Biology subjects

Lin, D.

Publications and source records attributed to Lin, D..

At least 19 recordsLinked to original sources

bioRxiv2026

Hypothalamic plasticity for alloparenting in male mice

Repeated exposure to young can induce caregiving in virgin female mice, a phenomenon known as pup sensitization, but whether virgin males can similarly acquire parental behavior and the neural mechanisms underlying this transition remain unclear. We show that 7 days of continuous pup exposure reliably converts virgin adult male mice to a parental state. This transition requires calcitonin receptor (CalcR)-expressing neurons in the medial preoptic area (MPOA): silencing MPOACalcR neurons disrupts both the acquisition and expression of paternal behavior, whereas optogenetic activation of GABAergic MPOACalcR neurons promotes caregiving in virgin males. Longitudinal two-photon calcium imaging reveals that MPOACalcR neurons develop enhanced pup-selective responses as males transition to a parental state. Moreover, CalcR signaling in the MPOA promotes synaptic potentiation and facilitates the emergence of parental behavior. These results identify an experience-dependent hypothalamic plasticity mechanism that enables parental behavior in non-father males.

neuroscience↗

bioRxiv2026

DLGAP5 promotes vascular cell proliferation and remodeling in pulmonary arterial hypertension

Background: Pulmonary arterial hypertension (PAH) manifests by pulmonary vascular remodeling, caused by hyper-proliferation and apoptosis resistance of resident PA cells, elevated right ventricular (RV) afterload, and death of RV failure. The goal of this study is to determine the role and mechanisms of action of mitotic spindle-associated microtubule regulator DLG associated protein 5 (DLGAP5) in pulmonary vascular remodeling in PAH. Methods: DLGAP5 expression was assessed in human PAH transcriptomic datasets, PAH patients' lung tissues, pulmonary artery smooth muscle cells (PASMCs), and pulmonary artery adventitial fibroblasts (PAAFs). Loss-of-function, molecular, functional, RNAseq, and network analyses were performed. Smooth muscle (SM)-specific DLGAP5 knockdown using adeno-associated virus serotype 6 (AAV6) in mice with SU5416/hypoxia-induced PH was performed. Results: DLGAP5 was overaccumulated in small muscular PAs, PASMCs, and PAAFs from PAH lungs. siRNA DLGAP5 down-regulated cyclin A2, suppressed hyper-proliferation, increased pro-apoptotic BIM, and induced apoptosis in human PAH PASMCs and PAAFs. DEP domain containing 1 (DEPDC1) was identified and validated as a downstream effector of DLGAP5 in PAH PASMCs responsible for hyper-proliferation and apoptosis resistance of human PAH PASMCs. SM-specific DLGAP5 knockdown with AAV6-enTagln-shDLGAP5 reversed DEPDC1 overaccumulation in small muscular PAs, reduced PA medial thickness, RV systolic pressure, mean PA pressure, and RV hypertrophy in mice with SuHx-induced PH. Conclusions: DLGAP5 supports proliferation and survival of human PAH PASMCs and PAAFs through up-regulation of cyclin A2, DEPDC1, and suppression of BIM, and promotes PA remodeling and PH in mice. DLGAP5 could serve as a potential molecular target to attenuate pulmonary vascular remodeling in PAH.

cell biology↗

bioRxiv2026

Deep-learning-based design of an orthogonal self-labeling protein from K-Ras(G12C)

Self-labeling protein (SLP) tags enable versatile labeling of proteins in live cells, yet only two SLPs are commonly used, limiting multiplexing. Here, we repurposed the oncoprotein K-Ras(G12C) and its covalent inhibitors to create a third, orthogonal SLP system. We used a deep-learning-based approach to radically redesign the sequence of K-Ras(G12C) while preserving its covalent-inhibitor binding pocket. Our top design, LUCI-tag, is a 19 kDa, monomeric, thermostable SLP that rapidly and covalently reacts with commercially available K-Ras(G12C) inhibitors bearing diverse payloads. Unlike existing SLPs, LUCI-tag exhibited payload-agnostic labeling kinetics, outperforming HaloTag7 and SNAP-tag for a negatively charged payload. X-ray crystal structures of drug-bound and drug-free LUCI-tag showed the design was structurally accurate and contained a preorganized inhibitor-binding pocket that could explain its rapid labeling kinetics. Proteomics and cell-signaling experiments confirmed LUCI-tag is biologically inert. LUCI-tag enabled rapid, wash-free, live-cell imaging and simultaneous three-color multiplexed experiments with HaloTag7 and SNAP-tag. This work establishes LUCI-tag as an immediately useful orthogonal SLP and demonstrates that covalent drug-target pairs can be repurposed into a broadly applicable platform for protein labeling.

bioengineering↗

bioRxiv2026

A self-limiting, TREM2-dependent anabolic program confers microglial resilience in Alzheimer's disease

Microglia are key drivers of Alzheimer's disease (AD), and TREM2, one of the strongest genetic risk factors, enables the disease-associated microglia (DAM) state required for plaque engagement. How TREM2 sustains this protection, and why it falters as disease advances, remain unclear. Using proteomics, single-cell transcriptomics, and in vivo metabolic labeling, we show that plaque-associated microglia mount a TREM2-dependent anabolic program coupling nascent protein synthesis to mitochondrial biogenesis. This program, not the DAM signature, marks phagocytically competent microglia; its loss is associated with proteostatic overload and mitochondrial dysfunction. Unexpectedly, this anabolic program is self-limiting, peaking at low amyloid burden and declining as burden rises. This decline is conserved in humans: across 523 donors, anabolic capacity tracks TREM2 but falls at advanced Braak stage even as DAM signature keeps rising. Thus, anabolic capacity, rather than activation state, marks microglial resilience in AD, and sustained stimulation of phagocytosis by anti-amyloid antibodies risks biosynthetic exhaustion and self-limiting efficacy.

neuroscience↗

bioRxiv2026

A methylome-guided toolkit for genetic engineering of the fast-growing cyanobacterium UTEX 3222

Cyanobacterium aponinum UTEX 3222 is a fast-growing marine cyanobacterium that reaches high cell densities, making it an attractive chassis strain for low-cost biomanufacturing. However, past efforts to genetically engineer UTEX 3222 have been unsuccessful. We hypothesized that the complex restriction modification systems in the UTEX 3222 genome constitute a major barrier to genetic transformation. Using a combined methylation avoidance and methylation mimicking approach, we overcame this barrier and successfully transformed UTEX 3222 by natural transformation, generating a large panel of fully segregated axenic strains. Transformation method was also established for a novel shuttle vector that replicates in UTEX 3222. A large-scale promoter screen identified promoters which exhibited strong expression at high cell density. These advances establish the foundation for developing UTEX 3222 as a scalable platform for photosynthetic biomanufacturing.

synthetic biology↗

bioRxiv2026

miR-34/449 miRNAs regulate choroid plexus ciliogenesis to control cerebrospinal fluid production

A developmental increase in cerebrospinal fluid (CSF) production during development is essential for neuronal growth and ventricular expansion. A key regulator of CSF production is the specialized sensory multicilia of the choroid plexus (ChP), which mediate non-canonical Sonic hedgehog (Shh) signaling to suppress water channel and ion transporter expression, thereby limiting CSF production. ChP multicilia progressively shortens during development, attenuating Shh signaling and promoting CSF production. Here, we identify miR-34/449 miRNAs as essential regulators of ChP multiciliogenesis. Whereas mutations in canonical ciliogenesis genes elevate CSF production and contribute to hydrocephaly, deletion of miR-34/449 reduces CSF volume and causes microcephaly. Loss of miR-34/449 miRNAs causes excessive basal body amplification, defective basal body docking, and failure of developmental multiciliary shortening. Consequently, miR-34/449-deficient ChP cilia remain abnormally long and fail to attenuate Shh signaling, resulting in sustained repression of water channel and ion transporter expression and reduced CSF production. Mechanistically, miR-34/449 miRNAs directly target Gmnc, a master transcriptional regulator of multiciliogenesis, to restrain basal body amplification and promote basal body docking. Together, our findings identify miR-34/449 miRNAs as critical regulators of ChP multiciliogenesis and establish the developmental remodeling of ChP multicilia as a mechanism to couple Shh signaling dynamics to developmental control of CSF production.

developmental biology↗

bioRxiv2026

LncRNA-mediated organization of oncogenic chromatin state is a targetable vulnerability in leukemia

Long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of gene expression underlying various cellular functions, however, the functional and mechanistic contributions of most lncRNAs to tumorigenesis remain poorly defined, and targeting of lncRNAs is challenging with conventional therapeutic approaches. Here, we uncover human PAN3-AS1 and its murine ortholog Lnc35682, previously uncharacterized lncRNAs embedded within a conserved syntenic genomic locus, as highly expressed in acute myeloid leukemia (AML). Using genetic mouse models, human cell lines and primary patient samples, we show that PAN3-AS1 is essential for leukemia maintenance but dispensable for normal hematopoiesis. Mechanistically, we find that elevated PAN3-AS1 influences chromatin accessibility, thus promoting leukemia gene expression programs. This is mediated, at least in part, by PAN3-AS1s association with the nuclear lamina through a defined functional region that is required for its leukemogenic function. We further characterize a feed-forward regulatory circuit between PAN3-AS1 and its neighboring gene FLT3 that directly links the aberrant lncRNA functions to the FLT3-mutant AML subtype. To therapeutically exploit the regulatory node, we engineer a myeloid leukemia-preferentially targeted lipid nanoparticle (LNP) formulation and demonstrate effective delivery of siRNAs against endogenous targets into leukemia cells in experimental animals. LNP-siPAN3-AS1 alone or in combination with a clinically used FLT3 inhibitor, Gilteritinib, reduces leukemia burden and significantly delay leukemogenesis in vivo. Overall, our study uncovers a therapeutic vulnerable lncRNA-centric circuitry and provides compelling preclinical evidence for the development and application of a novel RNA targeting-LNP based therapy for treatment of myeloid leukemia. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/744058v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@10c9d42org.highwire.dtl.DTLVardef@12864e7org.highwire.dtl.DTLVardef@f87f6aorg.highwire.dtl.DTLVardef@750cbf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2026

Aging disrupts cumulus-oocyte NAD homeostasis

The age-related decline in oocyte nicotinamide adenine dinucleotide (NAD) is associated with reduced developmental potential and female infertility. Despite the extraordinary longevity of the female germline, the mechanism for maintaining oocyte NAD remains unresolved. Here, we used stable isotope tracing to identify a new mechanism for shared, intercellular NAD biosynthesis, whereby somatic-germline metabolic coupling between the oocyte and its surrounding cumulus cells is critical to maintain oocyte NAD homeostasis. We show that this coupling deteriorates with reproductive aging, identifying altered NAD metabolism in cumulus cells from mice and women of advancing reproductive age. This cumulus-oocyte metabolic coupling of NAD biosynthesis contributes to protection against the age-related increases in oocyte reactive oxygen species (ROS). In intact complexes, restoring NAD through supplementation with the precursor nicotinamide mononucleotide (NMN) increased glutathione, reduced ROS and improved mitochondrial membrane potential in oocytes from aged mice and in oocytes exposed to oxidative insult. Importantly, the ability of NMN to resolve elevated ROS depends on the presence of cumulus cells. Together, this new model of somatic-germline metabolic coupling of NAD biosynthesis places an age-related deterioration in cumulus cell-mediated metabolic support as a key driver of impaired oocyte NAD levels and redox dysregulation with aging.

cell biology↗

bioRxiv2026

Hypothalamic Representation of Aggressiveness across Mouse Strains

Aggression is an innate behavior conserved across species, serving as a critical means to compete for food, mating opportunities, and other essential resources. A central question in aggression research is the extent to which inter-individual variability in aggression is shaped by genetic factors. Here, we examine aggressive behaviors in naive male mice across seven genetically defined strains and find large cross-strain differences. We find a tight correlation between aggressiveness and anxiety levels across strains, but not within the same strain, suggesting strong genetic control of both traits. Pharmacologically elevating anxiety in high-aggression strains reduces aggression, revealing a causal relationship between these behaviors. We further demonstrate that differences in the synaptic and cellular properties of neurons in the ventrolateral ventromedial hypothalamus (VMHvl) largely account for cross-strain variability in male aggression, and that chemogenetically increasing VMHvl excitability enhances attack behavior in a low-aggression strain. Together, these findings reveal the neuronal implementation of the genetic control of innate aggression level.

neuroscience↗

bioRxiv2026

Systematic Evaluation of Signal Peptide-Driven Protein Secretion in the Fast-Growing Cyanobacterium Synechococcus sp. PCC 11901

The fast-growing cyanobacterium Synechococcus sp. PCC 11901 is emerging as a promising chassis for photosynthetic biomanufacturing. Here we report recombinant protein production in PCC 11901 via signal peptide-mediated secretion, enabling direct recovery of target proteins from the culture medium without cell disruption. Seven signal peptides spanning both Sec and Tat pathways are screened using eYFP as a reporter, with secretion quantified daily over seven days by fluorescence measurements. FutA, belonging to the Tat pathway from Synechocystis sp. PCC 6803, achieves 92.2% extracellular export by day 7, substantially outperforming all Sec candidates, including the best Sec signal peptide thermitase from Cyanobacterium aponinum PCC 10605 (55.7%). Signal peptide-bearing strains exhibit growth reductions of up to 26% relative to the wild-type, with FutA most affected, indicating a general metabolic cost correlated with secretion efficiency. The best-performing signal peptides from both pathways, FutA and thermitase, are validated with secretion of lichenase. Notably, the rank order of signal peptide performance is reversed for lichenase: thermitase demonstrates 2.6-fold higher extracellular activity than FutA, indicating that optimal signal peptide selection is cargo-dependent. These results establish PCC 11901 as a secretion-competent chassis and provide a rational framework for matching signal peptide pathways to target protein properties.

bioengineering↗

bioRxiv2026

A complete human pancreatic cancer genome

Cancer genome sequencing is essential for understanding tumor evolution and advancing precision medicine.1 However, reference gaps and germline variants obscure detection of small and large somatic variants and methylation in repetitive regions.1-3 It is common for tumor cells to gain or lose chromosome arms due to somatic structural changes that occur inside highly repetitive satellite DNA sequences in the centromeres.4 To identify the full spectrum of somatic variants, including complex rearrangements, we construct and curate near-complete, haplotype-resolved assemblies of the most recent common ancestor of an early-passage broadly-consented hypodiploid pancreatic cancer cell line and matched normal tissues. The tumor assembly completely recapitulates all 35 tumor chromosomes observed with karyotyping, with multiple translocation-induced hybrid chromosomes. The hybrid chromosomes contain putative functional dicentric and fused centromeres, nested foldback inversions causing 14 breakpoints with a haplotype switch in a single event, and centromeric satellite tandem duplications up to 136 kbp. Direct comparison of tumor and normal assembly haplotypes uncovers >7,000 variants altering >1 Mbp of sequence in repetitive regions that have been hidden by reference gaps and germline variants. 44 % of somatic small variants change representation because they alter germline variants on GRCh38, impacting mutational signatures and kataegis/omikli clusters. Most somatic LINE insertions originate from two hypomethylated non-reference germline LINE insertions, highlighting their impact on insertion mutation burden. These assemblies demonstrate that centromeric, acrocentric, and telomeric regions conventionally excluded from analysis harbor extensive somatic and epigenetic changes. Resolving complete tumor genomes enables a deeper understanding of cancer structural plasticity and the endpoints of breakage-fusion-bridge cycles. These assembled, curated paired normal-tumor benchmarks will serve as a critical foundation for developing future algorithms to characterize the most intractable regions of cancer genomes.

genomics↗

bioRxiv2026

The neural control of infanticide and parental behaviors in male mice

Infanticide, the killing of conspecific young, is a natural behavior observed commonly in non-parental animals across species, including mice. Our recent study in female mice revealed a mutually inhibitory circuit, composed of estrogen receptor alpha cells in the medial preoptic area (MPOAEsr1) and the posterior part of the bed nucleus of stria terminalis (BNSTpEsr1), that controls pup-directed behaviors, with the former driving maternal care and the latter promoting infanticide. Given that both MPOA and BNSTp are sexually dimorphic, here we asked whether the same circuit operates in males. Our functional manipulations and in vivo and in vitro recordings reveal that MPOAEsr1 and BNSTpEsr1 cells similarly and respectively drive paternal care and infanticide and antagonize each other in male mice. Furthermore, during fatherhood, MPOAEsr1 cell excitability increases while BNSTpEsr1 cell excitability decreases to enable the switch from infanticide to paternal care. Despite the similarity in circuit organization, a direct comparison between males and females reveals sex differences in the intrinsic properties of MPOAEsr1 and BNSTpEsr1 cells. Thus, MPOAEsr1-BNSTpEsr1 emerges as a common circuit motif for controlling pup-directed behaviors in both sexes, whereas the activity balance between these two populations differs between sexes and likely contributes to the different tendencies in males and females to express pup-caring versus killing behaviors.

neuroscience↗

bioRxiv2026

Effects of the Coenzyme Q10 Analog 6-Bromo-ubiquinone (6-Br-Q0C10) on Mammalian Cell Growth

Synthetic 6-Br-Q0C10 has been shown to exhibit a partial electron transfer activity of native coenzyme Q in the isolated mitochondria. It reduces energy coupling efficiency by approximately 30%, suggesting that it may be useful in modulating cell growth in tissue culture. Whether or not it behaves in the same way in the whole cells, or animal, however, has not yet been fully examined. Recently we have investigated the effect of 6-Br-Q0C10 across multiple cell lines using three detection methods. Treatment with 6-Br-Q0C10 reduces cell proliferation in all cell lines tested, with different effectiveness. Obesity-related cell lines were the most susceptible, and a pronounced inhibitory effect was also observed in cancer cell lines. These results strengthen the idea of using 6-Br-Q0C10 to manage obesity or to retard the growth of rate cancer cells and thus prolonging life.

biochemistry↗

bioRxiv2026

Pharmacological targeting of EED is an effective therapeutic strategy in cellular models of incurable neuroendocrine prostate cancer

BackgroundNeuroendocrine Prostate Cancer (NEPC) is an incurable malignancy, originating from the trans-differentiation of prostate adenocarcinoma (PRAD). Compared to PRAD, NEPC shows over-activation of Polycomb Repressive complex-1(PRC1) and-2 (PRC2), which are multiprotein epigenetic writers that drive cancer progression via tumour suppressor gene silencing. Tazemetostat is a PRC2 inhibitor approved for the treatment of sarcomas and lymphomas. ORIC-944 is a novel EED (Embryonic Ectoderm Development) inhibitor, which is being tested in clinical trials. EED is an attractive target as it functions as a key component of both PRC1 and PRC2. Objective and MethodsWe compared the anticancer effects of tazemetostat and ORIC-944 in NEPC and PRAD cells. Cells were exposed to various concentrations of the two compounds to measure effects on cell viability (IC50) and apoptosis (flow cytometry). PRC2 inhibition was confirmed by measuring histone H3 Lys 27 trimethylation (H3K27me3) via ELISA and Western Blot. RNA Sequencing and pathway analysis was conducted to study modes of actions of tazemetostat vs ORIC-944. ResultsUnlike tazemetostat, ORIC-944 causes dose-dependent growth inhibition in both NEPC and PRAD cells. In this context, EED targeting achieves IC50 values that are comparable to those of compounds used for the clinical treatment of advanced prostate cancer. Moreover, ORIC-944 (but not tazemetostat) causes significant apoptosis in NEPC cells. Both tazemetostat and ORIC-944 reduce H3K27me3. Mechanistically, both compounds reactivate the expression of known PRC2 targets, such as genes that control neural differentiation. However, the EED inhibitor also reactivates PRC1 targets, including pro-apoptotic and anti-proliferating genes (e.g. metallothionines). This evidence suggests that EED inhibition is a promising therapeutic strategy for NEPC.

cancer biology↗

bioRxiv2026

An additional site mutation in MITA/STING gain-of-function mutants abolishes the autoimmune SAVI phenotypes and directs a therapeutic strategy.

STING-associated vasculopathy with onset in infancy (SAVI) is an autoimmune disease caused by gain-of-function mutations (GOFs) of MITA/STING and the most frequent GOFs for SAVI are MITAN154S and MITAV155M. However, how MITA GOFs are spontaneously activated remains incompletely understood. Here, we show that the activity of MITA hinge-region GOFs is compromised by an additional mutation at Lys150 and that the SAVI phenotypes of MITAN153S/WT mice are completely abolished in the MITAK150N/N153S (MITANS/NS) mice. Mechanistically, MITA GOFs constitutively associate with iRhom2 for the spontaneous ER-to-Golgi translocation, which is substantially inhibited by the introduction of a mutation at Lys150. Interestingly, cGAMP binds to MITANS, triggers the ER-to-Golgi translocation of MITANS as well as the MITANS-iRhom2 interaction, and induces the expression of downstream genes in MitaNS/NS cells similarly as in Mita+/+ cells. Consistently, structural studies demonstrate an inactive open conformation of apo-MITANS characterized by connector region crossover and a curved filament of cGAMP-bound MITANS characterized by parallel connector regions, similar to those observed in wild-type MITA. Furthermore, we design a SAVI-inhibitory peptide (SIP) that selectively inhibits the interaction between MITAN153S and iRhom2 and the activity of MITA GOFs and thereby abolishes the SAVI phenotypes of the MITAN153S/WT[->]WT chimeric mice. These findings reveal a previously uncharacterized mechanism for the spontaneous activation of MITA GOFs and highlight a potential therapeutic intervention for SAVI.

immunology↗

bioRxiv2025

Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in NSCLC

Glutathione peroxidase 4 (GPX4) is a master regulator of ferroptosis, a process that has been proposed as a potential therapeutic strategy for cancer. Here we have unexpectedly found that inducible knockout of GPX4 in tumor cells significantly promotes non-small cell lung cancer (NSCLC) progression in the autochthonous KrasLSL-G12D/+Lkb1fl/fl (KL) and KrasLSL-G12D/+Tp53fl/fl (KP) mouse models, whereas inducible overexpression of GPX4 in tumor cells exerts the opposite effect. GPX4-deficient tumor cells evade ferroptosis by upregulating the expression of DGAT1/2 to promote the synthesis of triacylglycerol (TAG) and oxidized TAG (oxTAG) and the formation of lipid droplets in cells. In addition, GPX4-deficient tumor cells secrete TAG and oxTAG into the extracellular space to induce dysfunction of antitumor CD8+ T cells, thereby coordinating an immunoinhibitory tumor microenvironment (TME). Consistently, treatment with DGAT1/2 inhibitors or inducible overexpression of GPX4 in tumor cells significantly resensitizes tumor cells to ferroptosis and ignites the activation of T cells in the TME to inhibit NSCLC progression. These findings highlight a previously uncharacterized role of tumor cell-specific GPX4 in NSCLC progression and provide potential therapeutic strategies for NSCLC.

cell biology↗

bioRxiv2025

Spatially Resolved Determination of Small Molecule Protein Affinities by Hydrogen Deuterium Exchange Mass Spectrometry

Hydrogen Deuterium Exchange Mass Spectrometry (HDX-MS) is an established tool in drug discovery, used to characterize target engagement and conformational dynamics, frequently used in both biopharmaceutical and small molecule development. Conventional HDX-MS experiments are performed at saturating ligand concentrations to generate a binding "footprint", where decreased solvent exchange reflects a local structural stabilization and/or reduced solvent accessibility upon binding. Here, we present an extended HDX-MS and HDX-MS/MS titration workflow with electron capture dissociation (ECD) fragmentation capable of estimating apparent dissociation constants (KDapp) at global, peptide and single amino acid resolution by fitting uptake-concentration relationships under EX2 exchange and Langmuir binding assumptions. The ability to determine affinity constants in a spatially resolved manner combined with the automation available in HDX-MS sample handling and data analysis enables quantitative mapping of ligand-protein interactions and provides a scalable approach for structure-activity relationship studies in drug discovery.

biophysics↗

bioRxiv2025

Universal super-resolution for subcellular fluorescence imaging

Super-resolution fluorescence microscopy has emerged as an essential instrument for investigating subcellular structures and monitoring intracellular physiology. Despite rapid advances driven by deep learning, most existing approaches are modality specific and exhibit limited generalizability, restricting their practical applicability. Here we introduce universal super-resolution (UniSR), a framework that operates across microscopes and subcellular structures without optical modifications or prior sample knowledge. UniSR is initially pre-trained on simulated image pairs to establish mappings from low-to high-resolution features and subsequently fine-tuned with only one experimental image pair, reducing data demand and acquisition time. Across wide-field and point-scanning modalities, UniSR enhances resolution to match structured illumination, single-molecule localization, or stimulated emission depletion microscopy. Applied to diverse biological samples, it reveals nanoscale structures, dynamic processes, and organelle interactions with high spatiotemporal fidelity. UniSR provides a practical and broadly generalizable tool for super-resolution imaging in live-cell research.

bioinformatics↗