Biology subjects

Paterson, C.

Publications and source records attributed to Paterson, C..

6 recordsLinked to original sources

bioRxiv2023

A BubR1-independent pathway for CENP-E targeting to the outer corona of kinetochores

For chromosome segregation to take place, unattached kinetochores expand in early mitosis, forming a fibrous structure called the fibrous corona that is captured by microtubules. The corona is assembled from the RZZ complex, Spindly, CENP-E and the Mad1/Mad2 spindle assembly checkpoint proteins. CENP-E aligns chromosomes along the mitotic spindle by moving them to the plus ends of microtubules. Here, we show that CENP-E is recruited to the outer corona independently of BubR1 in a dynein-dependent fashion. We determine the structure of this domain and show that a conserved loop is essential for CENP-E targeting to the outer corona. We show that both domains are essential for CENP-E recruitment to unattached kinetochores. We also report that the kinetochore-targeting domain of CENP-E contributes to the recruitment of the RZZ complex, Mad1 and Spindly, providing a feedback loop to assemble the outer corona. In this study, we propose that CENP-E uses 2 pathways to target to the kinetochore, which allows it to optimize kinetochore capture by microtubules for chromosome alignment and mitotic progression.

cell biology↗

bioRxiv2021

Video-rate remote refocusing through continuous oscillation of a membrane deformable mirror.

This paper presents the use of a deformable mirror (DM) configured to rapidly refocus a microscope employing a high numerical aperture objective lens. An Alpao DM97-15 membrane DM was used to refocus a 40x/0.80 NA water-immersion objective through a defocus range of -50 to 50 m at 26.3 sweeps per second. We achieved imaging with a mean Strehl metric of > 0.6 over a field of view in the sample of 200x200 m2 over a defocus range of 77 m. We describe an optimisation procedure where the mirror is swept continuously in order to avoid known problems of hysteresis associated with the membrane DM employed. This work demonstrates that a DM-based refocusing system could in the future be used in light-sheet fluorescence microscopes to achieve video-rate volumetric imaging.

bioengineering↗

bioRxiv2020

Mathematical Model of Colorectal Cancer Initiation

Quantifying evolutionary dynamics of cancer initiation and progression can provide insights into more effective strategies of early detection and treatment. Here we develop a mathematical model of colorectal cancer initiation through inactivation of two tumor suppressor genes and activation of one oncogene, accounting for the well-known path to colorectal cancer through loss of tumor suppressors APC and TP53, and gain of the KRAS oncogene. In the model, we allow mutations to occur in any order, leading to a complex network of incomplete mutational genotypes on the way to colorectal cancer. We parametrize the model using experimentally measured parameter values, many of them only recently available, and compare its predictions to epidemiological data on colorectal cancer incidence. We find that the reported incidence of colorectal cancer can be recovered using a mathematical model of colorectal cancer initiation together with experimentally measured mutation rates in colorectal tissues and proliferation rates of premalignant lesions. We demonstrate that the order of driver events in colorectal cancer is determined by the combined effect of the rates at which driver genes are mutated and the fitness effects they provide. Our results imply that there may not be significant immune suppression of untreated benign and malignant colorectal lesions.

cancer biology↗

bioRxiv2019

On measuring selection in cancer from subclonal mutation frequencies

Recently available cancer sequencing data have revealed a complex view of the cancer genome containing a multitude of mutations, including drivers responsible for cancer progression and neutral passengers. Measuring selection in cancer and distinguishing drivers from passengers have important implications for development of novel treatment strategies. It has recently been argued that a third of cancers are evolving neutrally, as their mutational frequency spectrum follows a 1/f power law expected from neutral evolution in a particular intermediate frequency range. We study a stochastic model of cancer evolution and derive a formula for the probability distribution of the cancer cell frequency of a subclonal driver, demonstrating that driver frequency is biased towards 0 and 1. We show that it is difficult to capture a driver mutation at an intermediate frequency, and thus the calling of neutrality due to a lack of such driver will significantly overestimate the number of neutrally evolving tumors. Our approach provides precise quantification of the validity of the 1/f statistic across the entire range of all relevant parameter values. Our results are also applicable to the question of distinguishing driver and passenger mutations in a general exponentially expanding population.

cancer biology↗

bioRxiv2018

Modulation of corneal tissue mechanics influences epithelial cell phenotype

Whilst the control of stem cell differentiation using substrates of differing compliance has been extensively explored in vitro, the significance of this mechanism at a physiological level is not known. Here we set to explore the role of corneal surface biomechanics in controlling epithelial cell proliferation and differentiation. Using non-contact high-resolution Brillouin spectro-microscopy we showed that the corneal outer edge (limbus) has significantly lower bulk modulus compared to the central cornea, and that this difference is precisely delimited in the organ. Furthermore, the areas of the limbus with distinctly softer properties were shown to be associated with limbal epithelial stem cell (LESC) residence. Based on these findings, we then provided the first demonstration of the capacity to modulate LESC phenotype, both in vivo and ex vivo, solely through the recreation/restoration of suitable biomechanical niches. These results thus confirm the fundamental role of corneal biomechanics in directing epithelial stem cell behavior.

cell biology↗

bioRxiv2016

An exactly solvable, spatial model of mutation accumulation in cancer

One of the hallmarks of cancer is the accumulation of driver mutations which increase the net reproductive rate of cancer cells and allow them to spread. This process has been studied in mathematical models of well mixed populations, and in computer simulations of three-dimensional spatial models. But the computational complexity of these more realistic, spatial models makes it difficult to simulate realistically large and clinically detectable solid tumours. Here we describe an exactly solvable mathematical model of a tumour featuring replication, mutation and local migration of cancer cells. The model predicts a quasi-exponential growth of large tumours even if different fragments of the tumour grow sub-exponentially due to nutrient and space limitations. The model reproduces clinically observed tumour growth times using biologically plausible rates for cell birth, death, and migration rates. We also show that the expected number of accumulated driver mutations increases exponentially in time if the average fitness gain per driver is constant, and that it reaches a plateau if the gains decrease over time. We discuss the realism of the underlying assumptions and possible extensions of the model.

cancer biology↗