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Biology subjects

Lin, J. Y.

Publications and source records attributed to Lin, J. Y..

3 recordsLinked to original sources

Natural Selection in the Wake of Catastrophe

Living organisms, from bacteria to humans, are more likely to survive if their traits enhance fitness. In populations well adapted to their environmental niches, natural selection proceeds via rarely beneficial mutations. But when a catastrophe wipes out niche diversity, sudden adaptation often follows. Here, we present a data-validated theory of natural selection in the wake of catastrophe and unveil a simple law that emerges during recovery: the mean fitness relaxes inversely with time, with a prefactor proportional to the number of traits coupled to the post-catastrophe environment. We put our approach to test using experimental fitness landscapes measured following antibiotic administration to E. coli. The resulting mean trait adaptation is not described by gradient ascent on a fitness landscape, instead it follows an algorithm known as Levenberg-Marquardt optimization. Near fitness peaks, evolutionary trajectories are biased against greediness -- from an optimization perspective, post-catastrophic selection is optimistic.

evolutionary biology↗

Dual-color optical activation and suppression of neurons with high temporal precision

A well-known phenomenon in the optogenetic toolbox is that all light-gated ion channels, including red-shifted channelrhodopsins (ChRs), are activated by blue light, whereas blue-shifted ChRs are minimally responsive to longer wave-lengths. Here, we took advantage of this feature to create a system which allows high-frequency activation of neurons with pulses of red light, while permitting the suppression of action potentials with millisecond precision by blue light. We achieved this by pairing an ultrafast red-shifted ChR with a blue light-sensitive anion channel of appropriately matching kinetics. This required screening several anion-selective ChRs, followed by a model-based mutagenesis strategy to optimize their kinetics and light spectra. Slice electrophysiology in the hippocampus as well as behavioral inspection of vibrissa movement demonstrate a minimal excitation from blue light. Of significant potential value, in contrast to existing tools, the system we introduce here allows high frequency optogenetic excitation of neurons with red light, while blue light suppression of action potentials is confined within the duration of the light pulse.

neuroscience↗

Chemogenetic ligands for translational neurotheranostics

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

neuroscience↗