Biology subjects

Nayak, I.

Publications and source records attributed to Nayak, I..

3 recordsLinked to original sources

bioRxiv2024

Impact of IL-21 on Natural Killer cell proliferation and Function - a mathematical and functional assessment

Natural killer (NK) cells are currently in use as immunotherapeutic agents for cancer. Many different cytokines are used to generate NK cells including IL-2, IL-12, IL-15 and IL-18 in solution and membrane bound IL-21. These cytokines drive NK cell activation through the integration of STAT and NF-{kappa}B pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for different cytokine combinations and indicates synergy between STAT3 and NF-{kappa}B transcription factors. Use of IL-21 in solution in the priming, but not post-priming phase of NK cell culture resulted in optimal NK cell proliferation, without compromising cytotoxicity or IFN-{gamma} secretion against hepatocellular carcinoma cell lines. Our work provides a mathematical framework for interrogating NK cell activation for cancer immunotherapy.

immunology↗

bioRxiv2022

Quantification of differential toxin expressions and their relation to distinct lifespans of bacterial subpopulations associated with diverse host immune mechanisms

An assortment of robust intracellular defence mechanisms are critical for restricting proliferation of pathogens and maintaining sanctity of the cytosol. Defect in these mechanisms could be exploited by the pathogens for creation of a safe sanctuary which can act as a transient reservoir for periodic dissemination into the host. While residing inside the host cell, pore forming toxins secreted by the pathogens compromises the integrity of the vacuole and exposes the microbe to diverse intracellular defence mechanisms. However, the correlation between toxin expression levels and consequent pore dynamics, fostering pathogens intracellular life, remains largely unexplored. In this study, using Streptococcus pneumoniae (SPN) and its secreted pore forming toxin pneumolysin (Ply), as model systems, we explored various facets of host-pathogen interactions in host cytosol, governed by the toxin expression and the resultant pore formation. The extent of damage on the endosomal membrane was found to dictate subsequent interaction with different host endosomal damage sensors. This in turn governed the routes of SPN clearance, revealing multiple layers of defence mechanisms at hosts disposal for counteracting invaded pathogens. A subset of SPN population producing extremely low amount of Ply inflicted minimal damage to the endomembrane, precluding decoration by endomembrane damage sensors and significantly prolonging its intracellular persistence. Such long persisting bacterial population could be key for pathogenic transmission or ensuing invasive disease. Using time-lapse fluorescence imaging, we monitored lifespans of different pneumococcal population subsets inside host cells. After quantitative analysis of various timescales such as pore formation time, vacuolar or cytosolic residence time and total degradation time, we developed a mathematical model that could correlate these to intravacuolar accumulation of Ply monomers. By proposing events like pore formation and vacuolar degradation of SPN as first passage processes, our theoretical modelling yields estimates of Ply production rate, burst size, and threshold Ply quantities which triggers these outcomes. Collectively, we present a general method by which intracellular lifespans of pathogens could be correlated to differential levels of toxins that they produce.

microbiology↗

bioRxiv2019

Kinetochore capture by spindle microtubules: why fission yeast may prefer pivoting to search-and-capture

The mechanism by which microtubules find kinetochores during spindle formation is a key question in cell biology. Previous experimental studies have shown that although search-and-capture of kinetochores by dynamic microtubules is a dominant mechanism in many organisms, several other capture mechanisms are also possible. One such mechanism reported in Schizosaccharomyces pombe shows that microtubules can exhibit a prolonged pause between growth and shrinkage. During the pause, the microtubules pivoted at the spindle pole body search for the kinetochores by performing an angular diffusion. Is the latter mechanism purely accidental, or could there be any physical advantage underlying its selection? To compare the efficiency of these two mechanisms, we numerically study distinct models and compute the timescales of kinetochore capture as a function of microtubule number N. We find that the capture timescales have non-trivial dependences on microtubule number, and one mechanism may be preferred over the other depending on this number. While for small N (as in fission yeast), the typical capture times due to rotational diffusion are lesser than those for search-and-capture, the situation is reversed beyond a certain N. The capture times for rotational diffusion tend to saturate due to geometrical constraints, while those for search-and-capture reduce monotonically with increasing N making it physically more efficient. The results provide a rationale for the common occurrence of classic search-and-capture process in many eukaryotes which have few hundreds of dynamic microtubules, as well as justify exceptions in cells with fewer microtubules.

biophysics↗