Biology subjects

Do, N.

Publications and source records attributed to Do, N..

4 recordsLinked to original sources

bioRxiv2025

A Co-Evolutionary Multi-Objective Framework for Joint Topology and Parameter Discovery in Gene Regulatory Networks

Inferring gene regulatory networks (GRN) poses a complex discrete-continuous, multi-objective optimization problem that requires the simultaneous discovery of both network topology and kinetic parameters. Current methods are often limited because they address these two challenges separately. We propose a novel co-evolutionary multi-objective framework that evolves topology and parameter populations in tandem to optimize three competing objectives: dynamic fidelity, network simplicity, and robustness. This algorithm utilizes biologically-inspired operators and is grounded in theoretical results on Pareto optimality for mixed discrete-continuous spaces. In computational experiments on synthetic benchmarks, our approach showed superior performance, attaining the lowest mean squared error in three of four test cases against single-objective and topology-fixed methods. The framework successfully discovers multiple functionally equivalent network configurations, a finding that highlights the degeneracy inherent in biological systems and offers practical insights for synthetic biology, where function is often prioritized over precise structural accuracy.

systems biology↗

bioRxiv2023

Comparative mutant analyses reveal a novel mechanism of ARF regulation in land plants

A major challenge in plant biology is to understand how the plant hormone auxin regulates diverse transcriptional responses throughout development, in different environments, and in different species. The answer may lie in the specific complement of auxin signaling components in each cell. The balance between activators (class-A AUXIN RESPONSE FACTORS) and repressors (class-B ARFs) is particularly important. It is unclear how this balance is achieved. Through comparative analysis of novel, dominant mutants in maize and the moss Physcomitrium patens, we have discovered a [~]500-million-year-old mechanism of class-B ARF protein level regulation, important in determining cell fate decisions across land plants. Thus, our results add a key piece to the puzzle of how auxin regulates plant development.

plant biology↗

bioRxiv2021

Structural dynamics determine voltage and pH gating in human voltage-gated proton channel

Voltage-gated ion channels are key players of electrical signaling in cells. As a unique subfamily, voltage-gated proton (Hv) channels are standalone voltage sensors without separate ion conductive pores. They are gated by both voltage and transmembrane proton gradient (i.e {Delta}pH), serving as acid extruders in most cells. Amongst their many functions, Hv channels are known to regulate the intracellular pH of human spermatozoa and compensate for the charge and pH imbalances caused by NADPH oxidases in phagocytes. Like the canonical voltage sensors, the Hv channel is a bundle of 4 helices (named S1 through S4), with the S4 segment carrying 3 positively charged Arg residues. Extensive structural and electrophysiological studies on voltage-gated ion channels generally agree on an outwards movement of the S4 segment upon activating voltage, but the real time conformational transitions are still unattainable. With purified human voltage-gated proton (hHv1) channel reconstituted in liposomes, we have examined its conformational dynamics at different voltage and pHs using the single molecule fluorescence resonance energy transfer (smFRET). Here we provided the first glimpse of real time conformational trajectories of the hHv1 voltage sensor and showed that both voltage and pH gradient shift the conformational dynamics of the S4 segment to control channel gating. Our results suggested the biological gating is determined by the conformational distributions of the hHv1 voltage sensor, rather than the conformational transitions between the presumptive resting and activated conformations. We further identified H140 as the key residue sensing extracellular pH and showed that both the intracellular and extracellular pH sensors act on the voltage sensing S4 segment to enrich the resting conformations. Taken together, we proposed a model that explains the mechanisms underlying voltage and pH gating in Hv channels, which may also serve as a general framework to understand the voltage sensing and gating in other voltage-gated ion channels.

biophysics↗

bioRxiv2020

Divergent pallidal pathways underlying distinct Parkinsonian behavioral deficits

The basal ganglia are a group of subcortical nuclei that regulates motor and cognitive functions1,2. Recent identification of neuronal heterogeneity in the basal ganglia suggests that functionally distinct neural circuits defined by their efferent projections exist even within the same nuclei3-5. This distinction may account for a multitude of symptoms associated with basal ganglia disorders such as Parkinsons disease (PD)6,7. However, our incomplete understanding of the basal ganglia functional organization has hindered further investigation of individual circuits that may underlie different behavioral symptoms in disease states. Here we functionally define two distinct classes of parvalbumin-expressing neurons in the mouse external globus pallidus (GPe-PV) embedded within discrete neural pathways and establish their contributions to different Parkinsonian behavioral deficits. We find that GPe-PV neurons projecting to the substantia nigra pars reticulata (SNr) or parafascicular thalamus (PF) undergo different electrophysiological adaptations in response to dopamine depletion. Furthermore, counteracting these adaptations in each population can selectively alleviate movement deficits or behavioral inflexibility in a Parkinsonian mouse model. Our findings provide a novel framework to understand the circuit basis of separate behavioral symptoms in Parkinsonian state which could provide better strategies for the treatment of PD.

neuroscience↗