Biology subjects

Krishnan, N.

Publications and source records attributed to Krishnan, N..

22 records · Page 2Linked to original sources

bioRxiv2021

Rab11 endosomes coordinate centrosome number and movement following mitotic exit

The last stage of cell division involves two daughter cells remaining interconnected by a cytokinetic bridge that is cleaved in a process called abscission. During pre-abscission, we identified that the centrosome moves in a Rab11-dependent manner towards the cytokinetic bridge in human cells grown in culture and in an in vivo vertebrate model, Danio rerio (zebrafish). Rab11-endosomes are dynamically organized in a Rab11-GTP dependent manner at the centrosome during pre-abscission and this organization is required for the centrosome protein, pericentrin, to be enriched at the centrosome. Using zebrafish embryos, we found that reduction in pericentrin expression or optogenetically disrupting Rab11-endosome function inhibited centrosome movement towards the cytokinetic bridge and abscission resulting in daughter cells prone to being binucleated and/or having supernumerary centrosomes. These studies suggest that Rab11-endosomes contribute to centrosome function during pre-abscission by regulating pericentrin organization resulting in appropriate centrosome movement towards the cytokinetic bridge and subsequent abscission.

cell biology↗

bioRxiv2021

Ghrelin O-acyltransferase interacts with extracellular peptides and exhibits unexpected cellular localization for a secretory pathway enzyme

Ghrelin O-acyltransferase (GOAT) plays a central role in the maturation and activation of the peptide hormone ghrelin, which performs a wide range of endocrinological signaling roles. Using a tight-binding fluorescent ghrelin-derived peptide designed for high selectivity for GOAT over the ghrelin receptor GHS-R1a, we demonstrate that GOAT interacts with extracellular ghrelin and facilitates ligand cell internalization in both transfected cells and prostate cancer cells endogenously expressing GOAT. Coupled with enzyme mutagenesis, ligand uptake studies provide the first direct evidence supporting interaction of the putative histidine general base within GOAT with the ghrelin peptide acylation site. Our work provides a new understanding of GOATs catalytic mechanism, establishes a key step required for autocrine/paracrine ghrelin signaling involving local reacylation by GOAT, and raises the possibility that other peptide hormones may exhibit similar complexity in their intercellular and organismal-level signaling pathways.

biochemistry↗

bioRxiv2019

Controlling the speed and trajectory of evolution with counterdiabatic driving

The pace and unpredictability of evolution are critically relevant in a variety of modern challenges: combating drug resistance in pathogens and cancer, understanding how species respond to environmental perturbations like climate change, and developing artificial selection approaches for agriculture. Great progress has been made in quantitative modeling of evolution using fitness landscapes, allowing a degree of prediction for future evolutionary histories. Yet fine-grained control of the speed and the distributions of these trajectories remains elusive. We propose an approach to achieve this using ideas originally developed in a completely different context - counterdiabatic driving to control the behavior of quantum states for applications like quantum computing and manipulating ultra-cold atoms. Implementing these ideas for the first time in a biological context, we show how a set of external control parameters (i.e. varying drug concentrations / types, temperature, nutrients) can guide the probability distribution of genotypes in a population along a specified path and time interval. This level of control, allowing empirical optimization of evolutionary speed and trajectories, has myriad potential applications, from enhancing adaptive therapies for diseases, to the development of thermotolerant crops in preparation for climate change, to accelerating bioengineering methods built on evolutionary models, like directed evolution of biomolecules.

evolutionary biology↗

bioRxiv2019

Clonal interference patterns shift during range expansion

Increasingly, predicting and even controlling evolutionary processes is a sought after goal in fields ranging from agriculture, artificial intelligence, astrobiology, oncology, and infectious diseases. However, our ability to predict evolution and plan such interventions in real populations is limited in part by our understanding of how spatial structure modulates evolutionary dynamics. Among current clinical assays applied to predict drug response in infectious diseases, for instance, many do not explicitly consider spatial structure and its influence on phenotypic heterogeneity, despite it being an inextricable characteristic of real populations. As spatially structured populations are subject to increased interference of beneficial mutants compared to their well-mixed counter-parts, among other effects, this population heterogeneity and structure may non-trivially impact drug response. In spatially-structured populations, the extent of this mutant interference is density dependent and thus varies with relative position within a meta-population in a manner modulated by mutant frequency, selection strength, migration speed, and habitat length, among other factors. In this study, we examine beneficial mutant fixation dynamics along the front of an asexual population expanding its range. We observe that multiple distinct evolutionary regimes of beneficial mutant origin-fixation dynamics are maintained at characteristic length scales along the front of the population expansion. Using an agent-based simulation of range expansion with mutation and selection in one dimension, we measure these length scales across a range of population sizes, selection strengths, and mutation rates. Furthermore, using simple scaling arguments to adapt theory from well-mixed populations, we find that the length scale at the tip of the front within which local mutant fixation occurs in a successive mode decreases with increasing mutation rate, as well as population size in a manner predicted by our derived analytic expression. Finally, we discuss the relevance of our findings to real cellular populations, arguing that this conserved region of successive mutant fixation dynamics at the wave tip can be exploited by emerging evolutionary control strategies.

evolutionary biology↗