Biology subjects

Yun, D.

Publications and source records attributed to Yun, D..

8 recordsLinked to original sources

bioRxiv2026

Accelerated discovery of thermostable vaccines using data-efficient AI

The inherent instability of mRNA- lipid nanoparticles (LNPs) necessitates ultra-cold storage, creating significant barriers for global distribution and limiting their broader application in advanced delivery systems. Solid-state, water-free formulations offer a promising solution by enhancing thermostability and enabling integration into emerging delivery modalities such as microneedle (MN) patches. Prior efforts to stabilize mRNA-LNPs have been constrained by narrow formulation scope and low-throughput screening methods. Here, we introduce AGENT (Algorithm-Guided Experimental design for lipid Nanoparticle Thermostabilization), an AI-driven framework that couples high-throughput experimentation with Bayesian optimization to rapidly identify thermostable mRNA-LNP formulations. Manual exploration of the formulation space required months of screening and yielded suboptimal candidates. In contrast, AGENT extracted maximal information from sparse experimental datasets, enabling efficient formulation optimization in only six iterations completed within one month. Using AGENT, we stabilized mRNA vaccines with diverse LNPs, including those in clinical use, into solid state formulations that retained 100% bioactivity after storage at 37 degree C for over two months. The thermostable vaccines induced antigen-specific IgG and germinal center B cell responses that were non-inferior to those elicited by freshly prepared soluble vaccines. The solid-state formulations were further incorporated into dissolvable MN patches and administered to rodents and nonhuman primates, yielding comparable neutralizing antibody titers compared to conventional intramuscular delivery of fresh vaccines. To our knowledge, this study presents the first demonstration of AI-driven design of thermostable RNA vaccines, offering a scalable, cold-chain-free solution for global immunization. By addressing both stability and delivery challenges, AGENT provides a potentially transformative platform for developing accessible next-generation therapeutics.

bioengineering↗

bioRxiv2025

Short Excitatory Projections Promote Burst Activity and Modular Functional Organization in Neural Networks

Physical constraints in the brain favor short, distance-dependent connections. How-ever, short-range projections are not merely a compromise imposed by these constraints; they also serve essential functional roles. Here, we explore networks with balanced excitation and inhibition, demonstrating that short excitatory projections fundamentally increase the number of common presynaptic inputs, thereby enhancing the correlations of neural responses. Strengthened recurrent correlations can lead to bursting states, amplifying postsynaptic neuronal activity and supporting signal propagation over long distances within the network. Moreover, even without an explicitly imposed modular structure, short excitatory connections can give rise to functional clustering and support a broad spectrum of modular functions. Therefore, this structural principle provides a mechanistic basis for functional column formation and dynamic burst propagation, suggesting that the brain transforms structural wiring constraints into opportunities for complex computation and distributed processing. These findings pave the way for a deeper understanding of how the brain transforms structural limitations into opportunities for complex computation.

neuroscience↗

bioRxiv2024

CD131 Contributes to Ulcerative Colitis Pathogenesis by Promoting Macrophage Infiltration

BackgroundUlcerative colitis (UC) is a group of chronic inflammatory bowel disease (IBD) mainly affecting the colon. The exact etiology of ulcerative colitis remains elusive. CD131 is a receptor subunit mediating the effects of hematopoietic growth factors GM-CSF and IL-3, which regulate various inflammatory responses. The pleiotropic effects of the cytokines on intestinal inflammation suggest that additional factors influence their overall function, where the receptor may play a role. MethodsIn the present study, we investigated the role of CD131 in the pathogenesis of ulcerative colitis, with the use of murine colitis model established by administration of DSS in the drinking water. ResultsBy comparing the immune and inflammatory responses between wt and CD131-deficient mice, we found that CD131 contributed to DSS-induced murine colitis, which functioned in synergy with tissue- infiltrating macrophages. Besides, CD131 may have promoted the chemotaxis of macrophages and T cells into the colon through CCL4. In addition, we analyzed clinical data and pathology specimens from ulcerative colitis patients and found that CD131 was associated with the endoscopic and pathological severity of intestinal inflammation. ConclusionsThe present study provides a novel way to the understanding of the mechanisms of GM-CSF and IL-3 effects in the intestine, which will benefit the development of therapeutic approaches.

immunology↗

bioRxiv2021

A modular protein subunit vaccine candidate produced in yeast confers protection against SARS-CoV-2 in non-human primates

Vaccines against SARS-CoV-2 have been distributed at massive scale in developed countries, and have been effective at preventing COVID-19. Access to vaccines is limited, however, in low- and middle-income countries (LMICs) due to insufficient supply, high costs, and cold storage requirements. New vaccines that can be produced in existing manufacturing facilities in LMICs, can be manufactured at low cost, and use widely available, proven, safe adjuvants like alum, would improve global immunity against SARS-CoV-2. One such protein subunit vaccine is produced by the Serum Institute of India Pvt. Ltd. and is currently in clinical testing. Two protein components, the SARS-CoV-2 receptor binding domain (RBD) and hepatitis B surface antigen virus-like particles (VLPs), are each produced in yeast, which would enable a low-cost, high-volume manufacturing process. Here, we describe the design and preclinical testing of the RBD-VLP vaccine in cynomolgus macaques. We observed titers of neutralizing antibodies (>104) above the range of protection for other licensed vaccines in non-human primates. Interestingly, addition of a second adjuvant (CpG1018) appeared to improve the cellular response while reducing the humoral response. We challenged animals with SARS-CoV-2, and observed a ~3.4 and ~2.9 log10 reduction in median viral loads in bronchoalveolar lavage and nasal mucosa, respectively, compared to sham controls. These results inform the design and formulation of current clinical COVID-19 vaccine candidates like the one described here, and future designs of RBD-based vaccines against variants of SARS-CoV-2 or other betacoronaviruses.

immunology↗

bioRxiv2021

Engineered SARS-CoV-2 receptor binding domain improves immunogenicity in mice and elicits protective immunity in hamsters

Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs).1 Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access.2 Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing costs.3 These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples.4-6 Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2.7,8 Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.

molecular biology↗

bioRxiv2020

LZTR1 inactivation promotes MAPK/ ERK pathway activation in glioblastoma by stabilizing oncoprotein RIT1

Large-scale sequencing studies on glioblastoma have identified numerous genetic alterations. Leucine-zipper-like transcription regulator 1 (LZTR1) is inactivated by non-synonymous mutations and copy number losses, suggesting that it is a tumor suppressor in glioblastoma. However, how LZTR1 mutations contribute to glioblastoma pathogenesis remains poorly understood. Here, we revealed that LZTR1, as an adaptor of the CUL3 E3 ubiquitin ligase complex, recognizes and triggers ubiquitin-dependent degradation of oncoprotein RIT1, a RAS-like GTPase. Wild-type LZTR1 suppresses glioblastoma cell proliferation and migration by inactivating the MAPK/ERK signaling pathway in a RIT1-dependent manner. However, the effects were abrogated by the glioblastoma-associated LZTR1 mutations. Our findings revealed the underlying molecular mechanism of LZTR1 mutations-driven glioblastoma, and provide novel therapeutic target for LZTR1 mutations-driven glioblastoma.

cancer biology↗

bioRxiv2019

Computationally guided high-throughput design of self-assembling drug nanoparticles

Nanoformulations are transforming our capacity to effectively deliver and treat a myriad of conditions. However, many nanoformulation approaches still suffer from high production complexity and low drug loading. One potential solution relies on harnessing co-assembly of drugs and small molecular excipients to facilitate nanoparticle formation through solvent exchange without the need for chemical synthesis, generating nanoparticles with up to 95% drug loading. However, there is currently no understanding which of the millions of possible combinations of small molecules can result in the formation of these nanoparticles. Here we report the development of a high-throughput screening platform coupled to machine learning to enable the rapid evaluation of such nanoformulations. Our platform identified 101 novel self-assembling drug nanoparticles from 2.1 million pairings derived from 788 candidate drugs with one of 2686 excipients, spanning treatments for multiple diseases and often harnessing well-known food additives, vitamins, or approved drugs as carrier materials - with potential for accelerated approval and translation. Given their long-term stability and potential for clinical impact, we further characterize novel sorafenib-glycyrrhizin and terbinafine-taurocholic acid nanoparticles ex vivo and in vivo. We anticipate that this platform could accelerate the development of safer and more efficacious nanoformulations with high drug loadings for a wide range of therapeutics.

bioengineering↗

bioRxiv2018

Upregulation of photosynthetic capacity and thylakoid membrane protein enhanced tolerance to heat stress in wucai (Brassica campestris L.)

The hot climate of southern China from late summer to early fall is one of the major factors limiting the yield and quality of wucai (Brassica campestris L.). Under high temperature stress, heat-tolerant cultivars presented moderate injury to the photosynthesic apparatus, less inhibition of photochemical activity, better osmotic adjustment and antioxidant defences capacity compared to heat-sensitive cultivars. To study the effects of high temperature on the growth and development of wucai, plants of WS-1 (heat-tolerant) and WS-6 (heat-sensitive) were exposed to four heat stress treatments in growth chambers for 3 days. Chloroplasts of two cultivars evaluated for photosynthetic characteristics, fatty acid composition and differentially expressed proteins of thylakoid membrane. The chlorophyll (Chl) content was markedly reduced by heat stress, inhibiting photochemical activity. However, larger decreases in growth and photosynthetic parameters [net photosynthetic rate (PN), stomatal conductance (GS), intercellular CO2 concentration (Ci), and leaf transpiration rate (E)] occurred under heat stress in WS-6, compared with WS-1. In addition, WS-6 showed an obviouse K point in O-J-I-P steps under extremely high temperature, which indicated OEC had been damaged. WS-1 showed higher of maximum quantum yield of primary PSII photochemistry (FV/FM), number of active reaction centres per cross section of PSII (RC/CSM), average absorbed photon flux per cross section of PSII (ABS/CSM), maximum trapped exciton flux per cross section of PSII (TR0/CSM), electron transport flux from QA to QB per cross section of PSII (ET0/ CSM) and performance index on absorption basis (PIABS) which indicated greater heat stability in terms of PSII function under higher temperature. Compared to WS-6, WS-1 showed higher membrane stability and photochemical efficiency, and greater increase of saturated fatty acids (SFA), especially palmitic acid under heat stress. WS-1 had higher recovery rate compared to WS-6 after 41{degrees}C heat stress treatment. Additionally, two-dimensional blue native/SDS-PAGE analysis of chloroplast was carried out to compare the differentially expressed proteins between two cultivars. We obtained seven major protein complexes included supercomplexes, PSI-LHCII/PSII monomer, PSII monomer, CP43 less PSII/ATP synthase, LHCII trimer, LHCII monomer and ATP synthase after first dimentional seperation in both cultivars after the first dimensional separation. Then ten differential membrane proteins included light-harvesting Chl a/b-binding (LHC) protein, ATP synthase subunit alpha, ATP synthase subunit beta, photosystem I P700 chlorophyll a apoprotein A2, photosystem II CP43 reaction center protein, photosystem II D2 protein and photosystem II\n\nOS have been found between WS-1 and WS-6. These differentially proteins in cellular membranes could contribute to the differential level of heat tolerance between two wucai cultivars. Our results demonstrated that the heat-tolerant cultivar WS-1 had a greater capacity for photosynthesis and membrane stability by upregulating proteins abundance including light harvesting (light-harvesting Chl a/b-binding protein), energy metabolism (ATPase), and proteins of PSII reaction center (D2, CP43) under heat stress.

biochemistry↗