Highlights XAD concentrated sample was more mutagenic than the liquid-liquid extracted samples. TA98 was the most responsive strain, indicating presence of frameshift mutagens in textile effluent. Cell damage was found to be maximum in case of pol A mutants (SOS defective mutants). The wastewater contained cytotoxic chemicals that resulted in reduction of mitotic index. The sample also induced chromosomal aberrations in the root meristematic cells of A. cepa .

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The unique occurrence of G-quadruplexes in the AT-rich genome of human malaria parasite Plasmodium falciparum provides hints about their critical roles in parasite survival, pathogenesis, and host immune evasion. An intriguing question is whether these noncanonical structures can serve as molecular targets for small molecule-based interventions against malaria. In this study, we have investigated the pharmacological targeting of G-quadruplexes for parasite inhibition. We observed that bisquinolinium derivatives of 1,8-naphthyridine and pyridine affected the stability and molecular recognition properties of G-quadruplexes in telomeric and subtelomeric regions in P. falciparum. Parasite inhibition and cytotoxicity assays revealed that these ligands effectively inhibit parasite growth with minimal toxic effects in human cells. G-quadruplex interacting ligands caused degeneration and shortening of parasite telomeres. Ligand-induced perturbations in telomere homeostasis also affected transcriptional state of the subtelomeric region harboring antigenic variation genes. Taken together, our results suggest that quadruplex-ligand interaction disturbs telomeric/subtelomeric chromatin organization and induces DNA damage that consequently leads to parasite death. Our findings also draw attention to the striking differences in telomere dynamics in the protozoan parasite and human host that can be exploited for selective targeting of the telomeric quadruplex of the parasite as a potential antimalarial strategy.

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Plasmodium falciparum, the human malaria parasite harbors a metastable proteome which is vulnerable to proteotoxic stress conditions encountered during its lifecycle. How parasite’s chaperone machinery is able to maintain its aggregation-prone proteome in functional state, is poorly understood. As HSP70-40 system forms the central hub in cellular proteostasis, we investigated the protein folding capacity of PfHSP70-1 and PfHSP40 chaperone pair and compared it with human orthologs (HSPA1A and DNAJA1). Despite structural similarity, we observed that parasite chaperones and their human orthologs exhibit striking differences in conformational dynamics. Comprehensive biochemical investigations revealed that PfHSP70-1 and PfHSP40 chaperone pair has better protein folding, aggregation inhibition and oligomer remodeling and disaggregase activities than their human orthologs. Chaperone-swapping experiments suggest that PfHSP40 can also efficiently cooperate with human HSP70 to facilitate folding of client-substrate. SPR-derived kinetic parameters reveal that PfHSP40 has higher binding affinity towards unfolded substrate than DNAJA1. Interestingly, the observed slow dissociation rate of PfHSP40-substrate interaction allows PfHSP40 to maintain substrate in folding-competent state to minimize its misfolding. Structural investigation through SAXS gave insights into the conformational architecture of PfHSP70-1 (monomer), PfHSP40 (dimer) and their complex. Overall, our data suggests that parasite has evolved functionally diverged and efficient chaperone machinery which allows human malaria parasite to survive in hostile conditions. The distinct allosteric landscapes and interaction kinetics of plasmodial chaperones open avenues for exploration of small-molecule based antimalarial interventions.

Dalam upaya mencari dimensi yang paling hakiki, manusia tidak boleh hanya berkutat pada level empiris dan apriori semata. Manusia harus melakukan perenungan dengan melepaskan diri dari segala sesuatu yang bersifat empiris dan apriori untuk menemukan prinsip utama. Tulisan ini menganalisis dimensi metafisik upacara kasada. Hasil kajian menunjukkan bahwa refleksi metafisik mampu ‘mengatasi’ realitas yang nampak, yang seakan-akan “sesungguhnya” namun pada kenyataanya ‘menipu’. Kepalsuan ini tanpa disadari masuk ke dalam ranah ideologis dan membuat manusia tak mampu keluar dari sakralisasi ruang, waktu dan tempat yang mewarnai ritual upacara Kasada. Bertitik tolak dari penemuan ini, pelacakan dimensi metafisik dilanjutkan untuk menemukan eksistensi dan makna dari sebuah simbol-simbol dan mitos. Pelacakan ini pada akhirnya memberi kesimpulan bahwa dimensi metafisik dalam upacara Kasada masyarakat Tengger pada hakekatnya adalah miniatur dari kehidupan semua.