Antimony resistance mechanism in genetically different clinical isolates of Indian Kala-azar patients

The central theme of this enterprise is to find common features, if any, displayed by genetically different antimony (Sb)-resistant viscerotropic Leishmania parasites to impart Sb resistance. In a limited number of clinical isolates (n = 3), we studied the breadth of variation in the following dimensions: (a) intracellular thiol content, (b) cell surface expression of glycan having N-acetyl-D-galactosaminyl residue as the terminal sugar, and (c) gene expression of thiol-synthesizing enzymes (CBS, MST, gamma-GCS, ODC, and TR), antimony-reducing enzymes (TDR and ACR2), and antimonial transporter genes (AQP1, MRPA, and PRP1). One of the isolates, T5, that was genotypically characterized as Leishmania tropica, caused Indian Kala-azar and was phenotypically Sb resistant (T5-LT-SSG-R), while the other two were Leishmania donovani, out of which one isolate, AG83, is antimony sensitive (AG83-LD-SSG-S) and the other isolate, T8, is Sb resistant (T8-LD-SSG-R). Our study showed that the Sb-resistant parasites, regardless of their genotype, showed significantly higher intracellular thiol compared with Sb-sensitive AG83-LD-SSG-S. Seemingly, T5-LT-SSG-R showed about 1.9-fold higher thiol content compared with T8-LD-SSG-R which essentially mirrored cell surface N-acetyl-D-galactosaminyl expression. Except TR, the expression of the remaining thiol-synthesizing genes was significantly higher in T8-LD-SSG-R and T5-LT-SSG-R than the sensitive one, and between the Sb-resistant parasites, the latter showed a significantly higher expression. Furthermore, the genes for Sb-reducing enzymes increased significantly in resistant parasites regardless of genotype compared with the sensitive one, and between two resistant parasites, there was hardly any difference in expression. Out of three antimony transporters, AQP1 was decreased with the concurrent increase in MRPA and PRP1 in resistant isolates when compared with the sensitive counterpart. Interestingly, no difference in expression of the above-mentioned transporters was noted between two Sb-resistant isolates. The enduring image that resonated from our study is that the genetically diverse Sb-resistant parasites showed enhanced thiol-synthesizing and antimony transporter gene expression than the sensitive counterpart to confer a resistant phenotype

The novel-molecule T11TS facilitated arousal of glioma-mediated dormancy of bone-marrow hematopoietic stem-cells

Aim: T11TS, a potent anti-gliomagenic glycoprotein, stimulates both peripheral and intracranial immune response. The status of bone marrow hematopoietic stem cells (BMHSCs), the cradle of regeneration of all blood cells, during gliomagenic global immune devastations has not yet been investigated. Therefore, we aimed to delineate the effects of T11TS on immature and mature compartments of hematopoietic machinery.Methods: Flowcytometric analysis of cultured BMHSCs was evaluated for assesing the expression pattern of early hematopoietic stem cells (HSCs) markers such as CD34+, Sca-1+, c-kit+ and also Angiopoietin-1 and Tie-2 both in normal, glioma, and in T11TS treated glioma-bearing animals. Immunofluresenece imaging and western blot analyses of BMHSCs were also carried out.Results: There was significant downregulation of HSCs-markers CD34+, Sca-1+, c-kit+ in ethyl nitrosourea-induced glioma-bearing animals followed by an increase in the expression level of Ang-1 and Tie-2 that determines the quiescence and self-renewability of stem cells. T11TS administration reversed the gliomagenic transformation of expression of the above mentioned markers. The results flowcytometric-analysis was also well corroborated with immunofluorescence imaging and western blot analysis.Conclusion: Collectively, the above experimental evidence hints towards gliomagenic maneuver of receptor expression of HSCs to derange the systemic immunity and T11TS mediated manipulation towards revival/rejuvenation of the same

Predictions for measuring the 21-cm multifrequency angular power spectrum using SKA-Low

The light-cone (LC) effect causes the mean as well as the statistical properties of the redshifted 21-cm signal $T_{\rm b}(\hat{\bf n},\nu)$ to change with frequency $\nu$ (or cosmic time). Consequently, the statistical homogeneity (ergodicity) of the signal along the line of sight (LoS) direction is broken. This is a severe problem particularly during the Epoch of Reionization (EoR) when the mean neutral hydrogen fraction ($\bar{x}_{\rm HI}$) changes rapidly as the universe evolves. This will also pose complications for large bandwidth observations. These effects imply that the 3D power spectrum $P(k)$ fails to quantify the entire second-order statistics of the signal as it assumes the signal to be ergodic and periodic along the LoS. As a proper alternative to $P(k)$, we use the multi-frequency angular power spectrum (MAPS) ${\mathcal C}_{\ell}(\nu_1,\nu_2)$ which does not assume the signal to be ergodic and periodic along the LoS. Here, we study the prospects for measuring the EoR 21-cm MAPS using future observations with the upcoming SKA-Low. Ignoring any contribution from the foregrounds, we find that the EoR 21-cm MAPS can be measured at a confidence level $\ge 5\sigma$ at angular scales $\ell \sim 1300$ for total observation time $t_{\rm obs} \ge 128\,{\rm hrs}$ across $\sim 44\,{\rm MHz}$ observational bandwidth. We also quantitatively address the effects of foregrounds on MAPS detectability forecast by avoiding signal contained within the foreground wedge in $(k_\perp, k_\parallel)$ plane. These results are very relevant for the upcoming large bandwidth EoR experiments as previous predictions were all restricted to individually analyzing the signal over small frequency (or equivalently redshift) intervals.Comment: Published in Monthly Notices of the Royal Astronomical Society (MNRAS). Available at https://doi.org/10.1093/mnras/staa102