Biology subjects

Zhang, L.

Publications and source records attributed to Zhang, L..

At least 379 records · Page 21Linked to original sources

bioRxiv2025

Intra-Tumoral Treg Ablation Unleashes NK Cell-Mediated Control of CD8 T Cell-Resistant Tumors

Cancer cells frequently lose MHC I to evade CD8+ T cell recognition. While Natural Killer (NK) cells are poised to target MHC I-deficient cancer cells, MHC I loss alone is often insufficient to unleash fully effective NK cell responses. Here we show that selective intra-tumoral (IT) ablation of regulatory T (Treg) cells elicited potent antitumor NK cell responses that controlled MHC I-deficient and even MHC I+ cancers. Tregs controlled the activation, maturation, and anti-tumor cytotoxic activity of NK cells within the tumor microenvironment. Mechanistically, IT Tregs prevented the cDC2-dependent induction of IL-2 production by CD4+ Tconv cells that was necessary for NK cell activation. Systemically administered antibodies that selectively depleted IT Tregs similarly empowered NK- dependent tumor control. These findings expand the breadth of Treg-mediated cancer immunosuppression to encompass antitumor NK cells and suggest that targeting Tregs in tumors can control CD8+ T cell-resistant cancers. One Sentence SummaryIT Treg ablation drives NK cell tumor control via CD4+ Tconv-derived IL-2, eliminating MHC I+/MHC I- cancers without systemic toxicity.

immunology↗

bioRxiv2025

Cross-talk between RNA secondary and three-dimensional structure prediction: a comprehensive study

In recent years, various computational methods have been developed to predict the three-dimensional (3D) structures of RNAs. Due to its hierarchical folding property, RNA secondary (2D) structure is usually used as input for 3D structure prediction to improve accuracy and efficiency. However, the extent to which the accuracy of input 2D structure affects the performance of 3D structure prediction remains to be further investigated. Additionally, whether and how the input base-pairing interactions are modified during the 3D structure modeling process is another question worth exploring. To address these issues, here we comprehensively benchmark five representative 3D structure prediction models on extensive datasets, using 2D structures of varied accuracies as input. Our results indicate that there is a pervasive cross-talk between RNA 2D and 3D structure predictions, where the performance dependence of 3D structure prediction on the accuracy of input 2D structure is closely associated with the 3D models ability to modify the input base-pairing interactions during structure modeling. Furthermore, we also observed that RNA 3D structure prediction performance is more sensitive to the occurrence of false positive base pairs in the input 2D structure than to true positive base pairs, suggesting a worthy direction to further improve the model performance. Author summaryThree-dimensional (3D) structural modeling of RNAs with large sizes and complex topologies remains challenging despite the availability of (predicted) 2D structures as constraints. Exploring the potential cross-talk between 2D and 3D structure predictions is a worthy direction to improve the performance of RNA structure modeling. In this study, we found that all tested popular RNA 3D structure prediction models were able to modify the original base pairing interactions contained in the input 2D structure during the 3D modeling process. Especially, all of these models presented increased F1-score for the optimal combination of RNA 2D and 3D structure prediction models. The results suggest that a worthwhile direction to further improve the performance of RNA 3D structure prediction is to minimize the incidence of incorrectly predicted base pairing interactions during modeling process without compromising or even improving the presence of correct interactions in the input 2D structure.

biophysics↗

bioRxiv2025

Genomic Evidence for Males of Exceptional Reproductive Output (ERO) in Apes and Humans

It is widely suspected that a small percentage of males have exceptional reproductive output (ERO) but progeny numbers of males are rarely measurable, even in humans. If we define the variance ratio of reproductive-output in males and females as = VM/VF, the ERO hypothesis would predict >>1. Since autosomal, X, and Y chromosomes are found in males 1/2, 1/3, and 100% of the time, their DNA diversities can inform about . For example, autosomal and Y-linked diversities are governed, respectively, by (VM+VF)/2 and VM. When comparing the chromosomal diversities, appears to be near 20 for chimpanzees and orangutans, and 1-10 for gorillas. The exception is bonobos with < 1. In humans, the extensive genomic data are coupled to a theory, developed herein, that can filter out selection influences on Y-linked diversities. Hence, the estimation of is rigorous, yielding values near or above 20, depending on the population. When >10, the presence of ERO males is very likely. These analyses can be applied more generally to species with XY sex determination.

evolutionary biology↗

bioRxiv2025

ContrastQA: A Label-guided Graph Contrastive Learning-based approach for protein complex structure quality assessment

Despite recent progress, the Estimation of Model Accuracy (EMA) for protein complexes remains less advanced compared to that for protein monomers. A key challenge lies in effectively integrating both interface-specific and global structural information to accurately assess the quality of protein complexes. Here, we introduce ContrastQA, the first EMA framework for protein complexes that incorporates the proposed label-guided graph contrastive learning based on interface quality. By integrating a geometric graph neural network to model global structural features, ContrastQA effectively captures both local (interface-level) and global (structure-level) information for accurate model quality estimation. ContrastQA achieved ranking losses of 0.123 and 0.116 on the TMscore and GDT-TS metrics on the CASP16 dataset, which are 0.015 (10.9%) and 0.012 (8.7%) lower than the second-best EMA method with ranking losses of 0.138 and 0.128. Furthermore, for the more challenging CASP16 hard targets, our method achieved a TMscore ranking loss of 0.131, which is 0.023 (14.9%) lower than that of the second-best EMA method with a ranking loss of 0.154. Our study demonstrates the strong effectiveness of the label-guided graph contrastive learning module. These findings suggest that our graph contrastive learning framework serves as a valuable pre-training strategy for learning protein structure representations. The source code is available at https://github.com/Cao-Labs/ContrastQA. Significance StatementHigh-quality proteins generated by high-precision structural prediction methods for protein complexes helping biologists prioritize models for drug discovery and understanding disease mechanisms. Recent advances in predicting protein complex structures (like AlphaFold3) still struggle to match experimental precision. A critical bottleneck lies in accurately estimating the quality of predicted models-known as Estimation of Model Accuracy (EMA). Here, we introduce ContrastQA, implementing label-guided graph contrastive learning framework to explore the generalization of high-quality proteins. Our method demonstrates outstanding performance, provides an effective solution for assessing the structural quality of protein complexes.

bioinformatics↗

bioRxiv2025

Genomic analysis identifies Campylobacter concisus genomospecies 2 as a novel species and proposes the name Campylobacter oralis

Campylobacter concisus comprises two distinct genomospecies (GS) based on core genome analysis. Here we conducted further analysis and demonstrated that C. concisus GS2 strains belong to a novel Campylobacter species. A total of 245 C. concisus genomes including 85 GS1 and 160 GS2 strains were analysed. DNA-DNA hybridization (DDH) values between strains of GS1 and GS2 C. concisus were from 42.8% to 66%. Average Nucleotide Identity (ANI) between GS1 and GS2 C. concisus strains were from 87.8% to 89.7%. The average GC contents of GS1 and GS2 C. concisus strains were 37.3% and 39.2% respectively. GS1 and GS2 specific genes have been identified. GS1 and GS2 C. concisus strains can also be differentiated based on core genome, 23S rRNA polymorphisms and protein profiles. Their morphology appears different under certain conditions. In conclusion, ANI and DDH values clearly support that C. concisus GS2 as a novel Campylobacter species, for which we propose the name Campylobacter oralis. The identification of C. concisus and C. oralis specific genes, along with differences in their protein profiles, morphology, core genome and 23S rRNA phylogeny, further support this classification.

microbiology↗

bioRxiv2025

Proteolytic processing of the Marburg virus glycoprotein depends on Sec616β and is required for cell entry

Ebola and Marburg virus (EBOV, MARV) cause severe disease and therapeutic options are urgently needed. The Sec61 translocon facilitates ER import of viral glycoproteins (GPs) and may represent a therapeutic target. Here, we report that the Sec61 subunit Sec61{beta}, although dispensable for GP expression, is required for proteolytic cleavage of MARV- but not EBOV-GP and that an intact furin motif is essential for robust cell entry of Marburg- but not Ebolaviruses. Further, MARV- but not EBOV-GP was cleaved by the furin-related enzyme SKI-1, for which a cleavage motif was identified in silico, and cleavage by SKI-1 was impaired in SEC61B-KO cells. In addition, Sec61{beta} was required for normal N-glycosylation of MARV-GP and mutation of a sequon (N563D) abrogated cleavage. Finally, the absence of Sec61{beta} modestly, and blockade of Sec61 via apratoxin S4 markedly, inhibited EBOV and MARV infection. These results reveal a differential protease dependence of MARV and EBOV and identify Sec61 as a potential therapeutic target. Author summaryThe filoviruses Ebola virus (EBOV) and Marburg virus (MARV) spread from animals to humans and can cause deadly outbreaks. These viruses rely on a surface glycoprotein (GP) for infection, which is processed by the enzyme furin in infected human cells. Cleavage of EBOV-GP was thought to be non-essential for infection. However, using lab models for filovirus entry into cells, we discovered that MARV, unlike EBOV, needs this cleavage step to infect cells efficiently. We also found that the host cell protein Sec61{beta} is necessary for proteolytic processing and glycosylation of MARV-GP but not EBOV-GP. In addition, we showed that another cellular enzyme, SKI-1, can process MARV- but not EBOV-GP. Finally, we found that removing Sec61{beta} or blocking Sec61 activity reduced infection by both viruses. These findings show key differences in how the two viruses interact with host cells and suggest that targeting Sec61 could be a promising new strategy to fight Ebola and Marburg virus infections.

microbiology↗

bioRxiv2025

Mycobacterial Metallophosphatase MmpE Acts as a Nucleomodulin to Regulate Host Gene Expression and Promote Intracellular Survival

Mycobacterium tuberculosis, the causative agent of tuberculosis, remains a major global health challenge. Nucleomodulins, bacterial effectors that target the host cell nuclei, are increasingly recognized as key virulence factors, but their roles in mycobacterial pathogenesis remain incompletely elucidated. Here, we characterize a hypothetical protein Rv2577 (designated MmpE) not only as a Fe3+/Zn2+-dependent metallophosphatase but also as a critical nucleomodulin involved in immune evasion and intracellular persistence. MmpE utilizes two nuclear localization signals, RRR20-22 and RRK460-462, to enter the host cell nucleus, where it binds to the promoter region of the vitamin D receptor (VDR) gene, thereby inhibiting host inflammatory gene expression. Additionally, MmpE regulates the PI3K-Akt-mTOR signaling pathway, thereby arresting lysosome maturation. These actions collectively facilitate immune suppression and promote mycobacterial survival in macrophages and in mice. Our findings identify MmpE as a conserved nucleomodulin in mycobacteria and reveal a novel mechanism of MmpE-mediated intracellular survival.

microbiology↗

bioRxiv2025

MF-ProtDisMap: protein real-valued distance prediction with fusion of sequence and coevolutionary features

The precise estimation of protein inter-residue distances is essential for high-accuracy protein structure modeling. Currently, the prediction methods are predominantly based on MSA-derived coevolutionary features or language model-based sequence features. To effectively leverage the strengths of both methods, this study developed MF-ProtDisMap (Multi-Feature Protein Distance Map), an integrative framework that effectively combines both feature types to achieve superior real-valued distance prediction. Briefly, MSA Transformer is employed to extract the coevolutionary features from protein multiple sequence alignments, whereas ESM2 is used to capture long-range interactions and sequence-level features. To reduce the computational cost while maximumly represent fused feature information, we implement group pooling for feature dimensionality reduction and introduce Diff-former--a novel module combining a diffusion model with a triangular attention mechanism to enhance representation learning. MF-ProtDisMap achieved a MAE of 2.20 [A] and an RMSE of 3.40 [A] in the protein real-valued distance prediction task. The predicted distances can be converted into contact results, achieving ROC and PR values of 84.56% and 81.01%, respectively. These results demonstrate that MF-ProtDisMap outperforms state-of-the-art real-valued protein distance methods.

bioinformatics↗

bioRxiv2025

Spleen-derived Small Extracellular Vesicles Protect against Myocardial Infarction via Mediating Spleen-heart Crosstalk

Background and AimsAcute myocardial infarction (AMI) triggers systemic responses that influence cardiac injury and repair, but protective mediators within the cardiosplenic axis remain incompletely understood. This study aimed to investigate whether spleen-derived small extracellular vesicles (sEVs) exert cardioprotection after AMI, identify critical cargo, and evaluate their clinical relevance. MethodsThe effects of splenectomy, spleen-derived sEVs and pharmacological inhibition of sEVs biogenesis on cardiac injury were evaluated in mice with AMI. Parabiosis, donor splenectomy, and fluorescent labelling traced the origin and myocardial recruitment of circulating sEVs. 4D-proteomics profiled sEVs cargo with a focus on pyruvate carrier-1 (MPC1). ResultsSplenectomy worsened survival, ventricular function, infarct size, and fibrosis in mice with AMI. AMI upregulated splenic extracellular-vesicle pathways, with sEVs release peaking at day 3 (M3D-sEVs). Labelled splenic sEVs preferentially accumulated in ischemic myocardium, confirmed by parabiosis experiments. M3D-sEVs improved survival and cardiac function and reduced infarct size, fibrosis, apoptosis, inflammation, and hypertrophy. In addition, anti-apoptotic effects were reproduced in vitro. Inhibition of sEVs biogenesis decreased circulating sEVs, aggravated injury, and was rescued by M3D-sEVs. M3D-sEVs were enriched in MPC1, and MPC1 neutralization or pharmacological blockade abrogated sEVs-mediated restoration of respiration, ATP generation, and reduction of reactive oxygen species. Plasma sEVs-associated MPC1 was highest in patients with AMI, intermediate in coronary heart disease, and lowest in controls. ConclusionsThe spleen responds adaptively to AMI by releasing MPC1lenriched sEVs that travel to injured myocardium, preserve mitochondrial energetics, and reduce damage, supporting cargolspecific sEVs augmentation and sEVslMPC1 as a potential therapeutic target and biomarker in ischemic heart disease. Structured graphical abstractAcute myocardial infarction activates a spleen-heart axis in which the spleen releases mitochondrial pyruvate carrier 1 (MPC1) enriched small extracellular vesicles that home to the infarcted myocardium, preserve mitochondrial oxidative phosphorylation, reduce ROS, and limit infarct size, apoptosis, fibrosis, and hypertrophy. Circulating sEVs-associated MPC1 might serve as a potential biomarker for estimating risk of ischemic heart disease. Translational perspectiveO_LIOur findings reveal a novel heart-spleen communication axis mediated by splenic small extracellular vesicles (sEVs) following AMI. These vesicular messengers predominantly deliver mitochondrial pyruvate carrier 1 (MPC1), enhancing cardiac mitochondrial energy metabolism in the injured myocardium, ultimately improving post-AMI functional recovery in experimental models. C_LIO_LIA higher plasma sEVs-associated MPC1 level was observed in AMI patients when compared with non-AMI patients. These findings support the clinical relevance of the spleen-heart axis, introduce sEVs-associated MPC1 as a potential circulating biomarker for early myocardial injury and therapeutic target. C_LI

molecular biology↗

bioRxiv2025

MimicNeoAI: An integrated pipeline for identifying microbial mimicry antigens and tumor neoantigen partners

Tumor-associated microbial antigens represent promising immunotherapy targets, yet systematic identification methods remain underdeveloped. We developed MimicNeoAI, a computational pipeline integrating BiLSTM networks to identify microbial epitopes, mutation-derived neoepitopes, and their microbial mimics from sequencing data. Training on validated epitope datasets yielded 0.90 AUC with 91% accuracy on experimental validation sets. Application to colorectal cancer revealed that microbial epitopes, despite originating from a nine-fold smaller peptide pool, generated twice the immunogenic candidates (153 vs 75) compared to mutation-derived neoepitopes. These microbial epitopes exhibited exclusive tumor-specificity with no overlap in normal tissues. Single-cell TCR sequencing confirmed clonal expansion against 75% of predicted highly immunogenic epitopes, with molecular dynamics simulations demonstrating positive correlation between predicted immunogenicity and HLA-epitope-TCR binding stability. Collectively, our pipeline systematically unveils abundant, tumor-specific, and highly immunogenic microbial epitopes, providing a computational framework for developing broadly applicable cancer immunotherapies that leverage the tumor microbiome as an untapped source of therapeutic targets.

bioinformatics↗

bioRxiv2025

Pathogenicity and transmissibility of Monkeypox virus in dormice

The global spread of the monkeypox virus (MPXV) poses a significant challenge to public health, yet reliable and consistent animal models for evaluating MPXV remain limited, which to some extent restricts the advancement of treatment strategies and transmission-blocking technologies. As natural hosts, African dormice (Graphiurus spp.) represent promising candidates. However, the biological characteristics of MPXV in dormice remain largely unexplored. This study systematically evaluated the pathogenicity and transmissibility of MPXV in dormice. Experimental results demonstrated that dormice are highly susceptible to MPXV infection. Following intranasal inoculation, MPXV induced significant weight loss, lethal infections, and multi-organ pathological damage, with robust viral replication in respiratory and liver tissues. Notably, MPXV can efficiently transmit among dormice through direct contact, with one-third of the contact-exposed dormice shedding infectious viruses and two-thirds exhibiting seropositivity. In addition, one-third of the airborne exposure dormice show seropositivity, yet no infectious viruses were detected in their respiratory tissues, indicating that the airborne transmissibility of MPXV among dormice is relatively restricted. Furthermore, it was observed that infected dormice continuously released large quantities of virus-laden aerosols, with emissions peaking on 12 dpi (3.78{+/-}1.01x106 copies/dormouse/hour of respiration). Particle size analysis revealed that the viral copies in [≥]7 m coarse particles accounted for >90.9% of exhaled viral aerosols during peak shedding (8-14 dpi). These findings demonstrate that the African dormice serve as an effective animal model for assessing MPXV infection, pathogenicity, and transmission dynamics. Simultaneously, enhanced monitoring of wild dormouse populations is critical due to their potential role in MPXV transmission chains.

microbiology↗

bioRxiv2025

Differential reliance on sensory reinstatement and internally transformed representation during vivid retrieval of visual and auditory episodes

Auditory memory is considered less detailed yet more durable than visual memory, implying a modality-specific memory retrieval process. We used fMRI and multivoxel pattern analyses to examine how 25 participants encoded and retrieved naturalistic sounds and videos. Both auditory and visual targets reinstated item-specific fine activation patterns in the association cortex during retrieval, and reinstatement strength correlates with subjective memory vividness. However, auditory episodes showed a markedly larger reliance on internally constructed representations than visual episodes, quantified by retrieval-retrieval similarity after removing encoding traces. Sensory reinstatement correlated more to the (detail-related) posterior hippocampus, while internal representations also correlated to the (gist-related) anterior hippocampus. Furthermore, temporal voice areas preserved gist-level (human versus non-human) information from encoding to retrieval, whereas fusiform face representations degraded. These findings reveal that auditory and visual memories share a common sensory reinstatement mechanism, but differ in the neural mechanism that supports retrieval, with participants favouring gist over perceptual details during auditory memory retrieval.

neuroscience↗

bioRxiv2025

The Spatial Atlas of Human Anatomy (SAHA): A Multimodal Subcellular-Resolution Reference Across Human Organs

The Spatial Atlas of Human Anatomy (SAHA) represents the first multimodal, subcellular- resolution reference of healthy adult human tissues across multiple organ systems. Integrating spatial transcriptomics, proteomics, and histological features across over 15 million cells from more than 100 donors, SAHA maps conserved and organ-specific cellular niches in gastrointestinal and immune tissues. High-resolution profiling using CosMx SMI, 10x Xenium, RNAscope, GeoMx DSP, and single-nucleus RNA-seq reveals spatially organized cell states, rare adaptive immune populations, and tissue-specific cell-cell interactions and ligand-receptor pairs. Comparative analyses with colorectal cancer and inflammatory bowel disease demonstrate the power of SAHA to detect disease-associated spatial disruptions, including crypt dedifferentiation, perineural invasion, and therapy-resistant immune remodeling. All data are openly accessible through a FAIR-compliant interactive portal to support exploration, benchmarking, and machine learning model training. Through SAHA, we provide a foundational framework for spatial diagnostics and next-generation precision medicine grounded in a comprehensive human tissue atlas, enabling the development of context-aware models that simulate tissue behavior, decode complex pathologies, and accelerate therapeutic innovation at unprecedented scale.

systems biology↗

bioRxiv2025

Two Specialized Intrinsic Cardiac Neuron Types Safeguard Heart Homeostasis and Stress Resilience

The intrinsic cardiac nervous system (ICNS), often referred to as "the little brain on the heart", plays a central role in heart-brain communication and is increasingly recognized as both a contributor to cardiac disorders, including atrial fibrillation, heart failure, and sudden cardiac death, and a growing target for therapeutic intervention. Despite its clinical relevance, the molecular and functional organization of the ICNS remains poorly understood. Using single-cell transcriptomics, high-resolution imaging, and cell-specific genetic tools in mice, we identified two molecularly distinct intrinsic cardiac neuron (ICN) subtypes marked by Npy and Ddah1, each exhibiting unique anatomical innervation patterns. Npy ICNs function as parasympathetic postganglionic neurons essential for maintaining coronary perfusion and cardiac homeostasis during routine physiological activity. In contrast, Ddah1 ICNs are crucial for preserving cardiac electrical stability and preventing sudden death under extreme stress. These findings uncover specialized ICNS pathways that support cardiac homeostasis and resilience, providing a foundation for developing targeted neurocardiac therapies for autonomic dysfunction in human heart disease.

neuroscience↗

bioRxiv2025

Ultra-wide-field, deep, adaptive two-photon microscopy

Observing the activity patterns of large neural populations throughout the brain is essential for understanding brain function. However, capturing neural interactions across widely distributed brain regions from both superficial and deep cortical layers remains challenging with existing microscopy technologies. Here, we introduce a state-of-the-art two-photon microscopy system, ULTRA, capable of single-cell resolution imaging across an ultra-large field of view (FOV) exceeding 50 mm{superscript 2}, enabling deep and very wide field in vivo imaging. To demonstrate its capabilities, we conducted a series of experiments under multiple imaging conditions, successfully visualizing brain structures and neuronal activities spanning a spatial range of over 7 mm from superficial layers to depths of up to 900 m, while covering a volume of 45.24 mm3 in the mouse brain. This versatile imaging platform overcomes traditional spatial constraints, providing a powerful tool for comprehensive exploration of neuronal circuitry over extensive spatial scales with cellular resolution.

neuroscience↗

bioRxiv2025

Altered susceptibility of rare yeast species causing vulvovaginal candidiasis at acidic vaginal environment

This study evaluated potency of antifungals against the rare emerging yeast causing VVC under the influence of acid pH (4.5). The antifungal susceptibility was evaluated by CLSI-M27A4 for 25 isolates represented 11 rare yeast species recovered from VVC patients. Among 11 yeast species (25 isolates), Clavispora lusitaniae (n=9) was the most common species, followed by Cyberlindnera fabianii (n=4), Kodamaea ohmeri, Candida metapsilosis and Candida bracarensis (n=2, respectively), Pichia norvegensis, Kluyveromyces marxianus, Diutina rugosa, Tricholoma matsutake, Candida nivariensis and Candida africana (n=1, respectively). The antifungal agents most affected by a lower pH were terconazole (4-fold higher, MIC >0.5-8mg/L) to all 11 yeast species; followed by amphotericin B (3-fold higher, MIC >2mg/L) to 9 species except K. ohmeri and D. rugose; nystatin (2-fold higher, MIC >2 - 4 mg/L) to 9 species except C. nivariensis and C.africana; micafungin (2-fold higher, MIC >0.125 - 1 mg/L) to 8 species except C. metapsilosis, D. rugosa and Tricholoma matsutake by acid pH, respectively. 5-flucytosine was not affected by pH to all tested yeast species, and maintained activity at low PH. The rare yeast species tested shared high MICs of terconazole, amphotericin B, nystatin at pH4.5 compared with those at pH7.0. The in vitro antifungal susceptibility at pH 7.0 did not consistently predict the activity of antifungals against those rare yeast species at vaginal acidic pH. Further investigations assessing the clinical utility of antifungal susceptibility testing should take these findings into consideration.

microbiology↗

bioRxiv2025

Hyperpolarization activated cation channel mediated intrinsic plasticity changes underlie the malleability of with-in cell-type electrophysiological heterogeneity

Within cell-type neuronal electrophysiological, morphological, and transcriptomic heterogeneity is the norm in the brain. Although generally considered a fixed property within cell-types, this heterogeneity is malleable and declines in regions of the human brain that generate seizures. Building off this foundational work we hypothesize that such plasticity of cell-type heterogeneity, specifically its decline, arises from the shared history of neuronal activity that drive intrinsic plasticity mechanisms in a concerted fashion. To explore this hypothesis we study neuronal activity in two model systems: human cortical slice cultures from patients with epilepsy as well as slices from the medial prefrontal cortex (mPFC) and subiculum of rodent kainic acid (KA) model of temporal lobe epilepsy. Biophysical properties and spiking dynamics were characterized using whole-cell patch clamp recordings of layer 2 and layer 3 (L2&3) pyramidal neurons in human slice culture as well as deep layer subicular neurons and layer 5 (L5) mPFC of KA mice. We found a significant decline in biophysical heterogeneity and a reduction in information coding in both the KA and slice culture models. In both these models we found a consistent increase in hyperpolarization-activated cation current (HCN) dependent electrophysiological properties, the blockade of which restored electrophysiological heterogeneity and information coding. Our findings demonstrate that within cell-type heterogeneity is malleable, and despite being a complex distributed network property, can be tuned by a single ionic current. These findings emphasize the plasticity of within cell-type heterogeneity, suggesting the potential for targeted interventions to restore neuronal heterogeneity changes that accompany epilepsy and potentially other neurological and neuropsychiatric diseases.

neuroscience↗

bioRxiv2025

A Cryptic Interfacial Pocket Uncovered in Full CRL4CRBN-IKZF3 Ubiquitylation Complex Enhances IMiD Efficacy

Immunomodulatory imide drugs (IMiDs) redirect the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ligase to ubiquitylate and degrade disease-linked proteins, but the full picture of how IMiDs glue the neosubstrate within the whole CRL4CRBN complex remains unknown. We determined cryo-electron microscopy structures of eight approved or clinical IMiDs in full CRL4CRBN ubiquitylation complexes at resolutions up to 3.4 [A], and revealed how these structurally distinct IMiDs exploit the structural plasticity of CRL4CRBN to organize conformationally conserved and compact active ubiquitylation assemblies with the neosubstrate IKZF3. Four "next-generation" IMiDs were found to additionally engage a cryptic gluing-driven interfacial (GDI) pocket at the non-degron zinc finger 3 (ZF3) of IKZF3, which contributes to their enhanced efficacy and neosubstrate specificity. The identification of cryptic gluing-driven pockets formed only in full ubiquitylation complexes provides new structure-directed design opportunities for IMiDs to improve therapeutic efficacy.

biochemistry↗