Biology subjects

Bao, Z.

Publications and source records attributed to Bao, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2022

Genetically-encoded photosensitizers enable light-controlled polymerization on living neuronal membranes

The ability to record, stimulate, and modify brains of living animals would unlock numerous research opportunities and create potential clinical interventions, but it is difficult to interface with a living neural network without damaging it. We previously reported a novel approach to building neural interfaces, namely: genetically programming cells to build artificial structures to modify the electrical properties of neurons in situ, which opens up the possibility of modifying neural circuits in living animals without surgery. However, the spatiotemporal resolution, efficiency, and biocompatibility of this approach were still limited and lacked selectivity on cell membrane. Here, we demonstrate an approach using genetically-targeted photosensitizers to instruct living cells to synthesize functional materials directly on the plasma membrane under the control of light. Polymers synthesized by this approach were selectively deposited on the membrane of targeted live neurons. This platform can be readily extended to incorporate a broad range of light-controlled reactions onto specific cells, which may enable researchers to grow seamless, dynamic interfaces directly in living animals.

bioengineering↗

bioRxiv2022

Soft and stretchable organic bioelectronics for continuous intra-operative neurophysiological monitoring during microsurgery

Continuous intra-operative neurophysiological monitoring (CINM) that provides precise mapping of neural anatomy through the entire microsurgery process is essential to preserve the structural and functional integrity of the nerve. However, bulky and rigid electrodes used currently in clinics are usually unable to reliably maintain continuous and stable contacts with the vulnerable and complex nerve networks, thus often resulting in detrimental post-operative complications, such as hemiplegia and sensory disturbances. Here, we describe a biomechanically compatible, suture-free, and individually reconfigurable CINM based on soft and stretchable organic electronic materials. Due to both low impedance and modulus of our conducting polymer electrodes, we achieved for the first time continuous recording of near-field action potential with high signal-to-noise ratio and minimal invasiveness during microsurgeries. Utilizing this unprecedented CINM modality, in conjunction with localized neurostimulation, we further demonstrated our approach in enabling optimal post-operative prognosis in preclinical animal models by preserving normal neural functions after a variety of tumor resection surgeries.

bioengineering↗

bioRxiv2022

A compound PCP scheme underlies sequential rosettes-based cell intercalation

Sequential rosettes are a type of collective cell behavior recently discovered in the C. elegans embryo to mediate directional cell migration through sequential formation and resolution of multicellular rosettes involving the migrating cell and its neighboring cells along the way. Here we show that a Planar Cell Polarity (PCP)-related polarity scheme regulates sequential rosettes, which is distinct from the known mode of how PCP regulates multicellular rosettes in the process of convergent extension. Specifically, non-muscle myosin (NMY) localization and edge contraction are perpendicular to that of Van Gogh as opposed to colocalizing with Van Gogh. Further analyses suggest a two-component polarity scheme: one being the canonical PCP pathway with MIG-1/Frizzled and VANG-1/Van Gogh localized to the vertical edges, the other being MIG-1/Frizzled and NMY-2 localized to the midline/contracting edges. Both MIG-1/Frizzled and VANG-1/Van Gogh are required for NMY-2 localization and contraction of the midline edges, but in redundancy with LAT-1/Latrophilin, an adhesion GPCR which has not been shown to regulate multicellular rosettes. Our results establish a distinct mode of PCP-mediated cell intercalation and shed light on the versatile nature of PCP pathway.

developmental biology↗

bioRxiv2022

The microtubule-associated protein SlMAP70 interacts with SlIQD21 and regulates fruit shape formation in tomato

The shape of tomato fruits is closely correlated to microtubule organization and the activity of microtubule associated proteins (MAP), but insights into the mechanism from a cell biology perspective are still largely elusive. Analysis of tissue expression profiles of different microtubule regulators revealed that functionally distinct classes of MAPs are highly expressed during fruit development. Among these, several members of the plant-specific MAP70 family are preferably expressed at the initiation stage of fruit development. Transgenic tomato lines overexpressing SlMAP70 produced elongated fruits that show reduced cell circularity and microtubule anisotropy, while SlMAP70 loss-of-function mutant showed an opposite effect with flatter fruits. Microtubule anisotropy of fruit endodermis cells exhibited dramatic rearrangement during tomato fruit development, and SlMAP70-1 is likely implicated in cortical microtubule organization and fruit elongation throughout this stage by interacting with SUN10/SlIQD21a. The expression of SlMAP70 (or co-expression of SlMAP70 and SUN10/SlIQD21a) induces microtubule stabilization and prevents its dynamic rearrangement, both activities are essential for fruit shape establishment after anthesis. Together, our results identify SlMAP70 as a novel regulator of fruit elongation, and demonstrate that manipulating microtubule stability and organization at the early fruit developmental stage has a strong impact on fruit shape.

plant biology↗

bioRxiv2022

Stretchable mesh microelectronics for the biointegration and stimulation of neural organoids

Advances in tridimensional (3D) culture approaches have led to the generation of organoids that recapitulate cellular and physiological features of domains of the human nervous system. Although microelectrodes have been developed for long-term electrophysiological interfaces with neural tissue, studies of long-term interfaces between microelectrodes and free-floating organoids remain limited. In this study, we report a stretchable, soft mesh electrode system that establishes an intimate in vitro electrical interface with human neurons in 3D organoids. Our mesh is constructed with poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) based electrically conductive hydrogel electrode arrays and an elastomeric poly(styrene-ethylene-butadiene-styrene) (SEBS) as the substrate and encapsulation materials. This mesh electrode can maintain stable electrochemical impedance in buffer solution under 50% compressive and 50% tensile strain. We have successfully cultured pluripotent stem cell-derived human cortical organoids (hCO) on this polymeric mesh for more than 3 months and demonstrated that organoids readily integrate with the mesh. Using simultaneous stimulation and calcium imaging, we show that electrical stimulation through the mesh can elicit intensity-dependent calcium signals comparable to stimulation from a bipolar stereotrode. This platform may serve as a tool for monitoring and modulating the electrical activity of in vitro models of neuropsychiatric diseases.

neuroscience↗

bioRxiv2022

Widespread employment of conserved C. elegans homeobox genes in neuronal identity specification

Homeobox genes are prominent regulators of neuronal identity, but the extent to which their function has been probed in animal nervous systems remains limited. In the nematode Caenorhabditis elegans, each individual neuron class is defined by the expression of unique combinations of homeobox genes, prompting the question of whether each neuron class indeed requires a homeobox gene for its proper identity specification. We present here progress in addressing this question by extending previous mutant analysis of homeobox gene family members and describing multiple examples of homeobox gene function in different parts of the C. elegans nervous system. To probe homeobox function, we make use of a number of reporter gene tools, including a novel multicolor reporter transgene, NeuroPAL, which permits simultaneous monitoring of the execution of multiple differentiation programs throughout the entire nervous system. Using these tools, we add to the previous characterization of homeobox gene function by identifying neuronal differentiation defects for 12 homeobox genes in 20 distinct neuron classes that are mostly unrelated by location, function and lineage history. 10 of these 20 neuron classes had no homeobox gene function ascribed to them before, while in the other 10 neuron classes, we extend the combinatorial code of transcription factors required for specifying terminal differentiation programs. Furthermore, we demonstrate that in a particular lineage, homeotic identity transformations occur upon loss of a homeobox gene and we show that these transformations are the result of changes in homeobox codes. Combining the present with past analysis, 111 of the 118 neuron classes of C. elegans are now known to require a homeobox gene for proper execution of terminal differentiation programs. Such broad deployment indicates that homeobox function in neuronal identity specification may be an ancestral feature of animal nervous systems.

neuroscience↗

bioRxiv2022

Hiplot: a comprehensive and easy-to-use web service boosting publication-ready biomedical data visualization

Modern web techniques provide an unprecedented opportunity for leveraging complex biomedical data generating in clinical, omics, and mechanism experiments. Currently, the functions for carrying out publication-ready biomedical data visualization represent primary technical hurdles in the state-of-art omics-based web services, whereas the demand for visualization-based interactive data mining is ever-growing. Here, we propose an easy-to-use web service, Hiplot (https://hiplot.com.cn), equipping with comprehensive and interactive biomedical data visualization functions (230+) including basic statistics, multi-omics, regression, clustering, dimensional reduction, meta-analysis, survival analysis, risk modeling, etc. We used the demo and real datasets to demonstrate the usage workflow and the core functions of Hiplot. It permits users to conveniently and interactively complete a few specialized visualization tasks that previously could only be done by senior bioinformatics or biostatistics researchers. A modern web client with efficient user interfaces and interaction methods has been implemented based on the custom components library and the extensible plugin system. The versatile output can also be produced in different environments via using the cross-platform portable command-line interface (CLI) program, Hctl. A switchable view between the editable data table and the file uploader/path selection could facilitate data importing, previewing, and exporting, while the plumber-based response strategy significantly reduced the time costs for generating basic scientific graphics. Diversified layouts, themes/styles, and color palettes in this website allow users to create high-quality and publication-ready graphics. Researchers devoted to both life and data science may benefit from the emerging web service.

bioinformatics↗

bioRxiv2022

Cross-modality Synthesis of EM Time Series and Live Fluorescence Imaging

Analyses across imaging modalities allow the integration of complementary spatiotemporal information about brain development, structure and function. However, systematic atlasing across modalities is limited by challenges to effective image alignment. We combine highly spatially resolved electron microscopy (EM) and highly temporally resolved time-lapse fluorescence microscopy (FM) to examine the emergence of a complex nervous system in C. elegans embryogenesis. We generate an EM pseudo time series at four classic developmental stages and create a landmark-based co-optimization algorithm for cross-modality image alignment, which handles developmental heterochrony among datasets to achieve accurate single-cell level alignment. Synthesis based on the EM series and time-lapse FM series carrying different cell-specific markers reveals critical dynamic behaviors across scales of identifiable individual cells in the emergence of the primary neuropil, the nerve ring, as well as a major sensory organ, the amphid. Our study paves the way for systematic cross-modality analysis in C. elegans and demonstrates a powerful approach that may be applied broadly. HighlightsO_LIAn EM time series to examine the emergence of an entire nervous system C_LIO_LIA landmark-based co-optimization algorithm for cross modality image alignment in the presence of developmental heterochrony C_LIO_LIIntegration of EM and fluorescence series reveals cell behaviors at high spatial and temporal resolution C_LIO_LISystematic single-cell annotation of EM data enables efficient navigation and targeted re-imaging C_LI

developmental biology↗

bioRxiv2022

Topological supramolecular network enabled highly conductive and stretchable organic bioelectronics

Intrinsically stretchable bioelectronic devices based on soft and conducting organic materials have been regarded as the ideal interface for seamless and biocompatible integration with the human body. However, the grand challenge remains for the conducting polymer to possess both high mechanical ductility and good electrical conduction at cellular level feature sizes. This longstanding material limitation in organic bioelectronics has impeded the full exploitation of its unique benefits. Here, we introduce a new molecular engineering strategy based on rationally designed topological supramolecular networks, which allows effective decoupling of competing effects from multiple molecular building blocks to meet complex requirements. We achieve two orders of magnitude improvement in the conductivity under 100% strain in physiological environment, along with the capability for direct photopatterning down to 2 m. These unprecedented capabilities allow us to realize previously inaccessible bioelectronic applications including high-resolution monitoring of soft and malleable creatures, e.g., octopus, and localized neuromodulation down to single nucleus precision for controlling organ-specific activities through delicate tissues, e.g., brainstem.

bioengineering↗

bioRxiv2022

Wireless closed-loop smart bandage for chronic wound management and accelerated tissue regeneration

Chronic non-healing wounds represent a major source of morbidity for patients and a significant economic burden. Current wound care treatments are generally passive and are unable to adapt to changes in the wound environment in real time. By integrating multimodal sensors and adding stimulators in a bandage, real-time physiological monitoring is possible and provides an opportunity for active intervention into the complex wound environment. Here, we develop a battery-free flexible bioelectronic system consisting of wirelessly powered, closed-loop sensing and stimulation circuits with tissue-interfacing tough conducting hydrogel electrodes for robust signal transduction, on-demand adhesion, and detachment. Using multiple pre-clinical models, we demonstrate the capability of our wound care system to continuously monitor skin impedance and temperature, to trigger directional electrical stimulation. The accelerated wound closure was confirmed to be due to the activation of pro-regenerative genes linked to accelerated wound closure, increased neovascularization, and enhanced dermal recovery.

bioengineering↗

bioRxiv2021

A single-cell transcriptome atlas of human early embryogenesis

The early window of human embryogenesis is largely a black box for developmental biologists. Here we probed the cellular diversity of 4- to 6-week human embryos when essentially all organs are just laid out. Based on over 180,000 single-cell transcriptomes, we generated a comprehensive atlas of 313 cell types in 18 developmental systems, which were annotated with a collection of ontology and markers from 157 publications. Together with spatial transcriptome on embryonic sections, we characterized the molecule and spatial architecture of previously unappreciated cell types. Combined with data from other vertebrates, the rich information shed light on spatial patterning of axes, systemic temporal regulation of developmental progression and potential human-specific regulation. Our study provides a compendium of early progenitor cells of human organs, which can serve as the root of lineage analysis in organogenesis.

developmental biology↗

bioRxiv2021

A flexible electronic strain sensor for the real-time monitoring of tumor progression

Healthcare professionals and scientists utilize tumor shrinkage as a key metric to establish the efficacy of cancer treatments. However, current measurement tools such as CT scanners and calipers only provide brief snapshots of the dynamic geometric changes occurring in vivo, and they are unable to characterize the continuous micrometer-scale volumetric transformations transpiring at minute timescales. Here we present a stretchable electronic strain sensor, with a 10-micron scale resolution, capable of continuously monitoring tumor volume progression in real-time. In mouse models with subcutaneously implanted lung cancer or B-cell lymphoma tumors our sensors discerned a significant change in the tumor volumes of treated mice within 5 hours after small molecule therapy or immunotherapy initiation. Histology, caliper measurements, and luminescence imaging over a one-week treatment period validated the data from the continuous sensor. We anticipate that real-time tumor progression datasets could help expedite and automate the process of screening cancer therapies in vivo.

bioengineering↗

bioRxiv2021

A landscape model for cell fate decisions during mesoendoderm differentiation in C. elegans based on Wnt dynamics

Geometric models allow us to quantify topography of the Waddington landscape and gain quantitative insights of gene interaction in cell fate differentiation. Often mutant phenotypes show partial penetrance and there is a dearth of quantitative models that can exploit this data and make predictions about new allelic combinations with no additional parameters. C. elegans with its invariant cell lineages has been a key model system for discovering the genes controlling development. Here we focus on the differentiation of the endoderm founder cell named E from its mother, the EMS cell. Mutants that convert E to its sister MS fate have figured prominently in deciphering the Wnt pathway in worm. We construct a bi-valued Waddington landscape model that predicts the effect on POP-1/TCF and SYS-1/beta-catenin levels based on the penetrance of mutant alleles and RNAi, and relates the levels to fate choice decisions. A subset of the available data is used to fit the model and remaining data is then correctly predicted. Simple kinetic arguments show that contrary to current belief the ratio of these two proteins alone is not indicative of fate outcomes. Furthermore, double mutants within a background reduction of POP-1 levels are predicted with no adjustable parameters and their relative penetrance can differ from the same mutants with the wild-type POP-1 level, which calls for further experimental investigations. Our model refines the content of existing gene networks and invites extensions to other manifestations of the Wnt pathway in worm.

developmental biology↗

bioRxiv2021

Design considerations of a wearable electronic-skin for mental health and wellness: balancing biosignals and human factors

Chronic stress has been associated with a variety of pathophysiological risks including developing mental illness. Conversely, appropriate stress management, can be used to foster mental wellness proactively. Yet, there is no existing method that accurately and objectively monitors stress. With recent advances in electronic-skin (e-skin) and wearable technologies, it is possible to design devices that continuously measure physiological parameters linked to chronic stress and other mental health and wellness conditions. However, the design approach should be different from conventional wearables due to considerations like signal-to-noise ratio and the risk of stigmatization. Here, we present a multi-part study that combines user-centered design with engineering-centered data collection to inform future design efforts. To assess human factors, we conducted an n=24 participant design probe study that examined perceptions of an e-skin for mental health and wellness as well as preferred wear locations. We complement this with an n=10 and n=16 participant data collection study to measure physiological signals at several potential wear locations. By balancing human factors and biosignals, we conclude that the upper arm and forearm are optimal wear locations.

bioengineering↗

bioRxiv2020

Species-resolved sequencing of low-biomass microbiomes by 2bRAD-M

Microbiome samples with low microbial biomass or severe DNA degradation remain challenging for amplicon-based (e.g., 16S/18S-rRNA) or whole-metagenome sequencing (WMS) approaches. Here, we introduce 2bRAD-M, a highly reduced and cost-effective metagenome-sequencing strategy which only sequences ~1% of metagenome and can simultaneously produce species-level bacterial, archaeal, and fungal profiles for low-biomass and highly degraded samples. For mock communities, 2bRAD-M can accurately generate species-level taxonomic profiles for otherwise hard-to-sequence samples with (i) low biomass of merely 1 pg of total DNA, (ii) high host DNA contamination (99%), and (iii) severely fragmented DNA (50-bp) from degraded samples. Tests of 2bRAD-M on stool, skin and environment-surface samples deliver successful reconstruction of comprehensive, high-resolution microbial profiles with agreement across 16S-rRNA, WMS and existing literature. In addition, it enables microbial profiling in formalin-fixed paraffin-embedded (FFPE) cervical tissue samples which were recalcitrant to conventional approaches due to the low amount and heavy degradation of microbial DNA, and discriminated healthy tissue, pre-invasive cancer and invasive cancer via species-level microbial profiles with 91.1% accuracy. Therefore, 2bRAD-M greatly expands the reach of microbiome sequencing.

microbiology↗

bioRxiv2020

A Genetic Screen for Temperature-sensitive Morphogenesis-defective Caenorhabditis elegans Mutants

Morphogenesis involves coordinated cell migrations and cell shape changes that generate tissues and organs, and organize the body plan. Cell adhesion and the cytoskeleton are important for executing morphogenesis, but their regulation remains poorly understood. As genes required for embryonic morphogenesis may have earlier roles in development, temperature-sensitive embryonic-lethal mutations are useful tools for investigating this process. From a collection of [~]200 such Caenorhabditis elegans mutants, we have identified 17 that have highly penetrant embryonic morphogenesis defects after upshifts from the permissive to the restrictive temperature, just prior to the cell shape changes that mediate elongation of the ovoid embryo into a vermiform larva. Using whole genome sequencing, we identified the causal mutations in seven affected genes. These include three genes that have roles in producing the extracellular matrix, which is known to affect the morphogenesis of epithelial tissues in multicellular organisms. The rib-1 and rib-2 genes encode glycosyltransferases, and the emb-9 gene encodes a collagen subunit. We also used live imaging to characterize epidermal cell shape dynamics in one mutant, or1219ts, and observed cell elongation defects during dorsal intercalation and ventral enclosure that may be responsible for the body elongation defects. These results indicate that our screen has identified factors that influence morphogenesis and provides a platform for advancing our understanding of this fundamental biological process. SUMMARYWe performed a systematic, forward genetics screen for temperature-sensitive embryonic-lethal (TS-EL) Caenorhabditis elegans mutants that are specifically defective in embryonic morphogenesis. By taking advantage of temperature-upshifts, we identified several essential genes influencing morphogenesis. We also demonstrated that one mutant has defects in epidermal cell shape changes that likely account for the failure in morphogenesis. The TS-EL mutants we identified will be useful tools for advancing our understanding of the gene networks controlling cell shape changes and movements during morphogenesis.

genetics↗

bioRxiv2020

Small RNAs couple embryonic developmental programs to gut microbes

Maternal exposure to microbes and other environmental factors is known to induce adaptive changes in the progeny, but little is understood about how development of the progeny is changed. We show that Caenorhabditis elegans undergoes additional embryonic cell divisions in response to maternal gut microbes such as one producing the biopolymer {gamma}-poly-DL-glutamic acid. The divisions coincide with anatomical changes including left-right asymmetric cell alignment, doubling the association between intestinal cells and primordial germ cells, and improved fecundity. The developmental changes are regulated by soma-to-germline transmission of endogenous RNAi and the miR-35 microRNA family, which targets the LIN-23/CDC-25 pathway. Our findings challenge the widespread assumption that C. elegans has an invariant cell lineage that consists of 959 somatic cells and provide insights into how organisms optimize embryogenesis to adapt to environmental changes through epigenetic controls.

microbiology↗

bioRxiv2020

Extensive MET alterations confer clinical response to MET inhibitors in gliomas

Activating alterations of the MET gene are well-characterized oncogenic drivers, and MET inhibitors could successfully treat several tumor types with MET alterations, including gliomas with PTPRZ1-MET fusion. However, the full diversity and prevalence of MET alterations in gliomas are still lacking to accurately identify a subset of patients likely to benefit from MET inhibitor treatment. Here, we interrogated genomic profiles of 1,351 gliomas, and further identify 60 cases harboring MET alterations, including MET fusions and various MET exon skipping events. MET RNA alterations, but not MET amplification, are highly enriched in the secondary glioblastomas (sGBM) with significantly worse prognosis. Further molecular analysis has shown that MET RNA alterations acting an additive effects of MET overexpression are induced in the course of glioma evolution. In vitro and clinical studies indicate cells and patients harboring MET alterations have better response to MET inhibitors. Collectively, these data suggest that a subgroup of gliomas harboring MET alterations likely to have benefit from MET-targeted therapy.

neuroscience↗