Biology subjects

Ng, A.

Publications and source records attributed to Ng, A..

3 recordsLinked to original sources

bioRxiv2018

Design and analysis of a Proportional-Integral-Derivative controller with biological molecules

The ability of cells to regulate their function through feedback control is a fundamental underpinning of life. The capability to engineer de novo feedback control with biological molecules is ushering in an era of robust functionality for many applications in biotechnology and medicine. To fulfill their potential, feedback control strategies implemented with biological molecules need to be generalizable, modular and operationally predictable. Proportional-Integral-Derivative (PID) control fulfills this role for technological systems and is a commonly used strategy in engineering. Integral feedback control allows a system to return to an invariant steady-state value after step disturbances, hence enabling its robust operation. Proportional and derivative feedback control used with integral control help sculpt the dynamics of the return to steady-state following perturbation. Recently, a biomolecular implementation of integral control was proposed based on an antithetic motif in which two molecules interact stoichiometrically to annihilate each others function. In this work, we report how proportional and derivative implementations can be layered on top of this integral architecture to achieve a biochemical PID control design. We illustrate through computational and analytical treatments that the addition of proportional and derivative control improves performance, and discuss practical biomolecular implementations of these control strategies.

synthetic biology↗

bioRxiv2018

Autoinhibition of kinesin-1 is essential to the dendrite-specific localization of Golgi outposts

Neuronal polarity relies on the selective localization of cargo to axons or dendrites. The molecular motor kinesin-1 moves cargo into axons but is also active in dendrites. This raises the question of how kinesin-1 activity is regulated to maintain the compartment-specific localization of cargo. Our in vivo structure-function analysis of endogenous Drosophila kinesin-1 reveals a novel role for autoinhibition in enabling the dendrite-specific localization of Golgi outposts. Mutations that disrupt kinesin-1 autoinhibition result in the axonal mislocalization of Golgi outposts. Autoinhibition also regulates kinesin-1 localization. Uninhibited kinesin-1 accumulates in axons and is depleted from dendrites, correlating with the change in outpost distribution and dendrite growth defects. Genetic interaction tests show that a balance of kinesin-1 inhibition and dynein activity is necessary to localize Golgi outposts to dendrites and keep them from entering axons. Our data indicate that kinesin-1 activity is precisely regulated by autoinhibition to achieve the selective localization of dendritic cargo.\n\nSummaryNeuronal polarity relies on the axon-or dendrite-specific localization of cargo by molecular motors such as kinesin-1. These studies show autoinhibition regulates both kinesin-1 activity and localization to keep dendritic cargo from entering axons.

cell biology↗

bioRxiv2017

Genome-Scale Mutational Signatures Of Aflatoxin In Cells, Mice And Human Tumors

Aflatoxin B1 (AFB1) is a mutagen and IARC Group 1 carcinogen that causes hepatocellular carcinoma (HCC). Here we present the first whole genome data on the mutational signatures of AFB1 exposure from a total of > 40,000 mutations in four experimental systems: two different human cell lines, and in liver tumors in wild-type mice and in mice that carried a hepatitis B surface antigen transgene - this to model the multiplicative effects of aflatoxin exposure and hepatitis B in causing HCC. AFB1 mutational signatures from all four experimental systems were remarkably similar. We integrated the experimental mutational signatures with data from newly-sequenced HCCs from Qidong County, China, a region of well-studied aflatoxin exposure. This indicated that COSMIC mutational signature 24, previously hypothesized to stem from aflatoxin exposure, indeed likely represents AFB1 exposure, possibly combined with other exposures. Among published somatic mutation data, we found evidence of AFB1 exposure in 0.7% of HCCs treated in North America, 1% of HCCs from Japan, but 16% of HCCs from Hong Kong. Thus, aflatoxin exposure apparently remains a substantial public health issue in some areas. This aspect of our study exemplifies the promise of future widespread resequencing of tumor genomes in providing new insights into the contribution of mutagenic exposures to cancer incidence.

cancer biology↗