomial, and our characterisation gives a recurrence for the computation of the polynomials. For all β>0 we express the Fourier–Laplace transform of the trace statistic in terms of a generalised hypergeometric function based on Jack polynomials. © 2022 Elsevier B.V.

Physica D: Nonlinear Phenomena

Differential recurrences for the distribution of the trace of the β-Jacobi ensemble

Glioblastoma multiforme (GBM) is known as the primary malignant and most devastating form of tumor found in the central nervous system of the adult population. The active pharmaceutical component in current chemotherapy regimens is mostly hydrophobic and poorly water-soluble, which hampers clinical implications. Nanodrug formulations using nanocarriers loaded with such drugs assisted in water dispersibility, improved cellular permeability, and drug efficacy at a low dose, thus adding to the overall practical value. Here, we successfully developed a water-dispersible and biocompatible nanocargo (GO-PEG) based on covalently modified graphene oxide (GO) with a 6-armed poly(ethylene glycol) amine dendrimer for effective loading of the two hydrophobic anticancer drug molecules, CPI444 and vatalanib. These drug molecules target adenosine receptor (A2AR), vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and type III stem cell receptor tyrosine kinase (c-KIT), which plays a crucial role in cancers. The effective cellular delivery of the drugs when loaded on GO-PEG is attributed to the increased permeability of the drug-nanoconjugate formulation. We observed that this combinatorial drug treatment with nanocargo resulted in a significant reduction in the overall cell survival as supported by reduced calcium levels and stem cell markers such as Oct4 and Nanog, which are two of the prime factors for GBM stem cell proliferation. Furthermore, reduced expression of CD24 upon treatment with nanoformulation impeded cellular migration. Cellular assays confirmed inhibition of cell proliferation, migration, and angiogenic potential of GBM treated with GO-PEG–Drug conjugates. Ultimately, GBM U87 cells assumed programmed cell death at a very low concentration due to nanocarrier-mediated drug delivery along with the chosen combination of drugs. Together, this study demonstrated the advantage of GO-PEG mediated combined delivery of CPI444 and vatalanib drugs with increased permeability, a three-pronged combinatorial strategy toward effective GBM treatment. Copyright © 2022 Mishra, Patil, Reddy and Lochab.

Frontiers in Oncology

Combinatorial delivery of CPI444 and vatalanib loaded on PEGylated graphene oxide as an effective nanoformulation to target glioblastoma multiforme: In vitro evaluation

Nanodiamonds (NDs) are increasingly being assessed as potential candidates for drug delivery in cancer cells and they hold great promise in overcoming the side effects of traditional chemotherapeutics. In the current work, carboxylic acid functionalized nanodiamonds (ND-COOH) were covalently modified with poly(amidoamine) dendrimer (PAMAM) to form amine-terminated nanodiamonds (NP). Unlike ND-COOH, the chemically modified nanodiamond platform NP revealed a pH-independent aqueous dispersion stability, enhancing its potential as an effective carrier. Physical encapsulation of poorly water soluble cabazitaxel (CTX) drug on NP formed ND-PAMAM-CTX (NPC) nanoconjugates and substantially reduced the size of CTX from micrometer to nanometer. CTX was localized within the pores of nanoparticle aggregates and the cavities of the PAMAM dendrimer, thus facilitating the loaded drug's controlled and sustained release. NPC's cumulative CTX release efficiency was determined to be ∼95% at pH 4 after 96 h. A high cellular uptake of NPC both within the cytoplasm and nucleus of U87 cells is confirmed, accounting for a reduced IC50value (1 nM). Both the cell cycle and Western blot analyses confirmed enhanced cell death and suppressed tubulin protein expression in NPC-treated cells. A significantly high inhibition to cell division with early apoptosis and reduced metastasis demonstrates the effective loading of CTX dosages on the nanocarrier. The present work highlights the potential of a newly designed nanocarrier NP as an efficient nanocargo for cellular delivery applications and may provide future insights to treat one of the most aggressive tumors in neuro-oncological research, glioblastoma multiforme (GBM). © 2022 American Chemical Society. All rights reserved.