Biology subjects

Zhu, E.

Publications and source records attributed to Zhu, E..

5 recordsLinked to original sources

bioRxiv2023

Top-down attention shifts behavioral and neural event boundaries in narratives with overlapping event scripts

Understanding and remembering the complex experiences of everyday life relies critically on prior schematic knowledge about how events in our world unfold over time. How does the brain construct event representations from a library of schematic scripts, and how does activating a specific script impact the way that events are segmented in time? We developed a novel set of 16 audio narratives, each of which combines one of four location-relevant event scripts (restaurant, airport, grocery store, lecture hall) with one of four socially-relevant event scripts (breakup, proposal, business deal, meet cute), and presented them to participants in an fMRI study and a separate online study. Responses in angular gyrus, parahippocampal gyrus, and subregions of medial prefrontal cortex (mPFC) were driven by both location and social script information, showing that these regions can track schematic sequences from multiple domains. For some stories participants were primed to attend to one of the two scripts, by training them to listen for and remember specific script-relevant episodic details. Activating a location-related event script shifted the timing of subjective event boundaries to align with script-relevant changes in the narratives, and this behavioral shift was mirrored in the timing of neural responses, with mPFC event boundaries (identified using a Hidden Markov Model) aligning to location-relevant rather than socially-relevant boundaries when participants were location primed. Our findings demonstrate that neural event dynamics are actively modulated by top-down goals, and provide new insight into how narrative event representations are constructed through the activation of temporally-structured prior knowledge.

neuroscience↗

bioRxiv2023

Harnessing the power of whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation

Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important in the era of personalized medicine. Liver-directed gene therapies present a unique challenge due to the complexity of the human liver. In this work, we describe the application of whole human liver explants in an ex situ normothermic perfusion system to evaluate a set of fourteen natural and bioengineered adeno-associated viral (AAV) vectors directly in human liver, in the presence and absence of neutralizing human sera. Under non-neutralizing conditions, the recently developed AAV variants, AAV-SYD12 and AAV-LK03, emerged as the most functional variants in terms of cellular uptake and transgene expression. However, when assessed in the presence of human plasma containing anti-AAV neutralizing antibodies (NAbs), vectors of human origin, specifically those derived from AAV2/AAV3b, were extensively neutralized, whereas AAV8-derived variants performed efficiently. This study establishes the use of normothermic liver perfusion as an invaluable preclinical model for evaluating liver-targeted gene therapies and providing guidance for making essential decisions that promote the most effective translational programs.

molecular biology↗

bioRxiv2023

High-Resolution Characterization of Human Brain Cortex with High-Fidelity Spatial Transcriptomic Slides (HiFi-Slides)

Spatial transcriptomic tools and platforms help researchers to inspect tissues and cells with fine details of how they differentiate in expressions and how they orient themselves. With the higher resolution we get and higher throughput of expression targets, spatial analysis can truly become the core player for cell clustering, migration study, and, eventually, the novel model for pathological study. We present the demonstration of HiFi-slide, a whole transcriptomic sequencing technique that recycles used sequenced-by-synthesis flow cell surfaces to a high-resolution spatial mapping tool that can be directly applied to tissue cell gradient analysis, gene expression analysis, cell proximity analysis, and other cellular-level spatial studies.

bioengineering↗

bioRxiv2022

Assessment of pre-clinical liver models based on their ability to predict the liver-tropism of AAV vectors

The liver is a prime target for in vivo gene therapies using recombinant adeno-associated viral vectors (rAAV). Multiple clinical trials have been undertaken for this target in the past 15 years, however we are still to see market approval of the first liver-targeted AAV-based gene therapy. Inefficient expression of the therapeutic transgene, vector-induced liver toxicity and capsid, and/or transgene-mediated immune responses reported at high vector doses are the main challenges to date. One of the contributing factors to the insufficient clinical outcomes, despite highly encouraging preclinical data, is the lack of robust, biologically- and clinically-predictive preclinical models. To this end, this study reports findings of a functional evaluation of six AAV vectors in twelve preclinical models of the human liver, with the aim to uncover which model is the most relevant for the selection of AAV capsid variant for safe and efficient transgene delivery to primary human hepatocytes. The results, generated by studies in models ranging from immortalized cells, iPSC-derived and primary hepatocytes, and primary human hepatic organoids to in vivo models, increased our understanding of the strengths and weaknesses of each system. This should allow the development of novel gene therapies targeting the human liver.

bioengineering↗

bioRxiv2022

Sensory regulation of absence seizures in a mouse model of Gnb1 encephalopathy

Absence seizures, a type of non-convulsive epilepsy manifested by spike-wave discharges (SWD) in the electroencephalogram (EEG), display synchronous reciprocal excitation between the neocortex and thalamus. Recent studies have revealed that inhibitory neurons in the reticular thalamic (RT) nucleus and excitatory thalamocortical (TC) neurons are two key subcortical players in generating SWD. However, the signals that drive SWD-related thalamic activity remain elusive. Here, we show that SWD predominately occurs during wakefulness in several mouse models of absence epilepsy. In more focused studies of Gnb1 mutant mice, we found that sensory input regulates SWD. Using in vivo recording, we demonstrate that TC cells are activated prior to the onset of SWD and then inhibited during SWD. On the contrary, RT cells are slightly inhibited prior to SWD, but are strongly activated during SWD. Furthermore, chemogenetic activation of TC cells leads to the enhancement of SWD in Gnb1 mice. Together, our results indicate that sensory input in the periphery can regulate SWD by activating the thalamocortical pathway.

neuroscience↗