02394nas a2200253 4500008004100000245009100041210006900132260000800201300001100209490000600220520153500226653001201761653004001773653002801813653002701841100001801868700002001886700001601906700002101922700002401943700002801967700002401995856012102019 2021 eng d00aConserved RNA binding activity of phosphatidyl inositol 5-phosphate 4-kinase (PIP4K2A)0 aConserved RNA binding activity of phosphatidyl inositol 5phospha cMAY a6312810 v83 aPlasmodium falciparum is a causative agent for malaria and has a complex life cycle in human and mosquito hosts. During its life cycle, the malarial parasite Plasmodium goes through different asexual and sexual stages, in humans and mosquitoes. Expression of stage-specific proteins is important for successful completion of its life cycle and requires tight gene regulation. In the case of Plasmodium, due to relative paucity of the transcription factors, it is postulated that posttranscriptional regulation plays an important role in stage-specific gene expression. Translation repression of specific set of mRNA has been reported in gametocyte stages of the parasite. A conserved element present in the 3 ` UTR of some of these transcripts was identified. Phosphatidylinositol 5-phosphate 4-kinase (PIP4K2A) was identified as the protein that associates with these RNA. We now show that the RNA binding activity of PIP4K2A is independent of its kinase activity. We also observe that PIP4K2A is imported into the parasite from the host on Plasmodium berghei and Toxoplasma gondii. The RNA binding activity of PIP4K2A seems to be conserved across species from Drosophila and C. elegans to humans, suggesting that the RNA binding activity of PIP4K may be important, and there may be host transcripts that may be regulated by PIP4K2A. These results identify a novel RNA binding role for PIP4K2A that may not only play a role in Plasmodium propagation but may also function in regulating gene expression in multicellular organisms.10amalaria10aposttranscriptional gene regulation10aRNA-protein interaction10atranslation regulation1 aBehari, Jatin1 aBorkar, Pranita1 aVindu, Arya1 aDandewad, Vishal1 aUpadrasta, Sindhuri1 aShanmugam, Dhanasekaran1 aSeshadri, Vasudevan uhttps://library.ncl.res.in/content/conserved-rna-binding-activity-phosphatidyl-inositol-5-phosphate-4-kinase-pip4k2a02296nas a2200241 4500008004100000022001400041245011200055210006900167260000800236300001100244490000800255520148600263653001801749653002401767653001201791653001501803653001501818100002501833700001901858700002801877700001701905856013201922 2022 eng d a0166-685100aProfiling of metabolic alterations in mice infected with malaria parasites via high-resolution metabolomics0 aProfiling of metabolic alterations in mice infected with malaria cNOV a1115250 v2523 a

Background: Malaria infection can result in distinct clinical outcomes from asymptomatic to severe. The association between patho-physiological changes and molecular changes in the host, and their correlation with severity of malaria progression is not fully understood. Methods: In this study, we addressed mass spectrometry-based temporal profiling of serum metabolite levels from mice infected with Plasmodium berhgei (strain ANKA). Results: We show global perturbations and identify changes in specific metabolites in correlation with disease progression. While metabolome-wide changes were apparent in late-stage malaria, a subset of metabolites exhibited highly correlated changes with disease progression. These metabolites changed early on following infection and either continued or maintained the change as mice developed severe disease. Some of these have the potential to be sentinel metabolites for severe malaria. Moreover, glycolytic metabolites, purine nucleotide precursors, tryptophan and its bioactive derivatives were many fold decreased in late-stage disease. Interestingly, uric acid, a metabolic waste reported to be elevated in severe human malaria, increased with disease progression, and subsequently appears to be detoxified into allantoin. This detoxification mechanism is absent in humans as they lack the enzyme uricase. Conclusions: We have identified candidate marker metabolites that may be of relevance in the context of human malaria.

10aHost response10aInfectious diseases10amalaria10ametabolite10aPlasmodium1 aChhibber-Goel, Jyoti1 aShukla, Anurag1 aShanmugam, Dhanasekaran1 aSharma, Amit uhttps://library.ncl.res.in/content/profiling-metabolic-alterations-mice-infected-malaria-parasites-high-resolution-metabolomics03191nas a2200313 4500008004100000022001400041245011700055210006900172260000800241300001200249490000700261520213700268653002902405653002602434653001202460653002602472653001802498100002302516700002502539700002802564700002402592700002802616700002202644700002402666700001902690700001802709700002202727856012802749 2023 eng d a1230-282100aAntimalarial activity of anacardium occidentale leaf extracts against plasmodium falciparum transketolase (PfTK)0 aAntimalarial activity of anacardium occidentale leaf extracts ag cDEC a832-8410 v683 a

BackgroundAs per estimates by WHO in 2021 almost half of the world's population was at risk of malaria and > 0.6 million deaths were attributed to malaria. Therefore, the present study was aimed to explore the antimalarial activity of extracts derived from the leaves of the plant Anacardium occidentale L., which has been used traditionally for the treatment of malaria. Different extracts of A.occidentale leaves were prepared and tested for their inhibitory activity against recombinant P. falciparum transketolase (rPfTK) enzyme, in vitro. Further, growth inhibitory activity against cultivated blood stage P. falciparum parasites (3D7 strain), was studied using SYBR Green fluorescence-based in vitro assays. Acute toxicity of the hydro alcoholic extracts of leaves of A. occidentale (HELA) at different concentrations was evaluated on mice and Zebra fish embryos. HELA showed 75.45 +/- 0.35% inhibitory activity against the recombinant PfTk and 99.31 +/- 0.08% growth inhibition against intra-erythrocytic stages of P. falciparum at the maximum concentration (50 mu g/ml) with IC50 of 4.17 +/- 0.22 mu g/ml. The toxicity test results showed that the heartbeat, somite formation, tail detachment and hatching of embryos were not affected when Zebra fish embryos were treated with 0.1 to 10 mu g/ml of the extract. However, at higher concentrations of the extract, at 48 h (1000 mu g/ml) and 96 h (100 mu g/ml and 1000 mu g/ml, respectively) there was no heartbeat in the fish embryos. In the acute oral toxicity tests performed on mice, the extract showed no toxicity up to 300 mg/kg body weight in mice.ConclusionThe hydro-alcoholic extract of leaves of A. occidentale L. showed potent antimalarial activity against blood stage P. falciparum. Based on the observed inhibitory activity on the transketolase enzyme of P. falciparum it is likely that this enzyme is the target for the development of bioactive molecules present in the plant extracts. The promising anti-malarial activity of purified compounds from leaves of A. occidentale needs to be further explored for development of new anti-malarial therapy.

10aAnacardium occidentale L10aAntimalarial activity10amalaria10aPlasmodium falciparum10aTransketolase1 aKaushik, Meenakshi1 aHoti, Sugeerappa, L.1 aSaxena, Jitendra, Kumar1 aHingamire, Tejashri1 aShanmugam, Dhanasekaran1 aJoshi, Rajesh, K.1 aMetgud, Sharada, C.1 aUngar, Banappa1 aSingh, Ishwar1 aHegde, Harsha, V. uhttps://library.ncl.res.in/content/antimalarial-activity-anacardium-occidentale-leaf-extracts-against-plasmodium-falciparum03461nas a2200301 4500008004100000022001400041245012200055210006900177260000800246300001200254490000700266520249900273653002002772653001202792653002002804653001802824653001202842100002102854700001902875700001902894700001702913700002102930700002202951700001602973700001702989700002803006856012503034 2026 eng d a2328-895700aTargeted genomic surveillance unveils genetic variations linked to regional malaria drug resistance dynamics in India0 aTargeted genomic surveillance unveils genetic variations linked  cMAR aofag1060 v133 a

Background India has made substantial progress in reducing Plasmodium falciparum malaria cases and has set a target to eliminate malaria by 2030. Although artemisinin-based combination therapy (ACT) treatment remains effective, tracking regional differences in genetic variants associated with antimalarial resistance is required for effective drug policy implementation.Methods We analyzed 238 P. falciparum clinical samples from 6 Indian states by sequencing 15 parasite genes associated with reduced drug effectiveness. The method involved nanopore sequencing of target gene amplicons derived from dried blood spots using a highly-sensitive PfMDR15 surveillance panel.Results India's historical policy of artesunate-sulfadoxine-pyrimethamine in central India and artemether-lumefantrine in the Northeast has shaped contrasting resistance profiles. In the Northeast, chloroquine resistance persisted at high frequency (Pfcrt K76T and CVIET haplotype; Pfaat1 S258L), alongside quintuple and sextuple Pfdhfr-Pfdhps haplotypes conferring complete sulfadoxine-pyrimethamine resistance. Central India showed variable chloroquine resistance (parasites largely retained wild-type Pfcrt) and emerging lumefantrine tolerance (Pfmdr1 Y184F, Pfaat1 S258L). Interestingly, Delhi (Central India) parasites resembled profiles from the distant Northeast, which borders South East Asia. The detection of Pfaat1 S258L, previously reported only from Africa and associated with reduced lumefantrine susceptibility, suggests convergent evolution under ACT partner-drug pressure. No WHO-validated Pfk13 artemisinin resistance mutations were detected, supporting continued efficacy of ACT.Conclusions India's resistance landscape is fragmented, with signals of expanding lumefantrine tolerance and importation or evolution of globally relevant mutations. These findings highlight the importance of integrating molecular genomic surveillance into malaria control policy to monitor and protect ACT effectiveness and advance malaria elimination. Monitoring of drug resistance associated mutations in P. falciparum parasites is critical for effective drug treatment. We have demonstrated the use of a scalable genomic surveillance protocol for tracking drug resistance linked mutations in parasite genes from clinical isolates in India. The study suggests extensive regional diversity in antimalarial resistance profiles and provides the first hint of possible emergence of lumefantrine tolerance in India.

10adrug resistance10amalaria10aOxford nanopore10aP. falciparum10apfMDR151 aKhilari, Ajinkya1 aSharma, Shweta1 aBajpai, Manali1 aViswan, Anju1 aChaturvedi, Rini1 aMirdha, Bijay, R.1 aRahi, Manju1 aSharma, Amit1 aShanmugam, Dhanasekaran uhttps://library.ncl.res.in/content/targeted-genomic-surveillance-unveils-genetic-variations-linked-regional-malaria-drug