Biology subjects

Gong, H.

Publications and source records attributed to Gong, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Decision benchmarking reveals when protein foundation models add experimental value

Protein engineering is shifting from model-based variant scoring to deciding what to measure next. This exposes a limitation of fixed-dataset benchmarks, which rank predictors without showing when their advantage survives as evidence accumulates. We therefore introduce decision benchmarking across 217 ProteinGym assays, 2.47 million variants and 95 predictors to evaluate whether models and measurements improve decisions at matched cost. Zero-shot accuracy explained less than one-fifth of the variation in discovery after calibration. Calibrated priors exceeded budget-matched additivity at 20-100 measurements, but the advantage narrowed as component measurements accumulated. Measured additivity then overtook zero-shot models after 50-100 measurements for top-variant discovery and around 500 for global ranking. The same principle showed that double-mutant measurements improved prediction in models using mutation identity, whereas prediction-guided acquisition improved discovery. Evidence-based routing improved strategy selection. Decision benchmarking thus identifies which strategy adds value given the information already available and the decision that follows.

bioengineering↗

bioRxiv2026

From single-sequence structure prediction to protein fitness landscape through a composable, epistasis-aware mutation atlas

Mapping the multi-mutant fitness landscape is vital to protein engineering, but is challenging due to the vast combinatorial sequence space awaiting exploration. A central difficulty lies in the accurate and efficient modeling of non-additive epistatic effects among individual mutations, which partially arise from the physical inter-residue interactions prescribed by the protein structure. Existing fitness predictors usually perform well on single mutants but become less powerful for higher-order mutants, due to the lack of explicitly considering the relationship between sequence, structure and function of the target protein. Here, we present an end-to-end framework named Cerebra-Epistasis, which couples a single-sequence structure predictor that explicitly endows the structure awareness beyond the conventional sequence-fitness mapping with a downstream fitness prediction network that deliberately models the non-linear epistatic effects beyond the traditional additive terms. When evaluated across diverse assays, Cerebra-Epistasis outperforms the other state-of-the-art baselines in multi-mutant fitness prediction, with enhanced advantage over increasing mutation orders. Moreover, our special design on the epistasis modeling allows reliable extrapolation from low-order mutant data to unseen higher-order combinations, enabling one-shot inference of the overall mutation atlas from the starting sequence, a benefit that supposedly introduces three orders of magnitude acceleration in the landscape-scale prediction.

bioinformatics↗

bioRxiv2026

VEGFA-Positive Macrophages Regulate Aqueous Humor Outflow in Aged Mice and Humans

Elevated intraocular pressure (IOP) and aging are major risk factors for primary open-angle glaucoma (POAG), but how aging affects IOP regulation remains poorly understood. IOP remains within a narrow range despite age-associated changes predicted to increase aqueous humor outflow (AHO) resistance at the interface between the trabecular meshwork and Schlemm's canal (SC), suggesting compensatory mechanisms preserve AHO homeostasis during aging. Single-cell RNA sequencing of mouse ocular angle tissues revealed immunomodulatory transcriptional reprogramming of SC endothelial cells in older mice, while mouse and human imaging showed reduced SC size and increased peri-SC macrophage accumulation with aging. Ligand-receptor analysis predicted enhanced macrophage-to-SC VEGFA-VEGFR signaling in aged and Tie2-haploinsufficient mice, an independent model of vascular stress and glaucoma risk. Deletion of Vegfa in CX3CR1+ macrophages increased IOP and reduced AHO facility in 9-month-old mice, demonstrating that macrophage-derived VEGFA supports AHO homeostasis. Tie2 haploinsufficiency recapitulated key age-associated SC niche changes, including peri-SC macrophage accumulation, whereas gene therapy boosting TIE2 activity protected wild-type mice against age-related changes. Together, these findings identify peri-SC macrophage-derived VEGFA as a compensatory mechanism maintaining AHO homeostasis during aging and vascular stress and support TIE2 activation as a therapeutic strategy to preserve SC function and IOP regulation.

physiology↗

bioRxiv2026

Systematic identification of cell division proteins in haloarchaea and the discovery of a membrane anchor for the Z ring

Most archaea rely on the tubulin-like protein FtsZ for division. In the last decade, several novel cell division proteins have been discovered in the model haloarchaeon Haloferax volcanii which contains two FtsZ proteins, FtsZ1 and FtsZ2. However, the composition of this FtsZ-based archaeal divisome is largely uncharacterized. Here, using in vivo crosslinking coupled with immunoprecipitation and mass spectrometry (CLIP-MS), we identified ten proteins that localize to the division site, including wide-spread proteins predicted to be involved in DNA binding and energy metabolism. Deletion analysis indicate that most of these proteins have a modest or minor impact on cell division, but HVO_0399, renamed as Cell Division Protein C (CdpC), is important for cell division and functions as a membrane anchor for FtsZ1. CdpC consists of three domains, an N-terminal domain (NTD) containing an amphipathic helix critical for membrane binding, a long intrinsically disordered linker, and a C-terminal domain (CTD) that binds FtsZ1 with high affinity and likely promotes its polymerization. Notably, both the NTD and CTD of CdpC harbor a zinc finger that is indispensable for its function. Phylogenetic analysis indicates that CdpC sequences evolved fast across haloarchaea, but exhibited high conservation in domain structure and critical residues found in this study. Overall, our study expands the repertoire of candidate division proteins and establishes CdpC as a membrane anchor for FtsZ1 in haloarchaea. These findings pave the way for in-depth studies of arcaheal cell division and broaden the function of zinc finger proteins in archaea.

microbiology↗

bioRxiv2026

Assessing Microcirculation Impairment in Ischemic Stroke Mice Using Arteriovenous Co-fluctuation Analysis

Accurate assessment of cerebral hemodynamics impairment traditionally relies on arterial metrics, yet often overlooks venous drainage and arteriovenous dynamics, thereby limiting the evaluation of ischemia-induced microvascular dysfunction. To address this limitation, we implemented a signal-averaging framework, combined with co-fluctuation analysis, to extract predominantly arterial and venous hemodynamic signals and construct a dynamic arteriovenous co-fluctuation index that quantifies frame-by-frame coordination between arterial inflow and venous outflow activity. This time-resolved index enables spatial characterization of large-scale cortical arteriovenous coordination beyond conventional static correlation-based analyses. Comparative analyses between healthy controls and acute ischemic stroke mice demonstrated that the arteriovenous co-fluctuation index sensitively detects disruption of vascular coordination, revealing a slower state transition that occurs alongside distinct temporal abnormalities and regional heterogeneity between ischemic core and penumbral regions. These findings underscore the utility of arteriovenous coordination as a sensitive indicator of microcirculatory dysfunction, offering a practical analytical tool for assessing stroke-induced microvascular impairment.

neuroscience↗

bioRxiv2026

Environmental context reveals a conditional role of the Tol-Pal system in envelope organization in Acinetobacter baumannii

Gram-negative bacteria must coordinate remodeling of the peptidoglycan cell wall with invagination of the outer membrane to preserve envelope integrity during growth and division. The conserved Tol-Pal system has been implicated in coordinating these processes, yet its physiological contribution to envelope organization remains unclear and may depend on environmental context. Here, we examined the role of Tol-Pal in coordinating envelope remodeling in Acinetobacter baumannii across distinct growth environments. Loss of Tol-Pal did not cause a major population growth defect, and septal peptidoglycan incorporation remained largely preserved under standard laboratory growth conditions. In contrast, under specific environmental conditions--including nutrient-rich media, altered osmotic conditions, and host-like environments--Tol-Pal deficiency disrupted the spatial organization of cell division and cell morphology. Tol-Pal mutants also exhibited modest but reproducible reductions in outer membrane barrier robustness and decreased fitness in environmental and host-associated contexts. Together, these findings demonstrate that Tol-Pal is not an essential component of the core division machinery but instead contributes to the coordinated organization of the Gram-negative envelope under conditions that impose additional physiological demands. More broadly, our results highlight how environmental context can reveal conditional roles for conserved envelope systems that are not apparent during standard laboratory growth. ImportanceThe Gram-negative envelope is a complex, multilayered structure that must remain intact as cells grow and divide across diverse and often challenging environments. Coordination between peptidoglycan remodeling and outer membrane invagination is therefore critical for maintaining envelope organization and cellular fitness. Here, we show that the conserved Tol-Pal system in Acinetobacter baumannii contributes to the spatial organization of cell division and outer membrane robustness under specific environmental conditions. Although Tol-Pal deficiency permits sustained population growth under standard laboratory conditions, its absence disrupts envelope organization and compromises bacterial fitness in environmental and host-associated contexts. These findings demonstrate how environmental conditions can expose conditional roles for conserved envelope systems and highlight the importance of physiological context in shaping bacterial cell envelope organization.

microbiology↗

bioRxiv2026

Porcine Left Atrial and Ventricular Thick Filaments Exhibit Distinct Resting Structures and Calcium-dependent Responses

The heart maintains systemic perfusion through the coordinated function of its four chambers: the left and right atria and ventricles. Each chamber has distinct structural, functional, and molecular properties tailored to its role in circulation, which may result in chamber-specific differences in myofilament structure and regulation between atria and ventricles. To test this hypothesis, we employed muscle mechanics and X-ray diffraction to investigate functional and structural differences in porcine left atrial (LA) and left ventricular (LV) tissue. Here, we report the first X-ray diffraction study of atrial tissue, demonstrating that under resting conditions, myosin filaments in LA adopted a more ON-like, structurally distinct configuration compared with those in LV. Under contracting conditions, LV generated greater force and exhibited higher sinusoidal stiffness than LA across multiple calcium concentrations. LA showed faster kTR than in LV, with no calcium-dependence, in contrast to the calcium-dependence of kTR seen in LV. Structurally, the distinct myosin head configuration seen in the relaxed LA persisted during contraction. Furthermore, using the troponin inhibitor MYK-7660 to inhibit active contraction, we showed that, unlike LV, LA showed no direct calcium-dependent thick filament activation, reconciling discrepancies between fast rat and slow porcine ventricular myocardium regarding calciums role in thick filament regulation. Altogether, our study reveals that LA myosin filaments adopt a molecular architecture and regulatory mechanism distinct from their LV counterparts, suggesting that myosin filament structure and regulation have evolved differently to meet the unique functional demands of each cardiac chamber. Moreover, atrial disease is often associated with cardiomyopathy-related genetic variants, highlighting the atrial myocardium as an important therapeutic target and understanding atrial-specific regulatory mechanisms provides new insights into therapeutic strategies for atrial diseases.

physiology↗

bioRxiv2026

Outer membrane remodeling via lipid-peptidoglycan crosstalk enables lipooligosaccharide-deficient colistin resistance

Gram-negative bacteria rely on an asymmetric outer membrane (OM) for barrier integrity, with phospholipids confined to the inner leaflet and glycolipids such as lipopolysaccharide (LPS) or lipooligosaccharide (LOS) forming the outer leaflet. Although LPS/LOS was long considered essential, recent findings challenge this view, leaving the mechanistic basis and evolutionary flexibility unclear. Here, we identify lipid asymmetry as a structural checkpoint that governs access to LOS-independent survival. Using Acinetobacter baumannii as a model, we show that disrupting retrograde phospholipid transport and surface phospholipid degradation destabilizes OM lipid balance, creating a permissive state that enables emergence of LOS-deficient, colistin-resistant variants. Integrated lipidomic and transcriptomic analyses reveal a staged remodeling program that reinforces lipoprotein scaffolds, rewires peptidoglycan synthesis, and expands trafficking pathways to stabilize a glycolipid-free envelope. Critically, loss of LOS coincides with sharp repression of PBP1A, and maintaining its activity blocks adaptation, demonstrating interdependence between OM and peptidoglycan homeostasis. We propose a three-state model--basal, permissive, adapted--that explains how envelope architecture gates evolutionary trajectories to antibiotic resistance. SignificanceColistin is a last-resort antibiotic targeting lipopolysaccharide (LPS) or lipooligosaccharide (LOS) in Gram-negative pathogens, and many emerging antimicrobials aim to inhibit LPS/LOS biosynthesis and transport. Resistance usually arises via lipid A modification, which preserves LPS/LOS while reducing colistin binding. Resistance to colistin can also arise via complete loss of LOS, which occurs in some Acinetobacter baumannii strains but is constrained in others, such as strain ATCC 17978. Here, we demonstrate that LOS essentiality is not fixed but dictated by outer membrane architecture. Disrupting phospholipid homeostasis creates a permissive envelope that allows LOS-deficient, colistin-resistant variants to emerge, while reducing peptidoglycan synthesis further promotes this state. These findings identify lipid asymmetry as a structural checkpoint in resistance evolution and suggest that preserving envelope homeostasis could limit bacterial escape from colistin and guide strategies for next-generation antibiotic development.

microbiology↗

bioRxiv2026

PBP1A and LdtJ support cell envelope homeostasis and impact selection of Colistin-resistance in Acinetobacter baumannii

The multilayered cell envelope of Acinetobacter baumannii is an essential structure that maintains cellular integrity and protects the bacterial cell against external stresses and antibiotics. It consists of an inner membrane, a thin peptidoglycan (PG) layer and an asymmetric outer membrane (OM) enriched in lipooligosaccharide (LOS), whose lipid A moiety is the target of colistin, a last-resource antibiotic. Although lipid A is essential in most Gram-negatives, A. baumannii can survive without LOS through envelope remodeling, particularly in strains producing low levels of the bifunctional penicillin-binding protein PBP1A (encoded by mrcA) or in {Delta}mrcA mutants. Here, we identify a functional interplay between the LD-transpeptidase LdtJ, which generates 3-3 cross-links, and PBP1A, which catalyzes 4-3 transpeptidation during PG synthesis. We show that simultaneous inactivation of both enzymes severely affected growth, viability, morphology, and OM homeostasis. PG analyses revealed that the {Delta}ldtJ {Delta}mrcA mutants displays reduced overall cross-linkage and shorter glycan chains, producing a weakened sacculus. Co-immunoprecipitation demonstrated that PBP1A associates with LdtJ, supporting their coordinated activity at sites of PG synthesis. Notably, {Delta}ldtJ {Delta}mrcA mutants exhibited the highest recovery frequency of colistin-resistant, LOS-deficient variants compared with wild type or single mutants. Together, our findings demonstrate that coupling between 4-3 and 3-3 transpeptidation is critical for envelope stability in A. baumannii and highlight how disrupting this coordination favors the emergence of colistin resistance. This work identifies a conserved PG remodeling vulnerability that directly links PG integrity to the evolution of antibiotic resistance, offering a new conceptual framework for destabilizing the A. baumannii envelope. ImportanceThe global rise of multidrug-resistant Acinetobacter baumannii represents an urgent clinical threat, largely driven by its extraordinary capacity to withstand cell envelope damages and escape last-resort antibiotics such as colistin. Although peptidoglycan synthesis and remodeling are known to influence outer membrane stability, how these processes are coordinated in A. baumannii has remained unclear. Here, we identify a crucial interplay between two critical envelope biogenesis and remodeling activities, 4-3 and 3-3 transpeptidations, mediated by the bifunctional PBP1A and the LD-transpeptidase LdtJ, respectively. Disrupting this coordination weakens the peptidoglycan, destabilizes the outer membrane, and increases the emergence frequency of colistin-resistant, LOS-deficient variants. These findings highlight a previously unrecognized vulnerability in the envelope homeostasis of A. baumannii, suggesting that simultaneously targeting DD and LD-transpeptidation could potentiate therapeutic strategies aimed at limiting antibiotic resistance development.

microbiology↗

bioRxiv2026

Natural statistics of host odours predict species-specific olfactory behaviours in Drosophilids

Animals rely on olfaction to locate food, mates, and suitable habitats, yet natural odour environments contain thousands of volatile molecules, creating a high-dimensional sensory problem for both nervous systems and the researchers who study them 1-5. For example, a banana emits around 100 individual volatiles4,6. It remains unclear which components of complex odour blends animals have evolved to use as behavioural cues. Here, combining fieldwork, chemical and behavioural analyses, we show across multiple Drosophila species that behaviourally relevant cues can be predicted directly from the statistical structure of natural odour environments. Animals preferentially respond to components that are most distinctive within their natural host odour blends, and therefore most ecologically informative. These cues can be either major or minor blend components. Our results indicate that host-guided olfactory behaviours have evolved to exploit the statistical structure of natural odour environments by selectively targeting the most informative features of odour blends.

neuroscience↗

bioRxiv2026

Light-inducible proximity labelling in vivo captures sex-specific RNA at excitatory synapses

Local RNA regulation is essential for synaptic plasticity, yet the full repertoire of RNA species and associated isoforms within specific synaptic compartments in vivo has yet to be determined. Existing RNA profiling approaches lack the spatial and temporal precision needed to resolve RNA repertoires restricted to cell-type specific synaptic compartments. To overcome this challenge, we developed PSD-95-Halo-seq, a light-induced proximity labelling technique that, when combined with long-read sequencing, selectively captures all post-synaptic full length RNA species in the excitatory post-synaptic compartment. Here, we applied this approach to investigate sex differences in RNA expression within excitatory synapses following exposure to an associative fear learning task in C57/Bl6 mice. We found dramatic sex differences in pseudogene and protein coding RNA expression, which are most abundant in females, with males exhibiting multiple noncoding RNA classes, including lncRNA, snoRNA, and rRNA. Females generally showed more 3' UTR expression, and there was widespread differential exon usage following fear conditioning, including 179 isoforms in males, 69 in females, with no significant gene-level differential expression, indicating that behavioural state modifies sex-specific isoform usage rather than overall transcript abundance. Our discovery that synaptic RNA composition is dynamic, sexually dimorphic, and profoundly shaped by experience, offers new insight into previously inaccessible mechanisms underlying sex differences in fear-related learning and memory. PSD-95-Halo-seq is therefore a powerful method for the precise spatiotemporal identification of compartment-and cell-type-specific RNA. One sentence take-awaySynapse-targeted proximity labelling and Long-Read sequencing demonstrate that excitatory post-synapses encode experience through sex-specific, isoform-level RNA remodeling.

neuroscience↗

bioRxiv2026

Constructing the ensemble of representative structures for a protein via neural-surrogate-guided MSA recombination

AO_SCPLOWBSTRACTC_SCPLOWStructural dynamics is essential for the functional and mechanistic illustration of proteins. Previous research attempted to generate diversified protein structures by utilizing the multiple sequence alignment (MSA), but failed to provide physically relevant representative conformations without state annotations. In this work, we propose a framework named ProCEDiS to generate a compact ensemble of representative conformations for the target protein without prior knowledge. Adopting a neural surrogate to assist the exploration of MSA recombination and integrating with AlphaFold2 to model structures, this method can automatically find high-quality, mutually dissimilar conformations for the target sequence. Parallel short-timescale molecular dynamics (MD) simulations on these structure seeds enable quick while crude free energy estimation, from which physically plausible representative states could be identified. In the benchmark on four protein systems, the ProCEDiS + MD pipeline is capable of providing valuable structural dynamics information within acceptable running time.

bioinformatics↗

bioRxiv2026

RodZ acts through MreBCD to activate the elongasome in Escherichia coli

Most bacteria are surrounded by a peptidoglycan (PG) matrix that maintains cell shape and provides protection against turgor pressure. In many rod-shaped bacteria, synthesis of PG along the cell cylinder is organized by the elongasome, also called the Rod complex, which consists of six highly conserved proteins, including the actin-like MreB, the PG synthase complex RodA-PBP2 and three regulatory membrane proteins, MreC, MreD and RodZ. However, how these proteins interact with each other to form the elongasome and synthesize lateral PG remains elusive. In this study, by characterizing MreC mutations affecting elongasome activity in Escherichia coli, we provide evidence that MreC alternates between an active and an inactive state and these mutations affect MreC interaction with PBP2. We also find that RodZ interacts with MreC via a periplasmic region and disruption of this interaction compromises elongasome function. Additionally, we show that the cytoplasmic region of RodZ, which interacts with MreB, work synergistically with activating MreC mutations to promote rod shape formation. These results indicate that RodZ activates the elongasome by initiating two signaling cascades, one in the periplasm via MreCD, and another in the cytoplasm through MreB. This role of RodZ in regulating elongasome activity is analogous to that of FtsN in activating the divisome, suggesting that the mechanisms governing the activation of PG synthesis in cell elongation and division are similar in E. coli. ImportanceThe elongasome, or Rod complex, mediates lateral peptidoglycan synthesis during cell elongation in many rod-shaped bacteria. It consists of the cytoskeletal protein MreB, the peptidoglycan synthase RodA-PBP2, and three regulatory proteins MreCD and RodZ. Although it has been extensively studied, how its activity is controlled remains incompletely understood. Here, we reveal the roles of MreCD and RodZ in regulating elongasome activity in Escherichia coli. Our results indicate that RodZ triggers lateral peptidoglycan synthesis by interacting with MreB in the cytoplasm and MreCD in the periplasm. These interactions likely switch MreBCD to the active state such that they can stimulate the activity of the RodA-PBP2 complex. This regulatory mechanism resembles the activation mechanism of the divisome that mediates septal peptidoglycan synthesis.

microbiology↗

bioRxiv2025

PROX1 loss in adult mouse Schlemm's canal causes permanent ocular hypertension

Glaucoma is associated with ocular hypertension and lowering intraocular pressure is a key objective of glaucoma therapies. Recent studies have established a role for the Schlemms canal endothelium in this pressure increase and have shown it to have a unique, lymphatic-like, hybrid phenotype. However, the role of these lymphatic phenotypes in the adult canal remains uncertain. Long-term functional studies have been limited by systemic importance of lymphatic genes and lack of Schlemms canal-specific animal models. Here, we designed and validated a strategy using 4OH-tamoxifen-loaded nanocarriers to generate targeted, Schlemms canal specific knockout mice lacking lymphatic phenotypes. Using this system, we selectively deleted Prox1, the master transcription factor governing lymphatic fate. Within four weeks, intraocular pressure significantly increased, and ocular hypertension was maintained for at least 24 weeks. Unlike lymphatic vessels, which degenerate following Prox1 deletion, Schlemms canal reverted to a less functional vein-like phenotype with no change in size or morphology. These results highlight the utility of nanocarriers for tissue-specific genetic recombination and demonstrate that changes in lymphatic phenotypes alter intraocular pressure, providing new targets for glaucoma therapy. Moreover, as we found that PROX1 was downregulated with age in human Schlemms canal, these canal-specific conditional Prox1 knockout mice are a valuable new adult-onset model of ocular hypertension that captures key features of age-related human disease.

physiology↗

bioRxiv2025

qcGEM: a graph-based molecular representation with quantum chemistry awareness

AO_SCPLOWBSTRACTC_SCPLOWThe advancement of artificial intelligence (AI) has reshaped drug discovery. AI-based models typically rely on molecular representations for prediction. However, the absence of physically grounded information in mainstream molecular representations not only limits the model performance in practical applications, but also hinders the mechanistic understanding and exploitation by human. To overcome this issue, we introduce qcGEM, a quantum-chemistry-aware graph-based embedding of molecules that incorporates physical priors into molecular representation learning. By integrating quantum chemistry knowledge with a physics-inspired architecture, qcGEM provides a compact, physics-informed molecular representation that supports a diverse range of downstream applications. Particularly, qcGEM demonstrates the state-of-the-art performance across a broad range of molecule-related benchmarks, as evidenced by comprehensive evaluations on 71 tasks including molecular property prediction, activity cliff detection, protein-ligand interaction modeling and opioid drug classification, and simultaneously offers strong interpretability at multiple representation levels. We additionally propose a simplified variant, qcGEM-Hybrid, with substantially accelerated embedding generation and robust performance. Overall, our method provides an advanced molecular representation that will benefit molecule-related modeling and prediction, supporting further progress in AI-aided drug discovery.

biophysics↗

bioRxiv2025

A mobile circular DNA element drives memory-related processes in mice

Extrachromosomal circular DNAs (ecDNAs) are double stranded, closed loop DNA molecules that act independently of the genome. Here we report the discovery of a brain-enriched ecDNA, ecCldn34d, that regulates the transcriptional state of plasticity-related genes and is temporally associated with the stability of fear memories. ecDNA therefore represents a novel class of mobile DNA elements that are involved in experience-dependent neuroadaptation.

neuroscience↗

bioRxiv2025

Local translation of circular RNAs is required for synaptic activity and memory

Circular RNAs (circRNAs) are enriched in synapses and implicated in cognitive processes, and recent studies have shown that circRNAs can encode micropeptides, which suggests that there may be novel synaptic proteoforms in the brain that await discovery. Here we report widespread learning-induced local circRNA translation in the prefrontal cortex of male C57BL/6 mice. More than 1500 synapse-enriched circRNAs contain active IRES elements, with 842 interacting with the ribosome and 241 exhibiting direct evidence of activity-induced translation. We discovered a synapse-enriched micropeptide (P1) that is derived from a single exon circRNA, the mRNA host of which encodes an enzyme associated with protein repair. Although P1 is only a third of the size of the full-length protein, it is locally expressed, enzymatically active, and interacts with plasticity-related proteins, including CaMKII. In addition to direct effects on synaptic activity, targeted P1 knockdown impairs whereas its overexpression enhances fear extinction memory. These findings shed new light on the dark proteome in the brain and reveal local circRNA translation as a novel mechanism of plasticity and memory.

neuroscience↗

bioRxiv2025

qcMol: a large-scale dataset of 1.2 million molecules with high-quality quantum chemical annotations for molecular representation learning

AO_SCPLOWBSTRACTC_SCPLOWRecent advancements in deep learning have greatly prompted the de novo design of drugs and materials. Previous studies have shown that a well-designed molecular representation is critical for improving the accuracy of deep-learning-based molecular property prediction methods. However, the lack of large-scale data enriched with detailed physicochemical information hinders effective learning of an informative molecular representation. To fill this data gap, we introduce qcMol, a dataset consisting of 1.2 million molecules from 95 datasets with high-quality quantum chemical annotations, to facilitate molecular representation learning as well as downstream molecular property prediction. Chemicals in this dataset include drug-like compounds, metabolites and molecules with matched experimental data, covering 247,448 kinds of scaffolds and a broad spectrum of molecular sizes. Each compound in qcMol is annotated with detailed quantum chemical information, obtained through reliable quantum chemical calculations based on B3LYP-D3/def2-SV(P)//GFN2-xTB as well as the follow-up wave function post-analysis. These features are organized into multiple formats, allowing for flexible integration into diversified molecular representation learning frameworks. The broad data distribution, comprehensive quantum chemical annotations and flexible data formats jointly enable qcMol to serve as the pre-training resource as well as the benchmark test set for deep learning models, benefiting the practical in silico drug discovery. qcMol is freely accessible from https://structpred.life.tsinghua.edu.cn/qcmol/.

biophysics↗