Biology subjects

Jian, Y.

Publications and source records attributed to Jian, Y..

13 recordsLinked to original sources

bioRxiv2026

Developmental Elimination of Electrical Synapses by UNC-51/UNC-76-Mediated Vesicular Transport

Neural circuit maturation requires precise elimination of transient synaptic connections, but how electrical synapses are eliminated remains unknown. Using C. elegans PLM mechanosensory neurons, we found that gap junctions form transiently during early development and are subsequently eliminated as the circuit matures. These transient electrical synapses drive high-frequency calcium oscillations, and optogenetic ablation of early gap junctions abolishes calcium dynamics and disrupts chemical synapse formation, demonstrating their critical developmental function. Through forward genetic screening, we identified the conserved kinase UNC-51/ULK as essential for elimination. UNC-51 phosphorylates the kinesin adaptor UNC-76/FEZ to initiate RAB-10-dependent retrograde trafficking, progressively depleting innexin proteins from the synaptic site. Disrupting this pathway prevents elimination, causing persistent electrical synapses and neuronal hyperactivity. These findings establish a conserved framework for developmental elimination of functionally essential transient electrical connectivity.

cell biology↗

bioRxiv2026

Mitochondria Organize Gap Junctions to Enable Neural Circuit Scaling

Neural circuits must maintain function during dramatic growth-driven expansion. While chemical synapses can be independently reorganized in pre- and postsynaptic neurons, gap junctions physically couple partner cells, requiring coordinated spatial redistribution--a process whose mechanisms remain unknown. Using the C. elegans mechanosensory circuit, we show that gap junctions undergo stereotyped developmental reorganization, transitioning from clustered to dispersed configurations as partner neurites elongate. Forward genetic screening identified RIC-7, a mitochondrial adaptor protein, as essential for this redistribution. Loss of RIC-7 prevents gap junction dispersal, trapping partner neurites at clustered sites and severely impairing electrical transmission. Mechanistically, RIC-7 directs mitochondrial positioning to gap junctions, where mitochondria recruit the microtubule-organizing component PTRN-1 to locally enhance microtubule dynamics. Disrupting mitochondrial transport (miro-1;mtx-2 mutants) or PTRN-1 function phenocopies ric-7 defects, while metabolic dysfunction does not, establishing a non-metabolic role for mitochondria in organizing synaptic architecture. Remarkably, RIC-7 expression in one neuron alone suffices to restore gap junction and partner neurite distribution across both coupled cells. Structural modeling suggests mechanical adhesion between docked hemichannels enables this coordinated reorganization. These findings establish mitochondria as mobile organizers of synaptic spatial architecture, demonstrate that proper junction distribution is essential for electrical transmission efficacy, and reveal how cell-autonomous mechanisms can achieve bilateral structural coordination during circuit growth.

neuroscience↗

bioRxiv2024

Substrate tunnel regulates substrate specificity switching in hyaluronan synthase

Hyaluronic acid (HA), a ubiquitous linear polysaccharide in the extracellular matrix of vertebrates and the capsule of certain pathogenic bacteria, is characterized by its unique structure of alternating {beta}-1,3-N-acetylglucosamine and {beta}-1,4-glucuronic acid units. HA is synthesized by Class I hyaluronan synthase (HAS) in the majority of organisms, but the molecular mechanisms determining the alternating sequence of HA remain unclear. Here, we demonstrated that HA synthesized in vitro using Streptococcus equisimilis HAS maintained its alternating sequence, regardless of substrate ratios and concentrations. While the active pocket lacks intrinsic selectivity, a distal allosteric regulation from the transmembrane tunnel is revealed. The lingering HA terminals in the active pocket ensure lower binding energies for alternating substrates through Coulombic repulsion and competitive binding. Moreover, the dynamic C-terminal loop at the substrate tunnel entrance reduces transport distance for alternating substrates. Our findings indicate that HA-substrate interactions and enzyme dynamics in the substrate tunnel collectively govern the alternating substrate specificity of HAS. This study provides the first molecular insight into precise substrate specificity control within a single active pocket during template-independent polymer synthesis.

biophysics↗

bioRxiv2022

Brassinosteroids signaling component SlBZR1 promotes fruit ripening in tomato

Fruit ripening evolved to be attractive to frugivores that derive energy and nutrition from the fruits in exchange for assisting seed dispersal, which is accompanied by the dramatically change of fruit characteristics, including color, aroma, and texture. The plant hormone ethylene plays a key role in climacteric fruit ripening, while the role of other phytohormones as well as their cross talk with ethylene in modulating fruit ripening remains elusive. Here, we report growth-promoting phytohormone brassinosteroids promote fruit ripening in tomato through regulation of ethylene biosynthesis. Exogenous BR treatment and the increase of endogenous BR content in SlCYP90B3-OE promoted ethylene production and fruit ripening. SlBZR1, a central component and positive regulator of BR signaling pathway, promotes ethylene production and carotenoid accumulation through direct transcriptional regulation of SlACO1, SlACO3 and SlPSY1. Furthermore, SlBIN2, a negative regulator of BR signaling upstream of SlBZR1, decreases ethylene production and carotenoid accumulation. Together, our results demonstrate that BR signaling integrates ethylene and carotenoid biosynthetic pathway to regulate fruit ripening.

plant biology↗

bioRxiv2022

The N-terminal subunit of vitellogenin in planthopper eggs and saliva acts as a reliable elicitor that induces defenses in rice

Vitellogenins are essential for the development and fecundity of insects, but these proteins may also betray them, as we show here. We found that the small N-terminal subunit of vitellogenins of the planthopper Nilaparvata lugens (NlVgN) triggers strong defense responses in rice plants when it enters the plant during feeding or oviposition by the insect. The defenses induced by NlVgN in plants not only decreased the hatching rate of N. lugens eggs, but also induced volatile emissions in rice plants, which rendered them attractive to a common egg parasitoid. VgN of other planthoppers were found to trigger the same defense responses in rice. We further show that VgN deposited during planthopper feeding compared to during oviposition induces a somewhat different response, probably targeting the appropriate developmental stage of the insect. The key importance of VgN for planthopper performance precludes possible evolutionary adaptions to prevent detection by rice plants.

ecology↗

bioRxiv2021

Protein phosphatase 1 regulatory inhibitor subunit 14C promotes triple-negative breast cancer progression via sustaining inactive glycogen synthase kinase 3 beta

The majority of clinical deaths among patients with triple-negative breast cancer (TNBC) are caused by uncontrolled cell proliferation and aggressive metastases, which is regulated by hyperactive glycogen synthase kinase 3 beta (GSK3{beta}); however, the underlying mechanisms remain largely unknown. In the present study, we found that protein phosphatase 1 regulatory inhibitor subunit 14C (PPP1R14C) was specifically upregulated in TNBC, compared with that in normal tissues and non-TNBC. High PPP1R14C expression correlated significantly with shorter 5-year relapse-free survival and overall survival in patients with TNBC. Overexpressing PPP1R14C promoted, while suppression of PPP1R14C decreased the cell proliferation and the aggressive phenotype of TNBC cells, in vitro and in vivo. Importantly, we revealed that PPP1R14C interacted with and inactivated type 1 Ser/Thr protein phosphatase (PP1) to sustain GSK3{beta} phosphorylation at S9, and induced the ubiquitylation and degradation of non-phosphorylated GSK3{beta} (S9A) via recruiting E3 ligase, TRIM25. Furthermore, treating with C2 ceramide (C2), which recovered kinase activity of GSK3{beta}, resulted in tumor growth inhibition in PPP1R14C-overexpressing TNBC cells. Our findings reveal a novel mechanism whereby PPP1R14C sustains inactive GSK3{beta}, which might lead to targeted therapy for TNBC.

cancer biology↗

bioRxiv2021

High-speed widefield handheld swept-source OCT angiography with a VCSEL light source

Optical coherence tomography (OCT) and OCT angiography (OCTA) enable noninvasive structural and angiographic imaging of the eye. Portable handheld OCT/OCTA systems are required for imaging patients in the supine position. Examples include infants in the neonatal intensive care unit (NICU) and operating room (OR). The speed of image acquisition plays a pivotal role in acquiring high quality OCT/OCTA images, particularly with the handheld system, since both the operator hand tremor and subject motion can cause significant motion artifacts. In addition, having a large field of view and the ability of real-time data visualization are critical elements in rapid disease screening, reducing imaging time, and detecting peripheral retinal pathologies. The arrangement of optical components is less flexible in the handheld system due to the limitation of size and weight. In this paper, we introduce a 400-kHz, 55-degree field of view handheld OCT/OCTA system that has overcome many technical challenges as a portable OCT system as well as a high-speed OCTA system. We demonstrate imaging premature infants with retinopathy of prematurity (ROP) in the NICU, and patients with incontinentia pigmenti (IP) in the OR using our handheld OCT system. Our design may have potential for improving the diagnosis of retinal diseases and help provide a practical guideline for designing a flexible and portable OCT system.

bioengineering↗

bioRxiv2020

Rapid expression of COVID-19 proteins by transient expression in tobacco.

In 2020 we suffered from a major global pandemic caused by the SARS-CoV-2 coronavirus. Efforts to contain the virus include the development of rapid tests and vaccines, which require a ready supply of viral proteins. Here we report the production of two SARS-CoV-2 proteins by transient transformation of tobacco, leading to high expression within three days, and subsequent purification of the intact proteins. Such efforts may help to develop testing resources to alleviate the major impacts of this global pandemic.

plant biology↗

bioRxiv2020

Targeting Vitamin-D receptor (VDR) by a small molecule antagonist MeTC7 inhibits PD-L1 but controls THMYCN neuroblastoma growth PD-L1 independently

Vitamin-D receptor (VDR) mRNA is enriched in malignant lung, ovarian and pancreatic tissues and showed poor prognoses. Calcitriol and stable or CRISPR-directed VDR upregulation increased PD-L1mRNA and protein expression in cancer cells in-vitro. A ChIP assay showed the binding of VDR with VDREPD-L1. Stattic, a STAT3 phosphorylation inhibitor blocked calcitriol or VDR overexpression induced PD-L1 upregulation. MeTC7, a VDR antagonist developed by us, reduced PD-L1 expression on macrophages, ovarian, lung, breast, and pancreatic cancer cells in-vitro. In radiotherapy inducible PD-L1 model of orthotopic MC38 murine colon cancer, MeTC7 decreased PD-L1 surface expression, suppressed inflammatory monocytes (IMs) population and increased intra-tumoral CD69+PD1+CD8+T-cells. Intriguingly, MeTC7 reduced TH-MYCN transgenic neuroblastoma tumor growth without affecting PD-L1 and tumor immune milieu. In summary, Vitamin-D/VDR drives PD-L1 expression on cancer cells via STAT-3. Inhibiting VDR exhibited anti-checkpoint effects in orthotopic colon tumors, whereas PDL1-independent and anti-VDR/MYCN effects controlled growth of transgenic neuroblastoma and xenografted tumors. SummaryVitamin-D/VDR induces PD-L1 expression on cancer cells via STAT-3; and targeting VDR by a novel small molecule antagonist MeTC7 exhibits both anti-PD-L1 and anti-VDR/MYCN effects in tumor models.

cancer biology↗

bioRxiv2020

Potent Neutralizing Monoclonal Antibodies Directed to Multiple Epitopes on the SARS-CoV-2 Spike

The SARS-CoV-2 pandemic rages on with devasting consequences on human lives and the global economy1,2. The discovery and development of virus-neutralizing monoclonal antibodies could be one approach to treat or prevent infection by this novel coronavirus. Here we report the isolation of 61 SARS-CoV-2-neutralizing monoclonal antibodies from 5 infected patients hospitalized with severe disease. Among these are 19 antibodies that potently neutralized the authentic SARS-CoV-2 in vitro, 9 of which exhibited exquisite potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng/mL. Epitope mapping showed this collection of 19 antibodies to be about equally divided between those directed to the receptor-binding domain (RBD) and those to the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that are overlapping with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody targeting RBD, a second targeting NTD, and a third bridging two separate RBDs revealed recognition of the closed, "all RBD-down" conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2.

microbiology↗

bioRxiv2020

Klp2 and Ase1 synergize to maintain meiotic spindle stability during metaphase I

The spindle apparatus segregates bi-oriented sister chromatids during mitosis but mono-oriented homologous chromosomes during meiosis I. It has remained unclear if similar molecular mechanisms operate to regulate spindle dynamics during mitosis and meiosis I. Here, we employed live-cell microscopy to compare the spindle dynamics of mitosis and meiosis I in fission yeast cells and demonstrated that the conserved kinesin-14 motor Klp2 plays a specific role in maintaining metaphase spindle length during meiosis I, but not during mitosis. Moreover, the maintenance of metaphase spindle stability during meiosis I requires the synergism between Klp2 and the conserved microtubule crosslinker Ase1 as the absence of both proteins causes exacerbated defects in metaphase spindle stability. The synergism is not necessary for regulating mitotic spindle dynamics. Hence, our work reveals a new molecular mechanism underlying meiotic spindle dynamics and provides insights into understanding differential regulation of meiotic and mitotic events.

cell biology↗

bioRxiv2020

Compressive Big Data Analytics: An Ensemble Meta-Algorithm for High-dimensional Multisource Datasets

Health advances are contingent on continuous development of new methods and approaches to foster data driven discovery in the biomedical and clinical health sciences. Open-science offers hope for tackling some of the challenges associated with Big Data and team-based scientific discovery. Domain-independent reproducibility, area-specific replicability, curation, analysis, organization, management and sharing of health-related digital objects are critical components. This study expands the functionality and utility of an ensemble semi-supervised machine learning technique called Compressive Big Data Analytics (CBDA). Applied to high-dimensional data, CBDA identifies salient features and key biomarkers for reliable and reproducible forecasting of binary or multinomial outcomes. The method relies on iterative subsampling, combines function optimization and statistical inference, and generates ensemble predictions of observed univariate outcomes. In this manuscript, we extend the CBDA technique by (1) efficiently handling extremely large datasets, (2) generalizing the internal and external validation steps, (3) expanding the set of base-learners for joint ensemble prediction, (4) introduce an automated selection of CBDA specifications, and (5) provide mechanisms to assess CBDA convergence, evaluate the prediction accuracy, and measure result consistency. We validated the CBDA 2.0 technique using synthetic datasets as well as a population-wide census-like study, which grounds the mathematical models and the computational algorithm into translational health research settings. Specifically, we empirically validated the CBDA technique on a large-scale clinical study (UK Biobank), which includes imaging, cognitive, and clinical assessment data. The UK Biobank archive presents several difficult challenges related to the aggregation, harmonization, modeling, and interrogation of the information. These problems are related to the complex longitudinal structure, feature heterogeneity, multicollinearity, incongruency, and missingness, as well as violations of classical parametric assumptions that require novel health analytical approaches. Our results showcase the scalability, efficiency and potential of CBDA to compress complex data into structural information leading to derived knowledge and translational action. The results of the real case-study suggest new and exciting avenues of research in the context of identifying, tracking, and treating mental health and aging-related disorders. Following open-science principles, we share the entire end-to-end protocol, source-code, and results. This facilitates independent validation, result reproducibility, and team-based collaborative discovery.

bioinformatics↗

bioRxiv2018

Aperture Phase Modulation with Adaptive Optics: A Novel Approach for Speckle Reduction and Structure Extraction in Optical Coherence Tomography

AbstractSpeckle is an inevitable consequence of the use of coherent light in optical coherence tomography (OCT), and often acts as noise that obscures micro-structures of biological tissue. We here present a novel method of suppressing speckle noise intrinsically compatible with adaptive optics (AO) in OCT system: by modulating the phase inside the imaging system pupil aperture with a segmented deformable mirror, thus producing minor perturbations in the point spread function (PSF) to create un-correlated speckle pattern between B-scans, and further averaging to wash out the speckle but maintain the structures. It is a well-controlled and universal method which can efficiently determine the optimal range of phase modulation that minimizing speckle noise while maximizing image resolution and signal strength for different systems and/or samples. As an active method, its effectiveness and efficiency were demonstrated by both ex-vivo non-biological and in-vivo biological applications.

bioengineering↗