Biology subjects

Zhou, Z.

Publications and source records attributed to Zhou, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Fine-tuning an intracellular allosteric pocket programs GPCR signaling bias

Biased signaling of G protein-coupled receptors (GPCRs) offers a route for precise therapeutics with fewer adverse effects. Intracellular allosteric ligands can impose such bias, yet how subtle chemical changes within these pockets reshape receptor-transducer coupling and downstream signaling remains unclear. Here, we systematically fine-tuned the intracellular allosteric pocket of neurotensin receptor 1 (NTSR1) through chemical modification of the {beta}-arrestin-biased ligand SBI-553. Minor changes to the ligand scaffold altered transducer-coupling preferences, generating distinct profiles of G-protein and {beta}-arrestin signaling. Cryo-electron microscopy structures of NTSR1-{beta}-arrestin2 complexes bound to designed allosteric probes revealed ligand-dependent remodeling of the intracellular cavity that reshapes the receptor-effector interface. Alanine scanning identified transducer-sensitive residues within and beyond the immediate ligand-contact region. In mice, SBI-553 and N065 produced distinct physiological profiles, with N065 improving survival in a lethal endotoxemia model. Finally, phosphoproteomic profiling revealed partially overlapping but distinct downstream signaling profiles among the three modulators. Together, these findings establish the intracellular allosteric pocket as a tunable determinant of transducer coupling and show that closely related modulators can generate distinct signaling and physiological profiles.

pharmacology and toxicology↗

bioRxiv2026

Dysregulation of miR-103a-3p/AGFG1 axis links endocytic trafficking dysfunction to ER stress in Parkinson's disease

Background: Parkinson's disease is defined by progressive dopaminergic neurodegeneration and -synuclein pathology. Endoplasmic reticulum (ER) stress and clathrin-mediated endocytosis dysfunction are implicated in disease pathogenesis, but the molecular mechanisms connecting these processes remain poorly understood. Here, we investigate a miR-103a-3p/AGFG1 axis as a regulator link between endocytic trafficking and ER stress in Parkinson's disease. Methods: MiR-103a-3p and AGFG1 were examined in plasma and postmortem substantia nigra from patients with Parkinson's disease and controls. Gain- and loss-of-function studies, target validation and live-cell imaging were used to define the role of the miR-103a-3p/AGFG1 axis in ER stress and endocytic trafficking. The pathway was further investigated in SNCA A53T and LRRK2 G2019S hiPSC-derived neurons. Therapeutic targeting of AGFG1 was evaluated using antisense oligonucleotides (ASOs) in vitro and in a 6-hydroxydopamine mouse model. Results: MiR-103a-3p was significantly reduced in Parkinson's disease plasma and substantia nigra, whereas AGFG1 was increased in nigral tissue. MiR-103a-3p directly repressed AGFG1 and attenuated thapsigargin-induced ER stress, while miR-103a-3p inhibition or AGFG1 overexpression exacerbated stress signalling. AGFG1 knockdown reversed the effects of miR-103a-3p inhibition, establishing AGFG1 as a functional downstream effector. Mechanistically, AGFG1 associated and co-trafficked with clathrin-positive vesicles, whereas ER stress progressively disrupted AGFG1-clathrin vesicle dynamics, revealing an association between endocytic trafficking and stress signalling. In genetic Parkinson's disease models, SNCA A53T and LRRK2 G2019S neurons showed mutation-dependent differences in AGFG1 expression and stress regulation. eIF2 phosphorylation increased in both SNCA A53T and LRRK2 G2019S neurons, whereas AGFG1 and GADD34 upregulation was selective to SNCA A53T neurons. Importantly, ASO-mediated AGFG1 suppression attenuated ER stress in vitro and preserved nigral dopaminergic neurons with improved motor performance in vivo. Conclusion: Our findings identify the miR-103a-3p/AGFG1 axis as a previously unrecognised molecular link between endocytic trafficking dysfunction and ER stress in Parkinson's disease, and support AGFG1 as a mechanistically potential therapeutic target.

neuroscience↗

bioRxiv2026

ANO6 Scaffolds ER Mitochondria Contacts to Govern Spatial Lipid Compartmentalization and Ferroptosis Evasion in Chemoresistant Breast Cancer

Background: Metabolic glycerophospholipid remodeling promotes tumor persistence under neoadjuvant chemotherapy in breast cancer; however, how resistant cells evade lipotoxicity from accumulating peroxidizable lipids presents an intriguing metabolic conundrum. The underlying organelle-level spatial mechanisms remain poorly defined. Methods: Integrated multi-omic profiling of paired pre- and post-NAC clinical specimens was performed. Engineered ANO6 models (wild-type, knockout, and conformational mutants) were characterized using subcellular lipidomics of purified mitochondria-associated ER membranes (MAMs), electron microscopy, in situ proximity ligation assays, and preclinical xenograft models. Results: Chemoresistant lesions exhibited marked ANO6 upregulation and polyunsaturated phospholipid (PUFA-PL) accumulation without enhanced apoptosis. Beyond its canonical role as a plasma membrane scramblase, ANO6 operates as an organelle contact scaffold at MAMs, leveraging its conformational activation to coordinate inter-organellar tethering. ANO6 directly recruits vimentin (VIM) and VAPB to assemble a VIM-ANO6-VAPB-PTPIP51 tethering platform, structurally bridging intermediate filaments to organelle contact sites. This complex tightens ER-mitochondria coupling, establishing a specialized structural platform that routes and sequesters peroxidizable lipids into protective cytoplasmic lipid droplets, thereby shielding functional membrane bilayers from ferroptotic peroxidation. Functional dissection revealed that the active scaffolding conformation (I612A) sustains MAMs integrity and lipid packaging, whereas scaffold deficiency (D703R) compromises contact architecture. Pharmacologically perturbing this platform with niclosamide destabilized lipid sequestration, selectively resensitizing chemoresistant cells to synthetic lethal ferroptosis in vitro and in vivo. Conclusions: ANO6-mediated contact scaffolding governs spatial lipid compartmentalization, establishing the ANO6-MAMs structural axis as a potential target to exploit lipid metabolic vulnerabilities in refractory breast cancer.

cancer biology↗

bioRxiv2026

FLASH X-rays preserve neutrophil chromatin to boost antitumor immunity

Ultrahigh dose-rate FLASH radiotherapy spares normal tissue while preserving antitumor activity, positioning it as a promising technology in radiation oncology, but its immunomodulatory mechanisms remain elusive. Here, using a bilateral subcutaneous tumor model in mice, we show that 8-Gy FLASH X-rays, versus an equal dose of conventional dose-rate (CONV) X-rays, elicit a robust abscopal antitumor effect with anti-PD-1 therapy. Single-cell transcriptome and T cell receptor (TCR) profiling reveal that FLASH X-rays plus anti-PD-1 enhance antitumor immune infiltration and TCR clonal expansion in both irradiated and abscopal tumor lesions. Mechanistically, the ultrashort temporal continuity of FLASH dose delivery conserves chromatin compaction in neutrophils during exposure and inhibits neutrophil extracellular trap (NET) formation, thereby dismantling NET-mediated CD8+ T-cell exclusion within primary tumors. Conversely, CONV or split-dose FLASH X-rays induce marked chromatin modifications prior to dose completion, leading to chromatin hyper-relaxation which promotes NETosis and consequently abrogates systemic antitumor immunity. Notably, this detrimental effect can be reversed by pharmacologically suppressing PARylation-mediated chromatin modification and decondensation in neutrophils. These findings identify radiation-induced aberrant chromatin relaxation in neutrophils as a critical determinant of radioimmunotherapy outcomes, providing a rationale for redefining the FLASH effect and advancing its clinical translation.

cancer biology↗

bioRxiv2026

Voluntary Exercise Differentially Affects High-Fat Induced Metabolic Phenotypes Across BXD Mouse Strains

Obesity and metabolic diseases such as diabetes reflect long-term interactions between diet, lifestyle, and genetics, variables that are hard to control in humans but can be systematically varied in mice, though behavioral variables like long-term exercise remain harder to model. Having previously phenotyped ~50 BXD strains, we identified BXD40, BXD43, and BXD100 as predisposed to voluntary wheel-running (~6 km/day at 24 weeks) with variable susceptibility to diet-induced obesity and diabetes. We followed these strains from 8-32 weeks on a 60% kcal/fat high-fat (HF) diet, with or without access to running wheels. Wheel usage declined from ~9 km/day in the first two weeks to a steady ~5 km/day thereafter yet still improved oral glucose tolerance by 35% over sedentary controls by 24 weeks. Despite equivalent body weight, runners ate 20% more relative to body weight, indicating the glucose benefit was independent of caloric intake. We next asked whether the gut microbiome contributes to this benefit. Long-term exercise produced only modest, cohort-dependent shifts in cecal microbial composition, though functional profiling revealed exercise-associated differences in carbohydrate- and glucose-metabolism pathways. Reciprocal bedding exchange between sedentary and running BXD43 cages reduced microbial differentiation in a taxon-specific manner and coincided with marked attenuation of the glucose phenotype, despite unchanged running behavior. Together, these findings validate BXD40, BXD43, and BXD100, alongside the canonical C57BL/6, as a model for studying diet, exercise, and genetics in metabolic disease, and implicate gut microbial taxa in shaping exercise's metabolic effects during HF feeding.

genetics↗

bioRxiv2026

The functional neuronal lipotype is specified by activity and PS synthesis using dietary and lysosomal inputs

Neurons maintain specialized membranes necessary for lifelong circuit function. While neuronal membranes thus contain unique lipidomes, how and why specific lipids become synaptically enriched remains mysterious. Here, we identify a conserved hallmark of mature neurons, phosphatidylserines containing omega-3 fatty acids (n-3 PS), which dynamically accumulate during synaptogenesis from Drosophila to humans. This neuronal lipotype depends on dietary n-3 and lysosomal catabolism mediated by Saposin, the phospholipase PLA2G15, and the lysophospholipid transporter spin/SPNS1. Reducing neuronal PS biosynthesis by targeting the PS synthase (Pss) caused lipidomic, synaptic, and behavioral deficits exacerbated by impaired glycerophospholipid catabolism. While dietary, lysosomal, and lipoprotein manipulations broadly altered n-3 levels, silencing developmental activity-templating neurons selectively reduced n-3 PS. Remarkably, pathogenic Pss variants lacking feedback inhibition similarly reduced n-3 PS and impaired circuit function. As n-3 PS is reduced during neurodegeneration but absent from iPSC-derived neurons, important relationships between lipotype and physiology may not be recapitulated in vitro.

neuroscience↗

bioRxiv2026

A FIT2-BLTP1 module sustains lipid droplet phosphatidic acid and restrains overgrowth

Lipid droplets (LDs) are assembled at discrete endoplasmic reticulum (ER) subdomains whose local phospholipid composition, rather than their protein content alone, determines whether a LD nucleates and how large it grows. Phosphatidic acid (PA) is the pivotal lipid of this environment, yet how PA reaches a forming LD has remained unknown. Here we show that the bridge-like lipid transfer protein BLTP1 is required to maintain PA in LD-associated membranes. BLTP1 depletion impaired LD formation and produced fewer but enlarged LDs across mammalian cell types, and lowered LD accumulation during adipogenic differentiation. At the ER, BLTP1 engaged the LD emergence factor FIT2 through its N-terminal transmembrane segment, an interaction that strengthened upon induction of LD formation and was strongly reduced by the disease-associated FIT2 G232R substitution. Co-depletion of FIT2 relieved the LD overgrowth caused by loss of BLTP1. Wild-type BLTP1, but neither a FIT2-binding-defective chimera nor a lipid-transfer-groove mutant, rescued LD formation in BLTP1-depleted cells. Lipidomics of purified LDs showed that BLTP1 loss most strongly lowered PA, most prominently the species PA 36:2, whereas PA and the major phospholipid classes of bulk ER membranes were unchanged. Collectively, we propose that local PA supply by BLTP1 coordinates LD assembly and growth.

cell biology↗

bioRxiv2026

Sequence-specific and programmable catalytic degradation of extracellular microRNAs by membrane-anchored DNA nanomachines

Extracellular microRNAs (miRNAs) contribute to metastasis through communication between tumour cells and their microenvironment, yet their sustained, sequence-selective depletion remains challenging. Here we report Programmable RNA-Intercepting Molecular Eraser (PRIME), a membrane-anchored DNA nanomachine that organizes miRNA recognition and catalytic degradation at the cell surface. A double-tetrahedral DNA scaffold positions a programmable recognition hairpin beside RNase H. Target binding generates an RNA/DNA hybrid for RNase H-mediated cleavage, and product release resets the hairpin for subsequent degradation cycles. Membrane-anchored PRIME depleted matched extracellular miRNAs by 70.6-89.4% across lung, breast and cervical cancer cell models. Multi-target PRIME (M-PRIME) inhibited migration by 71.3-96.0% in Transwell assays across these models. To evaluate its therapeutic potential, we established an orthotopic lung-tumour model and an early-intervention breast-cancer lung-colonization model in mice. Aptamer-directed M-PRIME combined with gemcitabine reduced pulmonary tumour burden by 74.5% in established lung tumours and 93.2% in the lung-colonization model. These effects were consistent with PRIME-mediated extracellular miRNA degradation, with circulating target miRNA levels reduced by 77.5-98.7% relative to gemcitabine alone. Together, these findings establish a programmable material strategy for sustained extracellular RNA depletion and support its potential to enhance chemotherapy in preclinical tumour models.

biochemistry↗

bioRxiv2026

Spatiotemporal atlas resolves the mesenchymal-epithelial stem cell axis governing human hair follicle aging and pathology

How adult stem cell populations coordinate tissue regeneration across physiological and pathological states remains unclear. Hair follicles contain epithelial and mesenchymal stem cells that codetermine hair regeneration. Here, we integrate a multimodal spatiotemporal atlas with functional validation to define the mesenchymal-epithelial stem cell dynamics governing human hair follicle homeostasis, aging, and androgenetic alopecia. Aging is characterized by passive depletion of hDSC-derived regenerative cues, whereas AGA involves a shift of hDSC toward an inhibitory signaling hub that promotes HFSC dysfunction. We further pinpoint hDSC-secreted PTN as a key regenerative factor that promotes hair growth and counteracts androgen-induced growth suppression. This study provides a holistic framework of adult stem cell crosstalk across physiological and pathological states, offering a mechanistic roadmap to reinstate tissue regeneration.

cell biology↗

bioRxiv2026

A convergent behavioral-neural profile of parental dysregulation and the link between parent-child brain-state similarity and child negative affect

Parent-child neural similarity is often interpreted as a marker of attunement, but its developmental significance may not be uniformly positive across family environments. We tested whether the parent's own emotional and regulatory profile, measured both behaviorally and neurally, moderates the developmental significance of parent-child neural similarity. Applying a hidden Markov model (HMM-MAR; K = 6 states) to whole-brain fMRI timeseries from 32 parent-youth dyads who separately watched the same emotional film, we derived per-dyad measures of brain-state similarity. Parent-child dyads showed greater brain-state similarity than parent-shuffle null pairs (d = -0.55, p = .004), indicating dyad-specific alignment beyond responses shared across viewers of the same film. Parent self-reported internalizing showed only a weak direct relation to child negative affect (r = .31, p = .085). However, the association between neural similarity and child negative affect depended on parent internalizing (b = 5.62, p = .018; R^2): stronger parent-child similarity predicted higher child negative affect when parents reported higher, but not lower, internalizing. A parallel interaction emerged when parent internalizing was replaced by a neural index of the parent's own state dynamics (parent neural-state unpredictability, Htrans; b = 5.95, p = .004), indicating that the effect reflects the parent's broader regulatory profile rather than a single measurement modality. Both interactions were clearest in the primary model and only partially robust across model orders and parcellations. These findings suggest that dyadic neural similarity should be interpreted in context: resembling a parent with a dysregulated profile may confer risk rather than protection.

neuroscience↗

bioRxiv2026

An Artificial Intelligence Model for Longitudinal Assessment of TCR Repertoires in SARS-CoV-2 Vaccine Recipients

T cells play a crucial role in reducing disease severity during SARS-CoV-2 infection and in shaping long-term immune memory. However, the precise molecular immune responses, particularly involving T-cell receptor (TCR) repertoire changes after full vaccination, and the use of TCR analysis to evaluate vaccine efficacy, remain incompletely understood. In this study, we developed the DeepAir-Cov19 model (AUC=0.94), a large language model tailored to identify SARS-CoV-2-specific TCRs, and observed significant differences in the TCR profiles between antibody-negative and antibody-positive populations before and after vaccination, indicating that the immune status of pre-vaccine recipients can directly assess the efficacy of vaccination. Notably, SARS-CoV-2-specific TCRs expanded to peak levels after the second dose and remained detectable in most subjects up to 10 months post-vaccination. Meanwhile, we also identified three specific V genes, 20 V-J combinations, and 3 epitopes associated with these responses. Finally, by leveraging vaccine-specific TCRs as novel biomarkers, we developed a vaccine efficacy model that predicts antibody levels with a mean AUC of 0.96. These findings underscore the accuracy of the large model in predicting SARS-CoV-2-specific TCRs and reveal a strong correlation between SARS-CoV-2-specific TCR responses and antibody levels. This highlights the complementary and synergistic roles of T cells and antibodies in providing vaccine-mediated protection. Our results offer valuable insights into the longitudinal dynamics of SARS-CoV-2-specific TCRs and illustrate the potential for developing potency evaluation models based on these TCR insights.

bioinformatics↗

bioRxiv2026

Genomic splice-donor disruption rescues systemic disease in progeria

RNA splicing determines which protein isoforms a gene produces, and aberrant splice-site activation can cause severe disease. In Hutchinson-Gilford progeria syndrome, a synonymous LMNA mutation strengthens a cryptic 5' splice donor site to produce progerin, a toxic lamin A isoform driving premature cardiovascular death. Within this cryptic donor, the activating mutation lies near the canonical GT dinucleotide required for splice-site recognition. A single guide can therefore preferentially pair with the mutant sequence while positioning Cas9 cleavage at this dinucleotide. Here we show that CRISPR/Cas9-mediated disruption of this splice site suppresses progerin without requiring precise correction of the activating mutation and prolongs lifespan in progeroid mice. In patient-derived fibroblasts and induced pluripotent stem cell-derived mesenchymal stem cells, this intervention reduced progerin by 92.7-96.8% while retaining lamin A and lamin C expression. A single neonatal injection of AAV9 carrying the corresponding mouse guide increased median survival from 115 to 279 days in Cas9-expressing LmnaG609G/G609G mice. Treatment attenuated aortic, skeletal and multiorgan pathology. Treated homozygous pairs produced 52 offspring across seven litters. These findings establish pathogenic splice signals as genomic targets for sustained suppression of toxic isoforms while retaining canonical gene outputs.

cell biology↗

bioRxiv2026

SGFP-Grid Split GFP Graphene Grids

Affinity graphene grids provide a promising approach for selective protein capture in cryo-EM. Here, we introduce a split-GFP graphene grid platform(SGFP-G), in which graphene-conjugated GFP 1-10 selectively captures GFP11 tagged proteins from low concentration samples or cell lysates. This platform enables rapid assessment of target protein enrichment and particle distribution before vitrification via fluorescence imaging, while the grid design positions captured proteins away from the graphene surface and air-water interface. We also introduce a unique strategy to minimize nonspecific protein adsorption, thereby improving the selective enrichment of target proteins on this grid. Using GFP11-tagged apoferritin, we demonstrate fluorescence guided protein capture and obtain a 2.58 [A] cryoEM reconstruction, establishing SGFP-G as an affinity grid platform for high resolution structural studies with reduced sample requirements.

biochemistry↗

bioRxiv2026

Molecular Editing in Protein Degradation: From a Dual NSD2/GSPT1 Degrader to an NSD2-Selective PROTAC and a GSPT1-Selective Molecular Glue

Both NSD2 and GSPT1 represent compelling targets for anti-cancer drug discovery. Herein, we carried out single-atom modification of LLC0424, an NSD2 degrader with GSPT1 neosubstrate engagement, to yield two structurally analogous molecules with divergent modes of action: 424-ND, an NSD2-selective degrader, and 424-GD, a GSPT1-selective degrader. 424-ND drove selective NSD2 degradation and suppressed androgen receptor (AR) signaling in prostate cancer cells. 424-GD induced selective degradation of GSPT1 and upregulated the integrated stress response markers ATF4 and ATF3. Biolayer interferometry revealed distinct ternary complex cooperativity profiles in the presence of NSD2 or GSPT1, which directly correlate with the observed biased degradation activity. Molecular dynamics and metadynamics simulations showed that the compounds adopt distinct low-energy conformational ensembles with different spatial orientations, likely underlying their divergent cooperativity and selectivity. These findings demonstrate that minimal structural alteration permits precision control over degrader target selectivity, while furnishing selective chemical probes for NSD2 and GSPT1.

cancer biology↗

bioRxiv2026

Tracking a major evolutionary transition to superorganismality

Major transitions in evolution are associated with the loss of independent reproduction by formerly autonomous units. Termites provide a powerful system for studying this process because they exhibit diverse social systems in which worker developmental and reproductive potential declines with increasing colony-level organismality. However, the evolutionary sequence and developmental genetic basis of these transitions remain unresolved. Here, using comparative developmental transcriptomics across seven termite species that differ in workers' reproductive potential, we reconstructed the evolutionary history of termite social systems. We found that linear caste development, in which workers retain full reproductive potential, represents the ancestral state of termites. Bifurcated caste development, in which workers partially lose reproductive potential early in development, evolved independently multiple times, with two origins subsequently giving rise to superorganisms with unipotent, sterile workers. Ancestral gene regulatory network (GRN) reconstruction revealed that linear caste development evolved through retention of a juvenile-like worker state and co-option of a conserved developmental GRN characterizing hemimetabolous insect nymphal development, in which juvenile hormone, ecdysone and TGF-{beta} signaling pathways play central roles. The convergent evolution of bifurcated caste development repeatedly co-opted the GRN underlying linear caste development, heterochronically shifting its activity to earlier developmental stages. Finally, we found that the evolution of termite superorganisms involved somatization of the worker caste and co-option of a conserved endocrine GRN for terminal differentiation. Together, these findings uncovered repeated routes to reduced workers' reproductive potential through GRN co-option and highlight striking parallels between superorganism evolution in social insects and organismal evolution in metazoans.

evolutionary biology↗

bioRxiv2026

The C. elegans endonuclease NUC-1 acts in engulfing cells to degrade the apoptotic cell DNA

During C. elegans embryonic development, cells undergoing programmed cell death are engulfed by neighboring cells and degraded inside phagosomes. Here we characterize a DNase responsible for the degradation of the chromatin DNA of apoptotic cells. In the past, NUC-1, a homolog of mammalian DNase II, which is only active at acidic pH, was claimed to act in apoptotic cell nuclei for chromatin DNA degradation by some researchers, yet proposed to act in engulfing cells by others. We found that NUC-1 acts exclusively in engulfing cells to degrade apoptotic cell DNA. In nuc-1 mutant embryos, apoptotic cell chromatin DNA remains undegraded. We observed that being engulfed is necessary for the apoptotic chromatin DNA to be degraded. In addition, specific expression of nuc-1 in the engulfing but not dying cells rescues the nuc-1 mutant phenotype. Furthermore, blocking the fusion between lysosomes and a phagosome in engulfing cells blocks apoptotic chromatin DNA degradation. NUC-1 was reported to be a lysosome-located enzyme. We not only confirmed this localization pattern, but also further determined that NUC-1 does not reside in the nuclei of either apoptotic or live cells. This, together with our finding that the nucleus of an apoptotic cell is not acidic, indicates that NUC-1 does not act in the apoptotic cell nucleus; rather, it acts in the engulfing cell phagosomal lumen to degrade apoptotic chromatin DNA. Our work clarified a long-standing controversy regarding the action of NUC-1 and advanced our knowledge of the mechanisms that drive the degradation of specific components of dying cells.

genetics↗

bioRxiv2026

An AI System for Autonomous Algorithm Evolution in Drug Development

Artificial intelligence (AI) is increasingly permeating the drug development pipeline. Numerous algorithms for accelerating this multi-stage and multi-task process have been constructed, which depends heavily on expert design and labor-intensive task-specific optimization. Given that AI-driven acceleration of drug development is recognized as a cumulative, often synergistic, effect across multiple stages, the autonomous evolution of existing algorithms across the entire pipeline is demanded to achieve a holistic advancement. Here, we present DrugEvolve, a multi-role large language model system for systematic and autonomous algorithm evolution in drug development. DrugEvolve realizes a closed-loop evolution process by incorporating Researcher, Engineer, and Analyst domains, and enables an iterative design, implementation, evaluation, and refinement of algorithm by leveraging scientific knowledge and accumulated evolutionary experience. Across eleven representative tasks spanning target identification, drug discovery, preclinical study, and clinical trial, DrugEvolve autonomously evolved the corresponding task-specific algorithms and achieved substantial performance enhancement on 120 benchmark test sets. Moreover, it showed robust generalizabilities across heterogeneous data modalities (ranging from biological sequence and graph to molecular topology and textual language), and realized gains in both predictive and generative tasks. Collectively, this AI system can serve not only as an algorithmic infrastructure for drug development, but also as a transferable paradigm for broader scientific domains.

pharmacology and toxicology↗

bioRxiv2026

Gene circuit-driven amplified selection enables evolution of fast-growing Escherichia coli

The laboratory Escherichia coli K-12 strain has doubled no faster than [~]20 minutes for decades. This plateau could reflect a biophysical limit or simply the way batch culture selects on growth rate. Here we show it can be broken through amplified selection with a Red Queen gene circuit, which takes advantage of growth rate heterogeneity in monoclonal populations to selectively suppress slow-growing cells and creates a tunable mapping from intrinsic growth rate to survival. After 70 days ([~]1,000 generations) of amplified selection in MG1655+FHr and subsequent removal of the circuit, a top evolved clone (RQ70) reached a maximum specific growth rate of 2.61 h-{superscript 1} in shake-flask culture. This corresponds to a doubling time of 15.9 minutes, to our knowledge the shortest reported for E. coli K-12, against 18.1 minutes for evolved controls and 20.3 minutes for the ancestor. The gain came at the cost of a [~]3-fold increase in lag time, indicating that the 20-minute plateau is a multi-trait optimum under conventional batch selection rather than an absolute constraint. We argue that synthetic gene circuits can therefore reshape the evolutionary process itself, pushing performance beyond apparent physiological limits.

synthetic biology↗