Activation of neutrophils excels the therapeutic potential of Mycobacterium indicus pranii and heat-induced promastigotes against antimony-resistant Leishmania donovani infection.

Repurposing drugs and adjuvants is an attractive choice of present therapy that reduces the substantial costs, chances of failure, and systemic toxicity. Mycobacterium indicus pranii was originally developed as a leprosy vaccine but later has been found effective against Leishmania donovani infection. To extend our earlier study, here we reported the immunotherapeutic modulation of the splenic and circulatory neutrophils in favour of hosts as neutrophils actually serve as the pro-parasitic portable shelter to extend the Leishmania infection specifically during the early entry into the hosts' circulation. We targeted to disrupt this early pro-parasitic incidence by the therapeutic combination of M. indicus pranii and heat-induced promastigotes against antimony-resistant L. donovani infection. The combination therapy induced the functional expansion of CD11b+Ly6CintLy6Ghi neutrophils both in the post-infected spleen, and also in the circulation of post-treated animals followed by the immediate Leishmania infection. More importantly, the enhanced expression of MHC-II, phagocytic uptake of the parasites by the circulatory neutrophils as well as the oxidative burst were induced that limited the chances of the very early establishment of the infection. The enhanced expression of pro-inflammatory cytokines, like IL-1α and TNF-α indicated resistance to the parasite-mediated takeover of the neutrophils, as these cytokines are critical for the activation of T cell-mediated immunity and host-protective responses. Additionally, the induction of essential transcription factors and cytokines for early granulocytic lineage commitment suggests that the strategy not only contributed to the peripheral activation of the neutrophils but also promoted granulopoiesis in the bone marrow.

Soybean lectin-triggered IL-6 secretion induces autophagy to kill intracellular mycobacteria through P2RX7 dependent activation of the JAK2/STAT3/Mcl-1 pathway.

Cytokine therapy and cytokine-mediated autophagy have been used as prominent host-directed therapy (HDT) approaches to restrain M. tb growth in the host cell. In the present study, we have dissected the anti-tubercular activity of Soybean lectin (SBL) through cytokine-mediated autophagy induction in differentiated THP-1 (dTHP-1) cells. A significant increase in IL-6 expression was observed in both uninfected and mycobacteria infected dTHP-1 cells through the P2RX7 mediated pathway via PI3K/Akt/CREB-dependent signalling after SBL treatment. Inhibition of IL-6 level using IL-6 neutralizing antibody or associated signalling significantly enhanced the mycobacterial load in SBL-treated dTHP-1 cells. Further, autocrine signalling of IL-6 through its receptor-induced Mcl-1 expression activated autophagy via JAK2/STAT3 pathway, and inhibition of this pathway affected autophagy. Finally, blocking the IL-6-regulated autophagy through NSC 33994 (a JAK2 inhibitor) or S63845 (an Mcl-1 inhibitor) led to a notable increase in intracellular mycobacterial growth in SBL-treated cells. Taken together, these results indicate that SBL interacts with P2RX7 to regulate PI3K/Akt/CREB network to release IL-6 in dTHP-1 cells. The released IL-6, in turn, activates the JAK2/STAT3/Mcl-1 pathway upon interaction with IL-6Rα to modulate autophagy that ultimately controls mycobacterial growth in macrophages.

Interaction between p53 N terminus and core domain regulates specific and nonspecific DNA binding.

The p53 tumor suppressor is a sequence-specific DNA binding protein that activates gene transcription to regulate cell survival and proliferation. Dynamic control of p53 degradation and DNA binding in response to stress signals are critical for tumor suppression. The p53 N terminus (NT) contains two transactivation domains (TAD1 and TAD2), a proline-rich region (PRR), and multiple phosphorylation sites. Previous work revealed the p53 NT reduced DNA binding in vitro. Here, we show that TAD2 and the PRR inhibit DNA binding by directly interacting with the sequence-specific DNA binding domain (DBD). NMR spectroscopy revealed that TAD2 and the PRR interact with the DBD at or near the DNA binding surface, possibly acting as a nucleic acid mimetic to competitively block DNA binding. In vitro and in vivo DNA binding analyses showed that the NT reduced p53 DNA binding affinity but improved the ability of p53 to distinguish between specific and nonspecific sequences. MDMX inhibits p53 binding to specific target promoters but stimulates binding to nonspecific chromatin sites. The results suggest that the p53 NT regulates the affinity and specificity of DNA binding by the DBD. The p53 NT-interacting proteins and posttranslational modifications may regulate DNA binding, partly by modulating the NT-DBD interaction.

A Remarkable Fluorescence Quenching Based Amplification in ATP Detection through Signal Transduction in Self-Assembled Multivalent Aggregates.

Signal transduction is essential for the survival of living organisms, because it allows them to respond to the changes in external environments. In artificial systems, signal transduction has been exploited for the highly sensitive detection of analytes. Herein, a remarkable signal transduction, upon ATP binding, in the multivalent fibrillar nanoaggregates of anthracene conjugated imidazolium receptors is reported. The aggregates of one particular amphiphilic receptor sensed ATP in high pm concentrations with one ATP molecule essentially quenching the emission of thousands of receptors. A cooperative merging of the multivalent binding and signal transduction led to this superquenching and translated to an outstanding enhancement of more than a millionfold in the sensitivity of ATP detection by the nanoaggregates; in comparison to the "molecular" imidazolium receptors. Furthermore, an exceptional selectivity to ATP over other nucleotides was demonstrated.

Novel Agents against Miltefosine-Unresponsive Leishmania donovani.

Visceral leishmaniasis is a deadly endemic disease. Unresponsiveness to the only available oral drug miltefosine poses a big challenge for the chemotherapy of the disease. We report a novel molecule, PS-203 {4-(4,4,8-trimethyl-7-oxo-3-oxabicyclo[3.3.1]non-2-yl)-benzoic acid methyl ester}, as effective against a miltefosine-unresponsive strain of the parasite. Further, combinations of PS-203 with miltefosine were also evaluated and showed promising results against a miltefosine-unresponsive strain.

Probing the molecular mechanism of hypericin-induced parasite death provides insight into the role of spermidine beyond redox metabolism in Leishmania donovani.

Hypericin, a natural compound from Hypericum perforatum (St. John's wort), has been identified as a specific inhibitor of Leishmania donovani spermidine synthase (LdSS) using integrated computational and biochemical approaches. Hypericin showed in vitro inhibition of recombinant LdSS enzyme activity. The in vivo estimation of spermidine levels in Leishmania promastigotes after hypericin treatment showed significant decreases in the spermidine pools of the parasites, indicating target specificity of the inhibitor molecule. The inhibitor, hypericin, showed significant antileishmanial activity, and the mode of death showed necrosis-like features. Further, decreased trypanothione levels and increased glutathione levels with elevated reactive oxygen species (ROS) levels were observed after hypericin treatment. Supplementation with trypanothione in the medium with hypericin treatment restored in vivo trypanothione levels and ROS levels but could not prevent necrosis-like death of the parasites. However, supplementation with spermidine in the medium with hypericin treatment restored in vivo spermidine levels and parasite death was prevented to a large extent. The data overall suggest that the parasite death due to spermidine starvation as a result of LdSS inhibition is not related to elevated levels of reactive oxygen species. This suggests the involvement of spermidine in processes other than redox metabolism in Leishmania parasites. Moreover, the work provides a novel scaffold, i.e., hypericin, as a potent antileishmanial molecule.

Computational investigation on tunable optical band gap in armchair polyacenes.

Polyacenes in their armchair geometry (phenacenes) have recently been found to possess appealing electronic and optical properties with higher chemical stability and comparatively larger band gap as compared to linear polyacenes. They also behave as high-temperature superconductors upon alkali metal doping. Moreover, the optical properties of crystalline picene can be finely tuned by applying external pressure. We investigated the variation of optical gap as a function of altering the interplanar distances between parallel cofacial phenacene dimers. We employed both time-dependent density functional theory and density matrix renormalization group (DMRG) technique to investigate the lowest singlet excitations in phenacene dimer. Our study showed that the lowest singlet excitation in these systems evolved as a function of interplanar separation. The optical excitation energy gap decreases as a function of inverse interplanar separation of the phenacene dimer. The distant dependent variation of optical absorption at the dimer level may be comparable with experimental observation in picene crystal under pressure. DMRG study also demonstrates that besides picene, electronic properties of higher phenacenes can also be tunable by altering interplanar separation.

Low-lying excited states in armchair polyacene within Pariser-Parr-Pople model: a density matrix renormalization group study.

We studied the nature of the ground state and low-lying excited states of armchair polyacene oligomers (Polyphenanthrene) within long-range Pariser-Parr-Pople model Hamiltonian with up to 14 monomers using symmetrized density matrix renormalization group technique. The ground state of all armchair polyacenes studied is found to be singlet. The results show that lowest singlet dipole allowed excited state has higher energy for armchair polyacenes as compared to linear fused polyacenes. Moreover, unlike linear fused polyacenes, the lowest singlet excited state of these oligomers is always found to lie below the lowest dipole forbidden two-photon state indicating that these armchair polyacene oligomers strongly fluoresce. The calculations of low-lying excitations on singly and triply electron doped armchair polyacene oligomers show a low energy band with strong transition dipole moment that coupled to charge conductivity. This implies armchair polyacene posses novel field-effect transistor properties.

Acute disseminated encephalomyelitis presenting with hypertensive emergency.

We report a 12-year-old girl presenting with acute disseminated encephalomyelitis (ADEM) along with hypertensive emergency. Hypertension persisted for few weeks following recovery and subsided with oral clonidine. Although autonomic instability in ADEM has been reported before, hypertensive emergency was not previously documented as presenting feature of ADEM.

4-(Benzyloxy)phenol-induced p53 exhibits antimycobacterial response triggering phagosome-lysosome fusion through ROS-dependent intracellular Ca2+ pathway in THP-1 cells.

Drug-resistant tuberculosis (TB) outbreak has emerged as a global public health crisis. Therefore, new and innovative therapeutic options like host-directed therapies (HDTs) through novel modulators are urgently required to overcome the challenges associated with TB. In the present study, we have investigated the anti-mycobacterial effect of 4-(Benzyloxy)phenol. Cell-viability assay asserted that 50 µM of 4-(Benzyloxy)phenol was not cytotoxic to phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. It was observed that 4-(Benzyloxy)phenol activates p53 expression by hindering its association with KDM1A. Increased ROS, intracellular Ca2+ and phagosome-lysosome fusion, were also observed upon 4-(Benzyloxy)phenol treatment. 4-(Benzyloxy)phenol mediated killing of intracellular mycobacteria was abrogated in the presence of specific inhibitors of ROS, Ca2+ and phagosome-lysosome fusion like NAC, BAPTA-AM, and W7, respectively. We further demonstrate that 4-(Benzyloxy)phenol mediated enhanced ROS production is mediated by acetylation of p53. Blocking of p53 acetylation by Pifithrin-α (PFT- α) enhanced intracellular mycobacterial growth by blocking the mycobactericidal effect of 4-(Benzyloxy)phenol. Altogether, the results showed that 4-(Benzyloxy)phenol executed its anti-mycobacterial effect by modulating p53-mediated ROS production to regulate phagosome-lysosome fusion through Ca2+ production.

The long-term effects of childhood circumstances on older individuals: A systematic review.

Childhood experiences are known to shape individuals' development and can influence various aspects of life later on. Understanding the long-term effects is crucial for informing interventions and policies aimed at promoting healthy aging. This review aimed to explore the long-term effects of childhood experiences on older individuals. This systematic review comprised three distinct phases. Firstly, a systematic review was conducted, exploring databases such as Google Scholar, PubMed, EMBASE, PsycINFO, and the Web of Science. Out of the 2116 studies initially identified, 24 studies were selected based on the inclusion criteria. Secondly, these inclusion criteria were applied to ensure that the chosen studies specifically delved into the connection between childhood experiences and outcomes in older individuals. Finally, data extraction and synthesis techniques were employed to analyze findings, facilitating the drawing of conclusions concerning the enduring impacts of childhood experiences on the well-being of older individuals. The review's findings revealed how negative experiences in childhood continue to affect older individuals in various ways. These early-life events have far-reaching consequences, profoundly impacting their physical health, making them more susceptible to chronic diseases and weakening their immune system. Additionally, they affect mental health, leading to conditions like depression, anxiety, and substance abuse. Cognitive function is also affected, resulting in memory problems and cognitive decline. Furthermore, these experiences impact social relationships, affecting trust, emotional control, and social isolation in later life. This review highlighted the enduring influence of childhood circumstances on the health and well-being of older individuals. Policymakers and health care practitioners should consider these findings when developing strategies to support healthy aging and mitigate the long-term effects of adverse childhood experiences.

Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani.

World health organization has called for academic research and development of new chemotherapeutic strategies to overcome the emerging resistance and side effects exhibited by the drugs currently used against leishmaniasis. Diospyrin, a bis-naphthoquinone isolated from Diospyros montana Roxb., and its semi-synthetic derivatives, were reported for inhibitory activity against protozoan parasites including Leishmania. Presently, we have investigated the antileishmanial effect of a di-epoxide derivative of diospyrin (D17), both in vitro and in vivo. Further, the safety profile of D17 was established by testing its toxicity against normal macrophage cells (IC50∼20.7 µM), and also against normal BALB/c mice in vivo. The compound showed enhanced activity (IC50∼7.2 µM) as compared to diospyrin (IC50∼12.6 µM) against Leishmania donovani promastigotes. Again, D17 was tested on L. donovani BHU1216 isolated from a sodium stibogluconate-unresponsive patient, and exhibited selective inhibition of the intracellular amastigotes (IC50∼0.18 µM). Also, treatment of infected BALB/c mice with D17 at 2mg/kg/day reduced the hepatic parasite load by about 38%. Subsequently, computational docking studies were undertaken on selected enzymes of trypanothione metabolism, viz. trypanothione reductase (TryR) and ornithine decarboxylase (ODC), followed by the enzyme kinetics, where D17 demonstrated non-competitive inhibition of the L. donovani ODC, but could not inhibit TryR.

Efficacy of Intraperitoneal 0.2% Ropivacaine With Dexmedetomidine Versus 0.2% Ropivacaine With Ketamine in Laparoscopic Surgeries: A Randomized Controlled Trial.

BACKGROUND: Effective pain management modalities are the armamentarium for enhanced recovery in laparoscopic surgeries. Intraperitoneal instillation of local anaesthetics with adjuvants is advantageous in minimizing pain. So, we designed this study with the aim to compare the analgesic effectiveness of intraperitoneal ropivacaine with adjuvants like dexmedetomidine versus ketamine for postoperative analgesia. OBJECTIVE:  The objective of this study is to assess the total duration of analgesia and total rescue analgesic dose requirements in the first 24 hours postoperatively. MATERIALS AND METHODS: A total of 105 consenting patients for elective laparoscopic surgeries were enrolled and divided into three groups by computer-generated randomization as follows: Group 1: 30 ml of 0.2% ropivacaine with ketamine 0.5 mg/kg diluted to 1 ml; Group 2: 30 ml of 0.2% ropivacaine with dexmedetomidine 0.5 mcg/kg diluted to 1 ml; Group 3: 30 ml of 0.2% ropivacaine with 1 ml of normal saline. The postoperative visual analogue scale (VAS) score, total duration of analgesia, and total analgesic dose were calculated and compared among the three groups. RESULTS: The postoperative analgesic duration after intraperitoneal instillation of Group 2 was longer as compared to Group 1. The total analgesic requirement was lower in Group 2 as compared to Group 1, and the p-value was significant (p ≤ 0.001) for both parameters. Demographic parameters and VAS scores among the three groups were not statistically significant. CONCLUSION: We conclude that intraperitoneal instillation of local anaesthetics with adjuvants is effective for postoperative analgesia in laparoscopic surgeries, and ropivacaine 0.2% with dexmedetomidine 0.5 mcg/kg is more effective when compared to ropivacaine 0.2% with ketamine 0.5 mg/kg.

Ac-93253 inhibits intracellular growth of mycobacteria in human macrophages by inducing apoptosis in mitochondrial-dependent manner.

Recent studies suggest that apoptosis in macrophages plays a significant role in host defence against intracellular pathogens like viruses, fungi, protozoan, and bacteria, including Mycobacterium tuberculosis (M. tb). It is still unclear if micromolecules inducing apoptosis could be an attractive approach to combat the intracellular burden of M. tb. Hence, the present study has investigated the anti-mycobacterial effect of apoptosis mediated through phenotypic screening of micromolecules. Through MTT and trypan blue exclusion assay, 0.5 µM of Ac-93253 was found to be non-cytotoxic even after 72 h of treatment in phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 (dTHP-1) cells. Significant regulation in the expression of various pro-apoptotic genes like Bcl-2, Bax, and Bad and the cleaved caspase 3 was observed upon treatment with a non-cytotoxic dose of Ac-93253. Ac-93253 treatment also leads to DNA fragmentation and increased phosphatidylserine accumulation in the plasma membrane's outer leaflet. Further, Ac-93253 also effectively reduced the growth of mycobacteria in infected macrophages, Z-VAD-FMK a broad-range apoptosis inhibitor significantly brought back the mycobacterial growth in Ac-93253 treated macrophages. These findings suggest apoptosis may be the probable effector response through which Ac-93253 manifests its anti-mycobacterial property.

Involvement of epigenetics in affecting host immunity during SARS-CoV-2 infection.

Coronavirus disease 19 (COVID-19) is caused by a highly contagious RNA virus Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), originated in December 2019 in Wuhan, China. Since then, it has become a global public health concern and leads the disease table with the highest mortality rate, highlighting the necessity for a thorough understanding of its biological properties. The intricate interaction between the virus and the host immune system gives rise to diverse implications of COVID-19. RNA viruses are known to hijack the host epigenetic mechanisms of immune cells to regulate antiviral defence. Epigenetics involves processes that alter gene expression without changing the DNA sequence, leading to heritable phenotypic changes. The epigenetic landscape consists of reversible modifications like chromatin remodelling, DNA/RNA methylation, and histone methylation/acetylation that regulates gene expression. The epigenetic machinery contributes to many aspects of SARS-CoV-2 pathogenesis, like global DNA methylation and receptor angiotensin-converting enzyme 2 (ACE2) methylation determines the viral entry inside the host, viral replication, and infection efficiency. Further, it is also reported to epigenetically regulate the expression of different host cytokines affecting antiviral response. The viral proteins of SARS-CoV-2 interact with various host epigenetic enzymes like histone deacetylases (HDACs) and bromodomain-containing proteins to antagonize cellular signalling. The central role of epigenetic factors in SARS-CoV-2 pathogenesis is now exploited as promising biomarkers and therapeutic targets against COVID-19. This review article highlights the ability of SARS-CoV-2 in regulating the host epigenetic landscape during infection leading to immune evasion. It also discusses the ongoing therapeutic approaches to curtail and control the viral outbreak.

RNAi-Based Therapy: Combating Shrimp Viral Diseases.

Shrimp aquaculture has become a vital industry, meeting the growing global demand for seafood. Shrimp viral diseases have posed significant challenges to the aquaculture industry, causing major economic losses worldwide. Conventional treatment methods have proven to be ineffective in controlling these diseases. However, recent advances in RNA interference (RNAi) technology have opened new possibilities for combating shrimp viral diseases. This cutting-edge technology uses cellular machinery to silence specific viral genes, preventing viral replication and spread. Numerous studies have shown the effectiveness of RNAi-based therapies in various model organisms, paving the way for their use in shrimp health. By precisely targeting viral pathogens, RNAi has the potential to provide a sustainable and environmentally friendly solution to combat viral diseases in shrimp aquaculture. This review paper provides an overview of RNAi-based therapy and its potential as a game-changer for shrimp viral diseases. We discuss the principles of RNAi, its application in combating viral infections, and the current progress made in RNAi-based therapy for shrimp viral diseases. We also address the challenges and prospects of this innovative approach.

Evaluation of plumbagin and its derivative as potential modulators of redox thiol metabolism of Leishmania parasite.

Trypanothione and trypanothione reductase (TryR)-based redox metabolism found in Leishmania and other trypanosomatids exemplify the unique features of this group of organisms. Its absence in mammalian hosts, together with the sensitivity of trypanosomes against oxidative stress, makes this enzyme a unique target for exploitation for potential antileishmanial chemotherapeutics. Plumbagin, a plant-derived naphthoquinone, is reported to possess antileishmanial properties by inhibiting TryR. We here report the kinetics of the inhibitory mechanism of plumbagin and its derivative, 2-methoxy 1, 4-naphthoquinone. Interestingly, apart from acting as inhibitor, these compounds also act as subversive substrates and subvert the physiological function of enzyme by converting it from an antioxidant to a prooxidant. Both naphthoquinones show a significant effect on redox homeostasis and results in increased reactive oxygen species, resulting in morphological changes and parasite death.

Hypothermia Effectively Treats Tumors with Temperature-Sensitive p53 Mutations.

The p53 tumor suppressor is frequently inactivated by mutations in cancer. Most p53 mutations are located in the DNA-binding domain, causing local disruption of DNA-binding surface or global misfolding. Rescuing the structural defect of mutant p53 is an attractive therapeutic strategy, but its potential remains unproven due to a lack of drugs capable of efficiently rescuing misfolded p53. Although mutant p53 in tumors is inactive at 37°C, approximately 15% are temperature sensitive (ts) and regain DNA-binding activity at 32°C to 34°C (ts mutants). This temperature is achievable using a therapeutic hypothermia procedure established for resuscitated cardiac arrest patients. To test whether hypothermia can be used to target tumors with ts p53 mutations, the core temperature of tumor-bearing mice was lowered to 32°C using the adenosine A1 receptor agonist N6-cyclohexyladenoxine that suppresses brain-regulated thermogenesis. Hypothermia treatment (32 hours at 32°C × 5 cycles) activated endogenous ts mutant p53 in xenograft tumors and inhibited tumor growth in a p53-dependent fashion. Tumor regression and durable remission in a ts p53 lymphoma model was achieved by combining hypothermia with chemotherapy. The results raise the possibility of treating tumors expressing ts p53 mutations with hypothermia. SIGNIFICANCE: Pharmacologic inhibition of brain-regulated thermogenesis and induction of 32°C whole-body hypothermia specifically targets tumors with temperature-sensitive p53 mutations, rescuing p53 transcriptional activity and inducing tumor regression.See related commentary by Hu and Feng, p. 3762.

ESAT-6 impedes IL-18 mediated phagosome lysosome fusion via microRNA-30a upon Calcimycin treatment in mycobacteria infected macrophages.

The weaponry possessed by Mycobacterium tuberculosis (M. tb) in the form of immunodominant antigens hijack the host immune system to give a survival advantage to this intracellular fiend, but the mechanism of this control is not entirely known. Since we have previously reported the mechanism of autophagy inhibition by early secreted antigenic target 6 kDa (ESAT-6) through microRNA (miR)-30a-3p in Calcimycin treated differentiated THP-1 (dTHP-1) cells, the present study was undertaken to deduce the effect of miR-30a on the immunomodulatory profile of ESAT-6 treated cells and the mechanism involved thereof, if any. Initially, the effect of recombinant ESAT-6 (rESAT-6) on the immunomodulatory profile in Calcimycin-treated phorbol 12-myristate 13-acetate (PMA) dTHP-1 cells was checked. Later, transfection studies using miR-30a-3p inhibitor or -5p mimic highlighted the contrary roles of different arms of the same miRNA in regulating IL-18 response by ESAT-6 in dTHP-1 cells after Calcimycin treatment. By using either IL-18 neutralizing antibody or inhibitors of phosphoinositide 3-kinase (PI3K)/NF-κB/phagosome-lysosome fusion in the miRNA-30a transfected background, IL-18 mediated signaling and intracellular killing of mycobacteria was reversed in the presence of ESAT-6. Overall, the results of this study conclusively prove the contrary roles of miR-30a-3p and miR-30a-5p in regulating IL-18 signaling by ESAT-6 in dTHP-1 cells upon Calcimycin treatment that affected phagosome-lysosome fusion and intracellular survival of mycobacteria.

SARS-CoV-2 Spike Mutations, L452R, T478K, E484Q and P681R, in the Second Wave of COVID-19 in Maharashtra, India.

As the global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic expands, genomic epidemiology and whole genome sequencing are being used to investigate its transmission and evolution. Against the backdrop of the global emergence of "variants of concern" (VOCs) during December 2020 and an upsurge in a state in the western part of India since January 2021, whole genome sequencing and analysis of spike protein mutations using sequence and structural approaches were undertaken to identify possible new variants and gauge the fitness of the current circulating strains. Phylogenetic analysis revealed that newly identified lineages B.1.617.1 and B.1.617.2 were predominantly circulating. The signature mutations possessed by these strains were L452R, T478K, E484Q, D614G and P681R in the spike protein, including within the receptor-binding domain (RBD). Of these, the mutations at residue positions 452, 484 and 681 have been reported in other globally circulating lineages. The structural analysis of RBD mutations L452R, T478K and E484Q revealed that these may possibly result in increased ACE2 binding while P681R in the furin cleavage site could increase the rate of S1-S2 cleavage, resulting in better transmissibility. The two RBD mutations, L452R and E484Q, indicated decreased binding to select monoclonal antibodies (mAbs) and may affect their neutralization potential. Further in vitro/in vivo studies would help confirm the phenotypic changes of the mutant strains. Overall, the study revealed that the newly emerged variants were responsible for the second wave of COVID-19 in Maharashtra. Lineage B.1.617.2 has been designated as a VOC delta and B.1.617.1 as a variant of interest kappa, and they are being widely reported in the rest of the country as well as globally. Continuous monitoring of these and emerging variants in India is essential.