Although over the last 15 years, prevalence of malaria became reduced by over half but developing resistance against artemisinin derivatives and its combinations, which are only ray of hope to treat ...resistant malaria set back the control efforts and the key hinderence to achieve the goal of malaria elimination till 2030. In spite these artemisinins are precious antimalarials, their action mechanism is yet to be fully understood. Reactive oxygen species (ROS) produces by cleavage of endoperoxide bridge of artemisinin derivatives are known to be its antimalarial efficacy. Since ROS could induce apoptosis, here we had explored the effect of artemisinin derivatives on apoptotic machinery of malaria parasite,
and its survival. We have studied the effect of a/β arteether, artesunate and a synthetic 1, 2, 4 trioxane on mitochondria, caspase activity and DNA during asexual blood stages of
3D7. Results have shown that cleavage of peroxide bridge of artemisinin derivatives and 1,2,4 trioxane generate reactive oxygen species which depolarize mitochondrial membrane potential and make it permeable which further followed by activation of caspase like enzyme and DNA fragmentation, which are hallmark of apoptotic cell death. These findings suggest that artemisinin derivatives and synthetic trioxane induce apoptosis like phenomena in erythrocytic stage of malaria parasite;
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We performed a novel phase-sensitive microwave reflection experiment which directly probes the dynamics of the Josephson plasma resonance in both the linear and the nonlinear regime. When the ...junction was driven below the plasma frequency into the nonlinear regime, we observed for the first time the transition between two different dynamical states predicted for nonlinear systems. In our experiment, this transition appears as an abrupt change in the reflected signal phase at a critical excitation power. This controlled dynamical switching can form the basis of a sensitive amplifier, in particular, for the readout of superconducting qubits.
We present a thermometer based on the electrical noise from a tunnel junction. In this thermometer, temperature is related to the voltage across the junction by a relative noise measurement with only ...the use of the electron charge, Boltzmann's constant, and assumption that electrons in a metal obey Fermi-Dirac statistics. We demonstrate proof-of-concept operation of this primary thermometer over four orders of magnitude in temperature, with as high as 0.1% accuracy and 0.02% precision in the range near 1 kelvin. The self-calibrating nature of this sensor allows for a much faster and simpler measurement than traditional Johnson noise thermometry, making it potentially attractive for metrology and for general use in cryogenic systems.
Acetyl Coenzyme A Carboxylase (AccD6) is a homodimeric protein which is involved in the carboxylation of acetyl coenzyme A to produce malonyl coenzyme A, which plays an important role in the ...biosynthesis of fatty acid chain. However, studies suggest that AccD6 in combination with AccA3 produces malonyl co-A. Certain herbicides are known to inhibit plant ACC. Among these herbicides, haloxyfop was found to inhibit AccD6 at IC50 of 21.1 ± 1 µM. In this study, we have performed molecular docking of the Maybridge database consisting of ~55,000 compounds in the active site of the protein with haloxyfop as a reference molecule, followed by molecular dynamics study and biological activity determination of prioritized compounds. Out of the nine compounds selected for biological evaluation, three compounds - CD07230, HTS08529 and KM08871 - were found to exhibit anti-mycobacterial activity.
A novel class of hybrid 4-anilinoquinoline triazines have been synthesized and evaluated in vitro for their antimalarial activity against CQ-sensitive 3D7 strain of
P. falciparum as well as for their ...cytotoxicity toward VERO cell line. Five compounds (
19,
20,
23,
41 and
45) exhibited the antimalarial potency superior to CQ. Compounds
14 and
16 were found to be orally active at a dose of 100 mg/kg × 4 days against CQ-resistant strain of
P. yoelii. Inhibition of β-hematin formation assay and molecular docking study has been conducted in order to gain insight into the mechanism of action of proposed targets for the 4-anilinoquinoline and triazine moiety of the hybrid compounds.
A series of novel hybrid class 4-anilinoquinoline triazines have been synthesized and screened for their antimalarial activity in in vitro and in vivo assay.
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► A novel class of hybrid 4-anilinoquinoline triazines have been synthesized and evaluated in vitro for their antimalarial activity against CQ-sensitive 3D7 strain of
P. falciparum. ► Five compounds (
19,
20,
23,
41 and
45) exhibited the in vitro antimalarial potency superior to CQ. ► Compounds
14 and
16 were found to be orally active at a dose of 100 mg/kg × 4 days against CQ-resistant strain of
P. yoelii.
Advanced computational tools focusing on protein-protein interaction (PPI) based drug development is a powerful platform to accelerate the therapeutic development of small lead molecules and ...repurposed drugs. Toll/interleukin-1 receptor (TIR) domain-containing adapter protein (TIRAP) and its interactions with other proteins in macrophages signalling are crucial components of severe or persistent inflammation. TIRAP activation through Bruton's tyrosine kinase (BTK) and Protein Kinase C delta (PKCδ) is essential for downstream inflammatory signalling. We created homology-based structural models of BTK and PKCδ in MODELLER 9.24. TIRAP interactions with BTK and PKCδ in its non-phosphorylated and phosphorylated states were determined by multiple docking tools including HADDOCK 2.4, pyDockWEB and ClusPro 2.0. Food and Drug Administration (FDA)-approved drugs were virtually screened through Discovery Studio LibDock and Autodock Vina tools to target the common TIR domain residues of TIRAP, which interact with both BTK and PKC at the identified interfacial sites of the complexes. Four FDA-approved drugs were identified and found to have stable interactions over a range of 100 ns MD simulation timescales. These drugs block the interactions of both kinases with TIRAP in silico. Hence, these drugs have the potential to dampen downstream inflammatory signalling and inflammation-mediated disease.
Sodium antimony gluconate (SAG) unresponsiveness of Leishmania donovani (Ld) had effectively compromised the chemotherapeutic potential of SAG. 60s ribosomal L23a (60sRL23a), identified as one of the ...over-expressed protein in different resistant strains of L.donovani as observed with differential proteomics studies indicates towards its possible involvement in SAG resistance in L.donovani. In the present study 60sRL23a has been characterized for its probable association with SAG resistance mechanism.
The expression profile of 60s ribosomal L23a (60sRL23a) was checked in different SAG resistant as well as sensitive strains of L.donovani clinical isolates by real-time PCR and western blotting and was found to be up-regulated in resistant strains. Ld60sRL23a was cloned, expressed in E.coli system and purified for raising antibody in swiss mice and was observed to have cytosolic localization in L.donovani. 60sRL23a was further over-expressed in sensitive strain of L.donovani to check its sensitivity profile against SAG (Sb V and III) and was found to be altered towards the resistant mode.
This study reports for the first time that the over expression of 60sRL23a in SAG sensitive parasite decreases the sensitivity of the parasite towards SAG, miltefosine and paramomycin. Growth curve of the tranfectants further indicated the proliferative potential of 60sRL23a assisting the parasite survival and reaffirming the extra ribosomal role of 60sRL23a. The study thus indicates towards the role of the protein in lowering and redistributing the drug pressure by increased proliferation of parasites and warrants further longitudinal study to understand the underlying mechanism.
Meigs syndrome is an uncommon entity associated with benign ovarian tumor, pleural effusion, and ascites. Its association with pericardial effusion is extremely rare. We report a case of Meigs ...syndrome associated with recurrent pericardial effusion that resolved after surgical resection of the ovarian tumor. (Level of Difficulty: Beginner.)
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