Biology subjects

Tong, R.

Publications and source records attributed to Tong, R..

12 recordsLinked to original sources

bioRxiv2026

Hierarchical processing and polarization encoding in the cephalopod visual system

Coleoid cephalopods (octopus, cuttlefish and squid, hereafter cephalopods) have evolved a range of complex visually-guided behaviours, from dexterous hunting to skin-pattern based camouflage and communication1. They have also evolved sensitivity to the polarization of light2, an adaptation thought to help detect camouflaged or semitransparent predators and prey in low visibility underwater environments3-10. How visual information is processed by the cephalopod brain to support their behaviours remains unclear. Here, studying the bigfin reef squid Sepioteuthis lessoniana, we performed calcium imaging and electrophysiological recordings from populations of neurons in the large visual center of the cephalopod brain, the optic lobe (OL). We revealed that the retina-recipient superficial OL contains a diversity of functionally distinct cell types, spatially organized into sub-layers, processing spatio-temporal features of light intensity and possessing polarization angle specificity. More complex features, e.g. direction selectivity, are seen in deeper regions of the OL cortex, which also exhibits spontaneous waves of neural activity in the absence of visual input. Neurons in the downstream OL medulla exhibit visual receptive field sizes and spontaneous activity levels which increase with brain depth, consistent with the hierarchical processing of visual information through the medullas tree-like anatomical organization. Medulla neurons exhibit sensitivity to local decreases in the degree of linear polarization (DoLP), which they integrate additively with light intensity information. Underwater imaging in the squids habitat off the coast of Okinawa, Japan, demonstrate that polarization sensitivity confers a robust short-range boost in object-background contrast over a range of objects and environmental conditions. These findings reveal convergent principles of hierarchical visual processing shared between cephalopods and vertebrates, and highlight how cephalopods utilise their distinct adaptation of polarization sensitivity to solve universal visual challenges underwater.

neuroscience↗

bioRxiv2024

Engineering anti-amyloid antibodies with transferrin receptor targeting improves safety and brain biodistribution

Although the first generation of immunotherapies for Alzheimers disease (AD) are now clinically approved, amyloid-related imaging abnormalities (ARIA) remain a major safety problem for this class of drugs. Here, we report an antibody transport vehicle (ATV) targeting the transferrin receptor (TfR) for brain delivery of amyloid beta (A{beta}) antibodies that significantly reduced ARIA-like lesions and improved plaque target engagement in a mouse model of amyloid deposition. Asymmetrical Fc mutations (ATVcisLALA) allowed the molecule to selectively retain effector function only when bound to A{beta} while mitigating TfR-related hematology liabilities. Mice treated with ATVcisLALA:A{beta} exhibited broad brain parenchymal antibody distribution; in contrast, anti-A{beta} IgG was highly enriched at arterial perivascular spaces where vascular A{beta} localizes and likely plays a role in induction of ARIA. Importantly, ATVcisLALA: A{beta} almost completely eliminated ARIA-like lesions and vascular inflammation associated with anti-A{beta} treatment. Taken together, ATVcisLALA has the potential to significantly improve both safety and efficacy of A{beta} immunotherapy through enhanced biodistribution mediated by transport across the blood-brain barrier.

neuroscience↗

bioRxiv2023

The feature landscape of visual cortex

Understanding computations in the visual system requires a characterization of the distinct feature preferences of neurons in different visual cortical areas. However, we know little about how feature preferences of neurons within a given area relate to that areas role within the global organization of visual cortex. To address this, we recorded from thousands of neurons across six visual cortical areas in mouse and leveraged generative AI methods combined with closed-loop neuronal recordings to identify each neurons visual feature preference. First, we discovered that the mouses visual system is globally organized to encode features in a manner invariant to the types of image transformations induced by self-motion. Second, we found differences in the visual feature preferences of each area and that these differences generalized across animals. Finally, we observed that a given areas collection of preferred stimuli ( own-stimuli) drive neurons from the same area more effectively through their dynamic range compared to preferred stimuli from other areas ( other-stimuli). As a result, feature preferences of neurons within an area are organized to maximally encode differences among own-stimuli while remaining insensitive to differences among other-stimuli. These results reveal how visual areas work together to efficiently encode information about the external world.

neuroscience↗

bioRxiv2023

Quantitative Learning of Cellular Features From Single-cell Transcriptomics Data Facilitates Effective Drug Repurposing

In this study, we have devised a computational framework SuperFeat that allows for the training of a machine learning model and evaluate the canonical cellular states/features in pathological tissues that underlie the progression of disease. This framework also enables the identification of potential drugs that target the presumed detrimental cellular features. This framework was constructed on the basis of an artificial neural network with the gene expression profiles serving as input nodes. The training data comprised single-cell RNA-seq datasets that encompassed the specific cell lineage during the developmental progression of cell features. A few models of the canonical cancer-involved cellular states/features were tested by such framework. Finally, we have illustrated the drug repurposing pipeline, utilizing the training parameters derived from the adverse cellular states/features, which has yielded successful validation results both in vitro and in vivo. SuperFeat is accessible at https://github.com/weilin-genomics/rSuperFeat.

cell biology↗

bioRxiv2023

Nanobead-based single-molecule pulldown for single cells

Investigation of cell-to-cell variability holds critical physiological and clinical implications. Thus, numerous new techniques have been developed for studying cell-to-cell variability, and these single-cell techniques can also be used to investigate rare cells. Moreover, for studying protein-protein interactions (PPIs) in single cells, several techniques have been developed based on the principle of the single-molecule pulldown (SiMPull) assay. However, the applicability of these single-cell SiMPull (sc-SiMPull) techniques is limited because of their high technical barrier and special requirements for target cells and molecules. Here, we report a highly innovative nanobead-based approach for sc-SiMPull that is based on our recently developed microbead-based, improved version of SiMPull for cell populations. In our sc-SiMPull method, single cells are captured in microwells and lysed in situ, after which commercially available, pre-surface-functionalized magnetic nanobeads are placed in the microwells to specifically capture proteins of interest together with their binding partners from cell extracts; subsequently, the PPIs are examined under a microscope at the single-molecule level. Relative to previously published methods, nanobead-based sc-SiMPull is considerably faster, easier to use, more reproducible, and more versatile for distinct cell types and protein molecules, and yet provides similar sensitivity and signal-to-background ratio. These crucial features should enable universal application of our method to the study of PPIs in single cells. Statement of SignificanceHeterogeneity between single cells holds critical physiological and clinical implications. Characterization of protein-protein interactions (PPIs) and identification of the interacting partners of a specific protein are critical for elucidating the function and regulation of the protein. However, the applicability of the currently available techniques for studying PPIs in single cells is limited by their high technical barrier and special requirements for cell/proteins types. Our single-cell single-molecule pulldown (sc-SiMPull) assay in this study is not only substantially simpler and faster than existing sc-SiMPull methods, but also considerably more widely applicable--to all cell types and to both soluble and transmembrane proteins. These two crucial features should enable universal application of our method to the study of PPIs in single cells.

bioengineering↗

bioRxiv2023

Targeting Transferrin Receptor to Transport Antisense Oligonucleotides Across the Blood-Brain Barrier

Antisense oligonucleotides (ASO) are promising therapies for neurological disorders, though they are unable to cross the blood-brain barrier (BBB) and must be delivered directly to the central nervous system (CNS). Here, we use a human transferrin receptor (TfR)-binding molecule to transport ASO across the BBB in mice and non-human primates, termed oligonucleotide transport vehicle (OTV). Systemically delivered OTV drives significant, cumulative, and sustained knockdown of the ASO target across multiple CNS regions and all major cell types. Further, systemic OTV delivery enables more uniform ASO biodistribution and knockdown compared to two other clinically relevant ASO delivery routes: a standard, high affinity TfR antibody, or direct ASO delivery to the CSF. Together, our data support systemically delivered OTV as a potential therapeutic platform for neurological disorders. One-Sentence SummarySystemically dosed OTV delivered via TfR1 targeting shows widespread and cumulative target knockdown in the mouse and NHP CNS.

neuroscience↗

bioRxiv2022

Integrated single-cell sequencing analysis reveals peripheral immune landscape across the human lifespan

Systematic understanding of immune dynamics across the entire human lifespan at single-cell resolution is currently lacking. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor (TCR)/B cell receptor (BCR) sequencing (scTCR/BCR-seq) on over 380,000 peripheral blood mononuclear cells collected from 45 healthy participants aged 0 to over 90 years. We revealed that the functions of T cell subsets were most susceptible to senescence among all PBMCs, featured by increased NF-{kappa}B signaling and IFN-{gamma} responses pathways, while reduced telomere maintenance and energy metabolism. We subsequently explored the rewiring of cell-cell interactions among different immune cells across the lifespan and revealed the major alteration of immune checkpoints in T cells within the cellular interaction networks. By combined analysis of scRNA-seq and scTCR-seq, we revealed that 1) GNLY+ CD8 Effector T cells exhibited a high clonal expansion with distinct functional signatures in children and the elderly; 2) Naive CD4+ T and naive CD8+ T cells displayed different aging patterns in both transcriptomes and immune repertoires; and 3) CD8+ MAIT cells showed a higher cell abundance and clonal diversity in adolescents. Furthermore, we identified a unique cytotoxic B cell subset enriched in children by scRNA-seq and scBCR-seq analysis and experimental validations. In summary, our work provided valuable insights and rich resources for understanding the development and aging of the human immune system across the lifespan.

immunology↗

bioRxiv2021

Homeostatic regulation of presynaptic NMDA receptor subunit composition modulates action potential driven Ca2+ influx into boutons setting the bandwidth for information transfer

N-Methyl-D-aspartate receptors (NMDARs) play a pivotal role in both short and long-term plasticity. While the functional role of postsynaptic NMDARs is well established, a framework of presynaptic NMDAR (preNMDAR) function is missing. Differences in subunit composition of preNMDARs are documented at central synapses, raising the possibility that subtype composition plays a role in transmission performance. Here, we use electrophysiological recordings at Schaffer collateral - CA1 synapses and Ca2+ imaging coupled to focal glutamate uncaging at boutons of CA3 pyramidal neurones to reveal two populations of presynaptic NMDARs that contain either the GluN2A or GluN2B subunit. Activation of the GluN2B population decreases action potential (AP)-evoked Ca2+ influx via modulation of small conductance Ca2+-activated K+ channels (SK-channels) while activation of the GluN2A containing population does the opposite. Moreover, the level of functional expression of each receptor population can be homeostatically modified, bidirectionally affecting short-term facilitation during burst firing, thus providing a capacity for a fine adjustment of the presynaptic integration time window and therefore the bandwidth of information transfer.

neuroscience↗

bioRxiv2020

High resolution visual information via a gap junction-mediated spike order code

Gap junctions promote correlated spiking between coupled neurons. Recording from pairs of coupled retinal ganglion cells, we find that differences in firing rate between coupled neurons dictates which cell leads correlated spike-pairs, and that the precise temporal order of spike activity between pairs of cells changes depending on the spatial position of a visual stimulus. We thus demonstrate a spike order spatial code for encoding sensory information.

neuroscience↗

bioRxiv2020

Heterosynaptic cross-talk of pre- and postsynaptic strengths along segments of dendrites

Dendrites are crucial for integrating incoming synaptic information. Individual dendritic branches are thought to constitute a signal processing unit, yet how neighbouring synapses shape the boundaries of functional dendritic units are not well understood. Here we addressed the cellular basis underlying the organization of the strengths of neighbouring Schaffer collateral-CA1 synapses by optical quantal analysis and spine size measurements. Inducing potentiation at clusters of spines produced NMDA receptor-dependent heterosynaptic plasticity. The direction of postsynaptic strength change showed distance-dependency to the stimulated synapses where proximal synapses predominantly depressed whereas distal synapses potentiated; potentiation and depression were regulated by CaMKII and calcineurin, respectively. By contrast, heterosynaptic presynaptic plasticity was confined to weakening of presynaptic strength of nearby synapses, which required CaMKII and the retrograde messenger nitric oxide. Our findings highlight the parallel engagement of multiple signalling pathways, each with characteristic spatial dynamics in shaping the local pattern of synaptic strengths.

neuroscience↗

bioRxiv2020

Molecularly Targeted Magnetic Resonance Imaging and Spectroscopy

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) have tremendous utility in many fields, such as clinical diagnosis, medical research and brain science. MRI provides high resolution anatomic images of tissues/organs, and MRS provides functional molecular information related to specific regions of tissues/organs. However, it is often difficult for conventional MRI/MRS to selectively image/probe a specific metabolite molecule other than water and fat. This greatly limits study of the molecular mechanisms underlying metabolism and disease. Herein, we report a novel method for obtaining an exact molecularly targeted MRI and MRS. This method uses the nuclear spin singlet state to select the signals from a specific molecule. Several endogenous molecules in living organism such as N-acetylaspartate and dopamine have been exemplarily imaged and probed as the targeted molecules in the MRI and MRS experiments, demonstrating the unique molecular selectivity of the developed method. Endogenous-molecule-targeted MRI and MRS can be achieved by using the new pulse sequences O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/026252v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@483ca2org.highwire.dtl.DTLVardef@84d4c0org.highwire.dtl.DTLVardef@abca24org.highwire.dtl.DTLVardef@6423ae_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2017

Glutamate release is inhibitory and unnecessary for the long-term potentiation of presynaptic function

Long-term potentiation (LTP) and long-term depression (LTD) of transmitter release probability (Pr) are thought to be triggered by the activation of glutamate receptors. Here, we demonstrate that glutamate release at CA3-CA1 synapses is in fact inhibitory and unnecessary for increases in Pr. Instead, at active presynaptic terminals, postsynaptic depolarization alone can increase Pr by promoting the release of nitric oxide from neuronal dendrites in a manner dependent on L-type voltage-gated Ca2+ channels. The release of glutamate, in contrast, decreases Pr by activating presynaptic NMDA receptors (NMDAR). Thus, net changes in Pr are determined by the combined effect of both LTP-promoting and LTD-promoting processes, that is, by the amount of glutamate release and postsynaptic depolarization that accompany presynaptic activity, respectively. Neither of these processes directly depends on the activation of postsynaptic NMDARs. We further show that presynaptic changes can be captured by a simple learning rule, in which the role of presynaptic plasticity is to ensure that the ability for a presynaptic terminal to release glutamate is matched with its ability to predict postsynaptic spiking.

neuroscience↗