Comparison of Simple Ultrasound Rules by International Ovarian Tumor Analysis (IOTA) with RMI-1 and RMI-4 (Risk of Malignancy Index) in Preoperative Differentiation of Benign and Malignant Adnexal Masses.

Background: IOTA proposed Simple Ultrasound Rules in 2009 for preoperative diagnosis of ovarian masses based on ultrasound only. It is an accurate, simple and inexpensive method. RMI, however, requires CA125 level. While RMI-4 is the latest, RMI-1 is still the most widely used method. The present study was done to compare IOTA Rules with RMI-1 and RMI-4. Purpose: To differentiate benign and malignant adnexal masses preoperatively using IOTA simple rules and compare its accuracy with RMI-1 and RMI-4. Methods: A prospective observational study was performed from 1st November 2019 to 31st March 2021 in the Department of Obstetrics and Gynaecology, ABVIMS and Dr. RML Hospital, New Delhi. This study was conducted on 70 patients with adnexal masses who underwent pre-operative evaluation using IOTA Simple Rules, RMI-1 and RMI-4. Histopathology was used to compare the results. Results: Out of 70 patients, 59 (84.3%) cases were benign and 11 (15.7%) were malignant. The IOTA Rules were applicable to 60 cases (85.7%), and the results were inconclusive in 10 cases (14.3%). Where applicable, the sensitivity and specificity of the IOTA Rules (88.9% and 94.1%, respectively) were significantly higher than RMI-1 (45.5% and 93.2%, respectively) and RMI-4 (45.5% and 89.8%, respectively). When inconclusive results were included as malignant, the sensitivity of the IOTA Rules increased (88.9% vs 90.9%); however, the specificity decreased (94.1% vs 81.4%). Conclusion: IOTA Simple Rules were more accurate at diagnosing benign from malignant adnexal masses than RMI-1 and RMI-4. However, the rules were not applicable to 14% of the cases.

Exploring Genetic Diversity within aus Rice Germplasm: Insights into the Variations in Agro-morphological Traits.

The aus (Oryza sativa L.) varietal group comprises of aus, boro, ashina and rayada seasonal and/or field ecotypes, and exhibits unique stress tolerance traits, making it valuable for rice breeding. Despite its importance, the agro-morphological diversity and genetic control of yield traits in aus rice remain poorly understood. To address this knowledge gap, we investigated the genetic structure of 181 aus accessions using 399,115 SNP markers and evaluated them for 11 morpho-agronomic traits. Through genome-wide association studies (GWAS), we aimed to identify key loci controlling yield and plant architectural traits.Our population genetic analysis unveiled six subpopulations with strong geographical patterns. Subpopulation-specific differences were observed in most phenotypic traits. Principal component analysis (PCA) of agronomic traits showed that principal component 1 (PC1) was primarily associated with panicle traits, plant height, and heading date, while PC2 and PC3 were linked to primary grain yield traits. GWAS using PC1 identified OsSAC1 on Chromosome 7 as a significant gene influencing multiple agronomic traits. PC2-based GWAS highlighted the importance of OsGLT1 and OsPUP4/ Big Grain 3 in determining grain yield. Haplotype analysis of these genes in the 3,000 Rice Genome Panel revealed distinct genetic variations in aus rice.In summary, this study offers valuable insights into the genetic structure and phenotypic diversity of aus rice accessions. We have identified significant loci associated with essential agronomic traits, with GLT1, PUP4, and SAC1 genes emerging as key players in yield determination.

Biological evaluation of novel side chain containing CQTrICh-analogs as antimalarials and their development as PfCDPK1 kinase inhibitors.

The rapid emergence of resistance to existing frontline antimalarial drugs emphasizes a need for the development of target-oriented molecules with novel modes of action. Given the importance of a plant-like Calcium-Dependent Protein Kinase 1 (PfCDPK1) as a stand-alone multistage signalling regulator of P. falciparum, we designed and synthesized 7-chloroquinoline-indole-chalcones tethered with a triazole (CQTrICh-analogs 7 (a-s) and 9) directed towards PfCDPK1. This was accomplished by reacting substituted 1-phenyl-3-(1-(prop-2-yn-1-yl)-1H-indol-3-yl) prop-2-en-1-one and 1-(prop-2-yn-1-yl)-1H-indole-3-carbaldehyde with 4-azido-7-chloroquinoline, respectively via a 'click' reaction. The selected CQTrICh-analogs: 7l and 7r inhibited the growth of chloroquine-sensitive 3D7 strain and -resistant RKL-9 isolate of Plasmodium falciparum, with IC50 values of 2.4 µM & 1.8 µM (7l), and 3.5 µM & 2.7 µM (7r), respectively, and showed no apparent hemolytic activity and cytotoxicity in mammalian cells. Intra-erythrocytic progression studies revealed that the active hybrids: 7l and 7r are effective against the mature stages of the parasite. 7l and 7r were found to stably interact with the catalytically active ATP-binding pocket of PfCDPK1 via energetically favourable H-bonds. The interaction was confirmed in vitro by microscale thermophoresis and kinase assays, which demonstrated that the active hybrids interact with PfCDPK1 and inhibit its kinase activity which is presumably responsible for the parasite growth inhibition. Interestingly, 7l and 7r showed no inhibitory effect on the human kinases, indicating their selectivity for the parasite kinase. We report the antiplasmodial potential of novel kinase-targeting bio-conjugates, a step towards developing pan-kinase inhibitors which is a prerequisite for multistage anti-malarial protection.

Plasticizer-Induced Enhancement of Mesoscale Dissymmetry in Thin Films of Chiral Polymers with Variable Chain Length.

Conjugated polymers with chiral side chains are of interest in areas including chiral photonics, optoelectronics, and chemical and biological sensing. However, the low dissymmetry factors of most neat polymer thin films have limited their practical application. Here, a robust method to increase the absorption dissymmetry factor in a poly-fluorene-thiophene (PF8TS series) system is demonstrated by varying molecular weight and introducing an achiral plasticizer, polyethylene mono alcohol (PEM-OH). Extending chain length within the optimal range and adding this long-chain alcohol significantly enhance the chiroptical properties of spin-coated and annealed thin films. Mueller matrix spectroscopic ellipsometry (MMSE) analysis shows good agreement with the steady-state transmission measurements confirming a strong chiral response (circular dichroism (CD) and circular birefringence (CB)), ruling out linear dichroism, birefringence, and specific reflection effects. Solid-state NMR studies of annealed hybrid chiral polymer systems show enhancement of signals associated with aromatic π-stacked backbone and the ordered side-chain conformations. Further studies using Raman spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC), atomic force microscopy (AFM), and polarized optical microscopy (POM) indicate that PEM-OH facilitates mesoscopic crystal domain ordering upon annealing. This provides new insights into routes for tuning optical activity in conjugated polymers.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates.

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

Recent Developments in Vaccine Design: From Live Vaccines to Recombinant Toxin Vaccines.

Vaccines are one of the most effective strategies to prevent pathogen-induced illness in humans. The earliest vaccines were based on live inoculations with low doses of live or related pathogens, which carried a relatively high risk of developing the disease they were meant to prevent. The introduction of attenuated and killed pathogens as vaccines dramatically reduced these risks; however, attenuated live vaccines still carry a risk of reversion to a pathogenic strain capable of causing disease. This risk is completely eliminated with recombinant protein or subunit vaccines, which are atoxic and non-infectious. However, these vaccines require adjuvants and often significant optimization to induce robust T-cell responses and long-lasting immune memory. Some pathogens produce protein toxins that cause or contribute to disease. To protect against the effects of such toxins, chemically inactivated toxoid vaccines have been found to be effective. Toxoid vaccines are successfully used today at a global scale to protect against tetanus and diphtheria. Recent developments for toxoid vaccines are investigating the possibilities of utilizing recombinant protein toxins mutated to eliminate biologic activity instead of chemically inactivated toxins. Finally, one of the most contemporary approaches toward vaccine design utilizes messenger RNA (mRNA) as a vaccine candidate. This approach was used globally to protect against coronavirus disease during the COVID-19 pandemic that began in 2019, due to its advantages of quick production and scale-up, and effectiveness in eliciting a neutralizing antibody response. Nonetheless, mRNA vaccines require specialized storage and transport conditions, posing challenges for low- and middle-income countries. Among multiple available technologies for vaccine design and formulation, which technology is most appropriate? This review focuses on the considerable developments that have been made in utilizing diverse vaccine technologies with a focus on vaccines targeting bacterial toxins. We describe how advancements in vaccine technology, combined with a deeper understanding of pathogen-host interactions, offer exciting and promising avenues for the development of new and improved vaccines.

Tackling the emerging Artemisinin-resistant malaria parasite by modulation of defensive oxido-reductive mechanism via nitrofurantoin repurposing.

Oxidative stress-mediated cell death has remained the prime parasiticidal mechanism of front line antimalarial, artemisinin (ART). The emergence of resistant Plasmodium parasites characterized by oxidative stress management due to impaired activation of ART and enhanced reactive oxygen species (ROS) detoxification has decreased its clinical efficacy. This gap can be filled by development of alternative chemotherapeutic agents to combat resistance defense mechanism. Interestingly, repositioning of clinically approved drugs presents an emerging approach for expediting antimalarial drug development and circumventing resistance. Herein, we evaluated the antimalarial potential of nitrofurantoin (NTF), a clinically used antibacterial drug, against intra-erythrocytic stages of ART-sensitive (Pf3D7) and resistant (PfKelch13R539T) strains of P. falciparum, alone and in combination with ART. NTF exhibited growth inhibitory effect at submicro-molar concentration by arresting parasite growth at trophozoite stage. It also inhibited the survival of resistant parasites as revealed by ring survival assay. Concomitantly, in vitro combination assay revealed synergistic association of NTF with ART. NTF was found to enhance the reactive oxygen and nitrogen species, and induced mitochondrial membrane depolarization in parasite. Furthermore, we found that exposure of parasites to NTF disrupted redox balance by impeding Glutathione Reductase activity, which manifests in enhanced oxidative stress, inducing parasite death. In vivo administration of NTF, alone and in combination with ART, in P. berghei ANKA-infected mice blocked parasite multiplication and enhanced mean survival time. Overall, our results indicate NTF as a promising repurposable drug with therapeutic potential against ART-sensitive as well as resistant parasites.

Tuning of Morphological and Antibacterial Properties of Poly(3,4-ethylenedioxythiophene):Peroxodisulfate by Methyl Violet.

This study demonstrates a one-step synthesis of poly(3,4-ethylenedioxythiophene) (PEDOT) in the presence of the methyl violet (MV) dye. The structural properties of PEDOT:peroxodisulfate were studied using Raman and MALDI-TOF spectroscopies. The use of the MV dye in the polymerization process resulted in a change in the typical irregular morphology of PEDOT:peroxodisulfate, leading to the formation of spherical patterns. SEM and TEM analyses revealed that increasing the dye concentration can produce larger spherical aggregates probably due to the hydrophobic and π-π interactions. These larger aggregates hindered the charge transport and reduced the electrical conductivity. Interestingly, at higher dye concentrations (0.05 and 0.075 M), the PEDOT:peroxodisulfate/MV films exhibited significantly improved antibacterial activity against Staphylococcus aureus and Escherichia coli. Furthermore, the PEDOT:peroxodisulfate films with the incorporated MV dye exhibited a well-defined and repeatable redox behavior. The remarkable amalgamation of their optical, electrochemical and antibacterial properties provides the PEDOT:peroxodisulfate/MV materials with an immensely diverse spectrum of applications, including in optical sensors and medical devices.

Transposons are important contributors to gene expression variability under selection in rice populations.

Transposable elements (TEs) are an important source of genome variability. Here, we analyze their contribution to gene expression variability in rice by performing a TE insertion polymorphism expression quantitative trait locus mapping using expression data from 208 varieties from the Oryza sativa ssp. indica and O. sativa ssp. japonica subspecies. Our data show that TE insertions are associated with changes of expression of many genes known to be targets of rice domestication and breeding. An important fraction of these insertions were already present in the rice wild ancestors, and have been differentially selected in indica and japonica rice populations. Taken together, our results show that small changes of expression in signal transduction genes induced by TE insertions accompany the domestication and adaptation of rice populations.

Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites.

Despite several initiatives to subside the global malaria burden, the spread of artemisinin-resistant parasites poses a big threat to malaria elimination. Mutations in PfKelch13 are predictive of ART resistance, whose underpinning molecular mechanism remains obscure. Recently, endocytosis and stress response pathways such as the ubiquitin-proteasome machinery have been linked to artemisinin resistance. With Plasmodium, however, ambiguity persists regarding a role in ART resistance for another cellular stress defence mechanism called autophagy. Therefore, we investigated whether, in the absence of ART treatment, basal autophagy is augmented in PfK13-R539T mutant ART-resistant parasites and analyzed whether PfK13-R539T endowed mutant parasites with an ability to utilize autophagy as a pro-survival strategy. We report that in the absence of any ART treatment, PfK13-R539T mutant parasites exhibit increased basal autophagy compared to PfK13-WT parasites and respond aggressively through changes in autophagic flux. A clear cytoprotective role of autophagy in parasite resistance mechanism is evident by the observation that a suppression of PI3-Kinase (PI3K) activity (a master autophagy regulator) rendered difficulty in the survival of PfK13-R539T ART-resistant parasites. In conclusion, we now show that higher PI3P levels reported for mutant PfKelch13 backgrounds led to increased basal autophagy that acts as a pro-survival response to ART treatment. Our results highlight PfPI3K as a druggable target with the potential to re-sensitize ART-resistant parasites and identify autophagy as a pro-survival function that modulates ART-resistant parasite growth.

Whole Exome-Trio Analysis Reveals Rare Variants Associated with Congenital Pouch Colon.

Anorectal malformations (ARM) are individually common, but Congenital Pouch Colon (CPC) is a rare anorectal anomaly that causes a dilated pouch and communication with the genitourinary tract. In this work, we attempted to identify de novo heterozygous missense variants, and further discovered variants of unknown significance (VUS) which could provide insights into CPC manifestation. From whole exome sequencing (WES) performed earlier, the trio exomes were analyzed from those who were admitted to J.K. Lon Hospital, SMS Medical College, Jaipur, India, between 2011 and 2017. The proband exomes were compared with the unaffected sibling/family members, and we sought to ask whether any variants of significant interest were associated with the CPC manifestation. The WES data from a total of 64 samples including 16 affected neonates (11 male and 5 female) with their parents and unaffected siblings were used for the study. We examined the role of rare allelic variation associated with CPC in a 16 proband/parent trio family, comparing the mutations to those of their unaffected parents/siblings. We also performed RNA-Seq as a pilot to find whether or not the genes harboring these mutations were differentially expressed. Our study revealed extremely rare variants, viz., TAF1B, MUC5B and FRG1, which were further validated for disease-causing mutations associated with CPC, further closing the gaps of surgery by bringing intervention in therapies.

Effect of a Zr-Based Metal-Organic Framework Structure on the Properties of Its Composite with Polyaniline.

Composites of polyaniline (PANI) and Zr-based metal-organic frameworks (MOFs), UiO-66 and UiO-66-NH2, were synthesized by the oxidative polymerization of aniline in the presence of MOF templates with the MOF content in the resulting materials (78.2 and 86.7 wt %, respectively) close to the theoretical value (91.5 wt %). Scanning electron microscopy and transmission electron microscopy showed that the morphology of the composites was set by the morphology of the MOFs, whose structure was mostly preserved after the synthesis, based on the X-ray diffraction data. Vibrational and NMR spectroscopies pointed out that MOFs participate in the protonation of PANI and conducting polymer chains were grafted to amino groups of UiO-66-NH2. Unlike PANI-UiO-66, cyclic voltammograms of PANI-UiO-66-NH2 showed a well-resolved redox peak at around ≈0 V, pointing at the pseudocapacitive behavior. The gravimetric capacitance of PANI-UiO-66-NH2, normalized per mass of the active material, was also found to be higher compared to that of pristine PANI (79.8 and 50.5 F g-1, respectively, at 5 mV s-1). The introduction of MOFs into the composites with PANI significantly improved the cycling stability of the materials over 1000 cycles compared to the pristine conducting polymer, with the residual gravimetric capacitance being ≥100 and 77%, respectively. Thus, the electrochemical performance of the prepared PANI-MOF composites makes them attractive materials for application in energy storage.

Interchromosomal linkage disequilibrium and linked fitness cost loci associated with selection for herbicide resistance.

The adaptation of weeds to herbicide is both a significant problem in agriculture and a model of rapid adaptation. However, significant gaps remain in our knowledge of resistance controlled by many loci and the evolutionary factors that influence the maintenance of resistance. Here, using herbicide-resistant populations of the common morning glory (Ipomoea purpurea), we perform a multilevel analysis of the genome and transcriptome to uncover putative loci involved in nontarget-site herbicide resistance (NTSR) and to examine evolutionary forces underlying the maintenance of resistance in natural populations. We found loci involved in herbicide detoxification and stress sensing to be under selection and confirmed that detoxification is responsible for glyphosate (RoundUp) resistance using a functional assay. We identified interchromosomal linkage disequilibrium (ILD) among loci under selection reflecting either historical processes or additive effects leading to the resistance phenotype. We further identified potential fitness cost loci that were strongly linked to resistance alleles, indicating the role of genetic hitchhiking in maintaining the cost. Overall, our work suggests that NTSR glyphosate resistance in I. purpurea is conferred by multiple genes which are potentially maintained through generations via ILD, and that the fitness cost associated with resistance in this species is likely a by-product of genetic hitchhiking.

Antimalarial and Plasmodium falciparum serpentine receptor 12 targeting effect of FDA approved purinergic receptor antagonist.

Intraerythrocytic stages of Plasmodium falciparum responsible for all clinical manifestations of malaria are regulated by array of signalling cascades that represent attractive targets for antimalarial therapy. G-protein coupled receptors (GPCRs) are druggable targets in the treatment of various pathological conditions, however, there is limited understanding about the role of GPCRs in malaria pathogenesis. In Plasmodium, serpentine receptors (PfSR1, PfSR10, PfSR12 and PfSR25) with GPCR-like membrane topology have been reported with the finite knowledge about their potential as antimalarial targets. We analyzed the localization of these receptors in malaria parasite by immunofluorescence assays. All four receptors were expressed in blood stages with PfSR12 expressing more in late intraerythrocytic stages. Further, we evaluated the druggability of PfSR12 using FDA-approved P2Y purinergic receptor antagonist, Prasugrel and its active metabolite R138727, which is proposed to be specific towards PfSR12. Interestingly, biophysical analysis indicated strong binding between PfSR12 and R138727 as compared to the prodrug Prasugrel. This binding interaction was further confirmed by thermal shift assay. Treatment of parasite with Prasugrel and R138727 resulted in growth inhibition of P. falciparum indicating an important role of purinergic signalling and PfSR12 in parasite survival. Next, progression studies indicated the inhibitory effect of Prasugrel begins in late erythrocyte stages corroborating with PfSR12 expression at these stages. Furthermore, Prasugrel also blocked in vivo growth of malaria parasite in a mouse experimental model. This study indicates the presence of P2Y type of purinergic signalling in growth and development of malaria parasite and suggests PfSR12, putative purinergic receptor druggability through Prasugrel.Communicated by Ramaswamy H. Sarma.

A Look Into the Next Century After 100 Years of Insulin.

Being diagnosed with diabetes can be challenging, particularly if we do not know a similar individual with the same disease. A person's life may suddenly change and he/she may not be aware of the possibilities or treatment options available or the questions that need to be asked; hence, instead of looking for assistance, many people hide their diabetic condition from others. But due to innovative devices, individuals no longer need to be concerned. Various gadgets today help provision insulin via a subcutaneous route, for example, an insulin pen, pump, vial, or syringe. Despite being the most familiar way to provide insulin, subcutaneous insulin delivery is linked to needle pain, injection anxiety, lipodystrophy, compliance issues, and peripheral hyperinsulinemia; thus, there is a need for an insulin delivery system that is both less invasive and more biological. The discovery of insulin and its uses are linked to the beginning of diabetes treatment. Initially, the delivery of insulin was accomplished using giant, heavy, reusable syringes equipped with plungers, barrels, and wide-bore needles. To prepare these syringes and needles for reuse, these were boiled. The development of insulin syringes, which are presently in use and have revolutionized healthcare, resulted from manufacturers' continued efforts and technological innovations. Injections of insulin may become obsolete if research from the University of Alberta is successful. Researchers from the University of Alberta claim that insulin-producing cells developed from stem cells are secure for transplantation to wean diabetes patients from injectable insulin permanently. In a significant mice experiment, experts demonstrated the role of the inceptor (insulin inhibitory receptor), which protects the beta cells from insulin pathway activation. Insulin resistance in diabetes may be exacerbated by the inceptor's ability to block insulin signaling. Technologies known as "smart insulin" (glucose-responsive insulin) deliver insulin according to the patient's glycemic condition without needing additional monitoring by the patient or the physician in charge. The review of insulin administration devices and several cutting-edge insulin-related ideas are the main topics of this article.

A Rare Case of Recurrent Hematometra of Unknown Etiology.

An abnormal blood collection in the uterus is referred to as hematometra. Obstruction of the genitourinary outflow system caused by earlier surgeries or congenital defects is most frequently related to this rare disorder. The symptoms of hematometra include acute pelvic pain and a history of absent menarche. Here is a case of a 42-year-old female who presented with complaints of severe lower abdominal pain, and pain during urination that was accompanied by vulval itching in June 2021. She had undergone two Caesarean sections and a myomectomy in the past. She was given three monthly injections of gonadotropin-releasing hormone (GnRH) analogue after receiving USG-guided drainage because of a diagnosis of hematometra in January 2021. However, in June 2021, she experienced a recurrence of the same symptoms, necessitating a total abdominal hysterectomy and bilateral salpingo-oophorectomy, which completely resolved the patient's complaints. For a deeper understanding of this issue, further case reporting is necessary.

Clinical Evaluation of Stainless Steel Crown versus Zirconia Crown in Primary Molars: An In Vivo Study.

Aim: The objective of this clinical trial was to evaluate and compare two full-coronal restoration [stainless steel crowns (SSCs) and zirconia crown] in carious primary posterior teeth. Materials and methods: Forty endodontically treated primary teeth in children within the age-group of 3-9 years were selected and divided into two equal groups (20 SSCs and 20 zirconia crown). The two crowns were evaluated for retentivity of crown, temporomandibular joint (TMJ) problem, gingival response, plaque accumulation, and tooth wear in opposing teeth after 1st and 3rd month follow-up. Results: Both the crowns showed 100% results regarding TMJ problems, but SSCs performed better in terms of retention of crown, gingival response, plaque accumulation, and tooth wear in opposing teeth. The statistics showed significant result by using Mann-Whitney U test and Wilcoxon signed-rank test. Conclusion: Stainless steel crowns performed better among both the full-coronal restoration for posterior primary teeth. Clinical significance: Stainless steel crowns remain "Gold Standard", for posterior full coverage restorations in primary molars as compared to zirconia crowns. How to cite this article: Agrawal R, Khanduja R, Singhal M, et al. Clinical Evaluation of Stainless Steel Crown versus Zirconia Crown in Primary Molars: An In Vivo Study. Int J Clin Pediatr Dent 2022;15(1):15-19.

Target-Based Virtual Screening of Natural Compounds Identifies a Potent Antimalarial With Selective Falcipain-2 Inhibitory Activity.

We employed a comprehensive approach of target-based virtual high-throughput screening to find potential hits from the ZINC database of natural compounds against cysteine proteases falcipain-2 and falcipain-3 (FP2 and FP3). Molecular docking studies showed the initial hits showing high binding affinity and specificity toward FP2 were selected. Furthermore, the enzyme inhibition and surface plasmon resonance assays were performed which resulted in a compound ZINC12900664 (ST72) with potent inhibitory effects on purified FP2. ST72 exhibited strong growth inhibition of chloroquine-sensitive (3D7; EC50 = 2.8 µM) and chloroquine-resistant (RKL-9; EC50 = 6.7 µM) strains of Plasmodium falciparum. Stage-specific inhibition assays revealed a delayed and growth defect during parasite growth and development in parasites treated with ST72. Furthermore, ST72 significantly reduced parasite load and increased host survival in a murine model infected with Plasmodium berghei ANKA. No Evans blue staining in ST72 treatment indicated that ST72 mediated protection of blood-brain barrier integrity in mice infected with P. berghei. ST72 did not show any significant hemolysis or cytotoxicity against human HepG2 cells suggesting a good safety profile. Importantly, ST72 with CQ resulted in improved growth inhibitory activity than individual drugs in both in vitro and in vivo studies.

Highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives and in silico interaction analysis with putative target Plasmodium falciparum lactate dehydrogenase.

Malaria infection caused by Plasmodium falciparum is majorly responsible for millions of deaths in humans every year. Moreover, a rapid increase in resistance to existing drugs has posed an urgent need for new anti-malarials. Herein, we report the highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives, inspired from naturally occurring dependensin against chloroquine (CQ) sensitive and resistant P. falciparum strains. Chemically synthesized, four dependensin analogs 85(A-D) exhibited growth inhibition at nanomolar concentrations ranging from 63.96 to 725.8 nM by blocking the parasite development at the ring and early trophozoite stages. The growth inhibitory activity of dependensin analogs was correlated with their anti-plasmodial lactate dehydrogenase activity by computational analysis. Molecular docking, 50 ns simulation and a 2D-Quantitative Structure-Activity Relationship (2D-QSAR) modelling revealed the interaction with their putative target P. falciparum lactate dehydrogenase (PfLDH). Here, developing the predictive 2D descriptors such as thermodynamic, spatial, electronic, and topological with multiple linear regression analysis (MLRA), the structural requirements for potent and selective PfLDH inhibitory activity has been identified. The strong binding of compound 85D to the catalytic Nicotinamide adenine dinucleotide (NADH) binding pocket of the PfLDH further supported the PfLDH targeting potential of dependensin analogs. Overall, this study revealed a highly potent anti-malarial activity of benzopyrano(4,3-b)benzopyran derivatives with their putative anti-PfLDH activity.Communicated by Ramaswamy H. Sarma.

Deciphering LncRNA-protein interactions using docking complexes.

Deciphering RNA-protein interactions are important to study principal biological mechanisms including transcription and translation regulation, gene silencing, among others. Predicting RNA molecule interaction with the target protein could allow us to understand important cellular processes and design novel treatment therapies for various diseases. As non-coding RNAs do not have coding potential our knowledge about their functions is still limited. Therefore, RNA-binding proteins of non-coding RNAs regulating functions, viz. including cellular maturation, nuclear export and stability may play a very important role. Keeping in view of the need for refined methods to understand protein-RNA interactions, we have attempted a docking model to infer binding sites between lncRNA NONHSAT02007 and protein KIF13A for a rare disease phenotype that we are studying in our lab.Communicated by Ramaswamy H. Sarma.