Biology subjects

Zhu, R.

Publications and source records attributed to Zhu, R..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

A photostable genetically encoded voltage indicator for imaging neural activities in tissue and live animals

Genetically encoded voltage indicators (GEVIs) enable noninvasive, high-speed monitoring of electrical activity but are constrained by limited brightness and rapid photobleaching under continuous illumination. Here, we present Vega, a highly photostable green fluorescence GEVI with both high sensitivity ({Delta}F/F = -33% per 100 mV) and fast response (1.34 ms). Under one-photon excitation at 1 W/cm2, Vega exhibits more than 20-fold slower photobleaching than the spectrally similar GEVI, Ace-mNeon2. In acute mouse brain slice, Vega enabled wide-field high-fidelity recording of action potentials from 51 neurons simultaneously. In pancreatic islets, it revealed heterogeneous {beta}-cell activation and intercellular coupling in response to glucose elevation. Finally, one-photon imaging in awake mice demonstrated stable cortical voltage mapping in vivo. Vega thus overcomes the longstanding photostability-performance trade-off, enabling chronic, high-fidelity voltage imaging across preparations.

bioengineering↗

bioRxiv2025

From cognition to compensation: Neurocomputational mechanisms of guilt-driven and shame-driven altruistic behavior

Guilt and shame are key moral emotions that influence mental health and regulate social behavior. Although prior research has examined the psychological and neural correlates of these emotions, the cognitive antecedents that trigger them, as well as their transformation into social behavior, remain insufficiently understood. In this study, we developed a novel task to investigate how two crucial cognitive antecedents, harm and responsibility, elicit guilt and shame, and how these emotions subsequently drive compensatory behavior, by combining functional magnetic resonance imaging (fMRI) with computational modeling. Behaviorally, we found that harm had a stronger impact on guilt than on shame, whereas responsibility had a stronger impact on shame than guilt, which supports the functionalist theory of emotion. Moreover, compared to shame, guilt exerted a greater effect on compensation. Computational modeling results indicated that the integration of harm and responsibility by individuals is consistent with the phenomenon of responsibility diffusion. The fMRI results revealed that brain regions associated with inequity representation (posterior insula) and value computation (striatum) encode this integrated measure. Furthermore, individual differences in responsibility-driven shame sensitivity were associated with activity in theory-of-mind regions (temporoparietal junction and superior temporal sulcus). Guilt- and shame-driven compensatory behavior recruited distinct neural substrates, with shame-driven compensatory sensitivity being more strongly linked to activity in the lateral prefrontal cortex, a region implicated in cognitive control. Our findings provide computational, algorithmic, and neural accounts of guilt and shame.

neuroscience↗

bioRxiv2025

Optimizing electrode placement and information capacity for local field potentials in cortex

Recent neurosurgery advancements include improved stereotactic targeting and increased density and specificity of electrophysiological evaluation. This study introduces a subject-specific, in silico modeling tool for optimizing electrode placement and maximizing coverage with a variety of devices. The basis for optimization is the Shannon-Hartley information capacity of field potentials derived from dipolar sources. The approach integrates subject-specific MRI data with finite element modeling (FEM) used to simulate the sensitivity of subdural and intracortical devices. Sensitivity maps, or lead fields, from these models enable the comparison of different electrode placements, contact sizes, contact configurations, and substrate properties, which are often overlooked factors. One key tool is a genetic algorithm that optimizes electrode placement by maximizing information capacity. Another is a sparse sensor method, Sparse Electrode Placement for Input Optimization (SEPIO), that selects the best sensor subsets for accurate source classification. We demonstrate several use cases for clinicians, engineers, and researchers. Overall, these open-source tools provide a quantitative framework to select devices from a neurosurgical armament and to optimize device and contact placement. Using these tools may help refine electrode coverage with low channel count devices while minimizing the burden of invasive surgery. The study demonstrates that optimized electrode placement significantly improves the information capacity and signal quality of local field potential (LFP) recordings. The tools developed offer a valuable approach for refining neurosurgical techniques and enhancing the design of neural implants. HighlightsO_LItool for simulating subject-specific local field potentials and electrode sensitivity. C_LIO_LIptimized electrode placement enhances ROI source coverage, and signal quality. C_LIO_LIsensor-based classification boosts data quality without extra electrode cost. C_LIO_LIcomparisons of devices and contact arrangements. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/650658v3_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a3a7aaorg.highwire.dtl.DTLVardef@154a776org.highwire.dtl.DTLVardef@be4826org.highwire.dtl.DTLVardef@72caa9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

The influence of ceftriaxone, ceftazidime-avibactam, and piperacillin-tazobactam on the gut microbiota

PurposeThe administration of antibiotics can induce dysbiosis of the gut microbiota, leading to diseases, e.g., irritable bowel syndrome, metabolic syndrome, and Clostridium difficile infection. However, the specific effects of different {beta}-lactam antibiotics on the dysbiosis of the gut microbiota remain poorly understood, particularly in human studies. MethodsThis study assessed the impacts of ceftriaxone, ceftazidime-avibactam, and piperacillin-tazobactam on the diversity, composition, and bacterial interactions within the gut microbiota at days 1, 6, and 37 after administration. ResultsAll three antibiotics significantly altered beta diversity of the gut microbiota by day 6, with ceftriaxone showing the most prolonged effects. Changes in the composition of the gut microbiota were more similar between the ceftazidime-avibactam and piperacillin-tazobactam groups and differed markedly from those in the ceftriaxone group. Consistent with beta diversity changes, bacterial interaction networks showed greater and longer-lasting disruptions of bacterial interaction in the gut microbiota in the ceftriaxone group compared to the ceftazidime-avibactam and piperacillin-tazobactam groups. ConclusionThese findings highlight distinct patterns of microbiota disruption following ceftriaxone, ceftazidime-avibactam, and piperacillin-tazobactam treatments and provide insights for mitigating dysbiosis of the gut microbiota during {beta}-lactam therapy.

microbiology↗

bioRxiv2025

DeepSeMS: a large language model reveals hidden biosynthetic potential of the global ocean microbiome

Microbial biosynthetic diversity holds immense potential for discovering natural products with therapeutic applications, yet a substantial quantity of natural products derived from uncultivated microorganisms remains uncharacterized. The intricate nature of biosynthetic enzymes poses a major challenge in accurately predicting the chemical structures of secondary metabolites solely based on genome sequences using current rule-based methods. Here, we present DeepSeMS, a large language model designed to predict the chemical structures of secondary metabolites from various microbial biosynthetic gene clusters. Built on the Transformer architecture, DeepSeMS innovatively identifies sequence features using functional domains of biosynthetic enzymes, and incorporates feature-aligned chemical structure enumeration for training data augmentation. External evaluation results show that DeepSeMS predicts more accurate chemical structures of secondary metabolites with a Tanimoto coefficient up to 0.6 compared with the ground truth, significantly outperforming antiSMASH and PRISM with coefficients of only 0.14 and 0.45 respectively. Moreover, DeepSeMS successfully predicted secondary metabolites for 96.60% of cryptic biosynthetic gene clusters, surpassing existing methods with success rates less than 50%. Leveraging DeepSeMS, we characterized over 65,000 novel secondary metabolites from the global ocean microbiome with previously undocumented structural types, ecological distribution, and biomedical applications especially antibiotics. A login-free and user-friendly web server for DeepSeMS (https://biochemai.cstspace.cn/deepsems/) has been launched, featuring an integrated global ocean microbial secondary metabolites repository to expedite the discovery of novel natural products. Collectively, this study underscores the great capacity of a large language model-driven method in revealing hidden biosynthetic potential of the global ocean microbiome.

synthetic biology↗

bioRxiv2025

Inducible re-epithelialization of cancer cells increases autophagy and DNA damage: implications for breast cancer dormancy

Epithelial lineage differentiation is pivotal to mammary gland development and it can pause metastasis of breast cancer (BC) by inducing tumor dormancy. To simulate this, we expressed epithelial genes in mesenchymal BC cells. Inducible expression of the epithelial OVOL genes in metastatic BC cells suppressed proliferation and migration. We found that C1ORF116, an OVOLs target, is susceptible to genetic and epigenetic aberrations in BC. It is regulated by steroids and functions as a putative autophagy receptor that inhibits antioxidants like thioredoxin. Accordingly, boosting epithelialization lowered glutathione, elevated reactive oxygen species and increased both DNA oxidation and double strand breaks. Epithelialization also associated with redistribution of NRF2 and an altered interplay among p38, ATM, and the other kinases regulating the DNA damage response. Hence, hormonal regulation of OVOLs and chronic stress might permit epithelial differentiation and retard exit from dormancy, while altering redox homeostasis and permitting DNA damage accumulation, which may awaken dormant tumors.

cancer biology↗

bioRxiv2025

Avoidance of pyroptosis accounts for the relatively high metastatic potential observed in early hybrid EMT states

EMT converts epithelial (E) phenotypes to invasive mesenchymal (M) states. However, analyses of circulating tumor cells (CTCs) indicated that biphenotypic (E+M) CTCs better correlate with metastasis. Similarly, investigations of murine tumors undergoing EMT concluded that early E+M states posses the highest metastatic potential. To explore this, we selected in animals with breast cancer CTCs having progressively increasing intravasation abilities. This revealed that downregulation of arrestin Arrdc4 associates with CTC aggressiveness. In xenografts, depleting Arrdc4 accelerated tumor progression, whereas overexpression hindered progression in immunocompetent, but not in immunocompromised mice. Mechanistically, high Arrdc44 suppresses glucose uptake and enhances gasdermin E, triggering pyroptosis a type of pro-inflammatory cell death. Consistently, Arrdc4s lowest levels characterize the most metastatic biphenotypic states. In patients, both epigenetic and chromosomal aberrations downregulate ARRDC4 and predict poor prognosis. In summary, the uncovered mechanism portrays pyroptosis of biphenotypic EMT cells as a rheostat of CTCs, which may resolve the controversy on the role played by EMT in metastasis.

cancer biology↗

bioRxiv2025

Sparse Sequencing permits accurate and efficient quantification of genome-wide cytosine modification levels

5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) regulate gene expression and exhibit dynamic levels during development and disease. While high-depth, base-resolution studies offer the most detailed view of epigenetic landscapes, many open questions are answered by surveying changes in 5mC/5hmC levels across larger cohorts. Nonetheless, current global quantification methods, including mass spectrometry, are typically limited in accessibility, accuracy, or throughput. Here, to evaluate the viability of low-coverage sequencing as an alternative, we first computationally downsampled deeply sequenced data to resolve the three-way relationship between sequencing coverage, modification levels, and measurement error. This relationship allowed us to develop a facile online tool for error calculation and to define experimental targets: <0.24% genome coverage can quantify 5mC and low-abundance 5hmC with minimal and predictable errors (<5%). Importantly, in direct comparisons, low-depth sequencing (Sparse-Seq) demonstrated high accuracy and less variability than mass spectrometry, while distinctively preserving genomic context. Applied serially to developing mouse brains, Sparse-Seq revealed an earlier emergence of 5hmCpG compared to 5mCpH and uncovered previously overlooked, genomic feature-specific epigenetic changes. This work establishes a rigorous foundation for employing Sparse-Seq as a highly accessible approach for 5mC/5hmC quantification, enabling economical first-pass analysis of epigenetic landscapes suited for large cohort studies and new hypothesis generation.

genomics↗

bioRxiv2024

N-Amino Peptide-Graphene Quantum Dot Loaded Small Extracellular Vesicles for Targeted Therapy of Tauopathies

Tauopathies, a group of neurodegenerative disorders, are characterized by the abnormal aggregation of tau proteins into neurofibrillary tangles (NFTs), driving synaptic dysfunction, neuronal loss, and disease progression through tau aggregate propagation. Graphene quantum dots (GQDs) functionalized with D- cysteine (D-GQDs) have shown promise in inhibiting tau aggregation and transmission via {pi}-{pi} stacking and electrostatic interactions with tau proteins. However, the non-specific binding of GQDs to various proteins in the physiological environment, such as serum albumin, limits their clinical translation. In this study, we aim to enhance the specificity of D-GQDs toward tau protein by incorporating a tau-targeting N- amino peptide, mxyl-NAP2. The mxyl-NAP2/D-GQD complex demonstrated improved selectivity for tau protein over serum albumin, effectively enhancing the inhibition of tau aggregation. To further minimize off-target effects and optimize therapeutic delivery, we loaded the mxyl-NAP2/D-GQD complex into small extracellular vesicles (sEVs), followed by functionalization of sEVs with neuron targeting ligand, rabies viral glycoprotein peptides. This strategy not only reduced off-target effects, but also enhanced uptake by neuron cells, which further improved inhibition of tau transmission between neurons. Our results indicated that mxyl-NAP2/D-GQD-loaded sEVs hold great promise for overcoming the off-target limitations of D- GQDs and advancing the development of precision therapeutics for neurodegenerative diseases.

bioengineering↗

bioRxiv2024

Deficits in forelimb reach learning in a mouse model of Fragile X syndrome

Fragile X syndrome is a leading cause of intellectual disability and autism spectrum disorder, for which therapies are limited. A mouse model of Fragile X syndrome, the Fmr1 knockout (KO) mouse, has been particularly valuable for interrogating the molecular, cellular, and circuit mechanisms that underlie the neurological deficits seen in this syndrome. Key deficits in Fragile X syndrome include impairments in social behaviors, cognition, and motor learning. Given the difficulties in extrapolating more complex human behaviors to mouse models, simple motor behaviors are a particularly tractable form of learning to study in the mouse. We investigated a form of forelimb reach learning in Fmr1 KO mice, precisely quantifying different parameters of the task using both manual analysis and DeepLabCut-based tracking of reach trajectories. While Fmr1 KO mice show impaired learning overall, our results demonstrated that the presence or absence of a cue that signals reward alleviates some of the deficits. In addition to a single metric of success in learning, we determined the specific parameters of the motor behavior that were responsible for that success or failure. In particular, our results suggested that Fmr1 KO mice showed impaired improvement in the trajectory of the reach, reflected by a greater likelihood of completely missing the target, and in a lower learning index for the optimal reach trajectory. In addition, we fully described the features underlying learning, including categorizing the first attempt during trials, failed reaches where mice make contact with the reward, the number of trials where no attempts were made, as well as how the pattern of these different behaviors varies in Fmr1 KO mice. Our findings provide an essential framework for linking specific behavioral impairments in motor learning to the cellular and circuit mechanisms that support them.

neuroscience↗

bioRxiv2024

IGF2 mediates Hippo signaling to control liver size

The Hippo pathway is a central mechanism in organ size control, but the mediator for its function remains elusive. Here, we show that the expression of insulin-like growth factor II (IGF2) is directly induced by YAP/TAZ transcription cofactors of the Hippo pathway in a developmental stage- and cell type-specific manner. In mouse livers, Igf2 expression is sustained by YAP/TAZ in hepatoblasts and immature hepatocytes at fetal and neonatal stages, coupling with rapid cell proliferation and liver size expansion, whereas turned off in matured hepatocytes following YAP/TAZ inactivation to prevent liver overgrowth. In contrast, YAP/TAZ fails to regulate Igf2 expression in cholangiocytes and diverse liver mesenchymal cells where epigenetic barriers, including DNA and histone methylation, are implanted near Igf2 promoters. Furthermore, IGF2 activates IGF1R signaling and promotes normal and neoplastic liver growth, while the inactivation of IGF2 or IGF1R effectively blocks YAP/TAZ-induced hepatomegaly and hepatoblastoma. In conclusion, our findings reveal that IGF2 is a bona fide mediator of the Hippo pathway, indicating a fundamental role of the Hippo-IGF2-IGF1R signaling axis in organ size regulation and malignancies.

cell biology↗

bioRxiv2024

Coarse-Grained Dynamic Simulation of Cytoskeletal Microtubule Twist

Microtubule, a key component of the cytoskeleton, plays a crucial role in cell mitosis. Modeling and dynamic simulation of microtubules at the micrometer scale remain a significant challenge. In this study, we developed the helix-based ultra-coarse-grained (HB-UCG) model for the dynamic simulation of microtubules, based on the helical characteristics obtained from electron microscopy density data. We constructed microtubules up to 35 m in length and investigated the relationship between persistence length and contour length. By comparing our results with experimental data, we validated the potential of the HB-UCG model in simulating microtubule functions. We also simulated the twist process of microtubules driven by motor proteins, successfully demonstrating the models effectiveness in simulating biological processes. This study can provide the foundation for theoretical simulations of microtubule functions during mitosis.

biophysics↗

bioRxiv2024

Annulate Lamellae biogenesis is essential for nuclear pore function

Nuclear pore complexes (NPCs) enable nucleocytoplasmic transport. While NPCs primarily localize to the nuclear envelope (NE), they also appear in cytoplasmic endoplasmic reticulum (ER) membranes called annulate lamellae (AL). Though discovered in the mid-20th century, ALs function and biogenesis remain unclear. Previously considered exclusive to embryonic and malignant cells, we find AL in somatic mammalian cells. Under normal conditions, AL store pre-assembled NPCs (AL-NPCs) that integrate into the NE during G1 to support nuclear expansion. Upon pathological stimuli, AL transfer to the NE is impaired, leading to their cytoplasmic accumulation. RanBP2 (Nup358) is essential for AL biogenesis, with its phenylalanine-glycine (FG) repeats promoting AL-NPC scaffold oligomerization. ER-associated Climp63 (CKAP4) directs AL-NPCs to ER sheets and the NE. This AL-driven nuclear pore formation is complementary to the canonical routes, constituting a distinct NPC assembly pathway. Our work uncovers the biogenesis mechanism of AL and the nuclear function of this key cellular organelle.

cell biology↗

bioRxiv2024

Systematic identification of secondary bile acid production genes in global microbiome

Microbial metabolism of bile acids (BAs) is crucial for maintaining homeostasis in vertebrate hosts and environments. Although certain organisms involved in BA metabolism have been identified, a global, comprehensive elucidation of the microbes, metabolic enzymes, and BA remains incomplete. To bridge this gap, we employed hidden Markov models to systematically search in a large-scale and high-quality search library comprising 28,813 RefSeq multi-kingdom microbial complete genomes, which enabled us to construct a secondary bile acid (SBA)-production gene catalog. This catalog greatly expanded the distribution of SBA-production genes across 11 phyla, encompassing bacteria, archaea and fungi, and extended to 14 habitats spanning hosts and environmental contexts. Furthermore, we highlighted the associations between SBAs and gastrointestinal and hepatic disorders, including inflammatory bowel disease, colorectal cancer and nonalcoholic fatty liver disease, further elucidating disease-specific alterations in SBA-production genes. Additionally, we proposed the pig as a particularly suitable animal model for investigating SBA production in humans, given its closely aligned SBA-production gene composition. This gene catalog provides a comprehensive and reliable foundation on microbial BA metabolism for future studies, offering new insights into the microbial contributions to health and disease.

genomics↗

bioRxiv2024

Enhanced microbiota profiling in patients with quiescent Crohn's disease through comparison with paired healthy first-degree relatives using fecal metagenomics and metabolomics

Prior studies indicate no correlation between gut microbiota of healthy first-degree relatives (HFDRs) of Crohns disease (CD) patients and development of CD. Here, we utilized HFDRs as controls to examine the microbiota and metabolome in individuals with active (CD-A) and quiescent (CD-R) CD, thereby minimizing the influence of genetic and environmental factors. Compared to non-relative controls, the use of HFDR controls identified fewer differential taxa. Faecalibacterium, Dorea, and Fusicatenibacter showed decreased abundances in CD-R, independent of inflammation, and correlated with fecal SCFAs. Validation with a large multi-center cohort confirmed decreased abundances in Faecalibacterium and other SCFA-producing genera in CD-R. Classification models based on these genera distinguished CD-R and CD-A from healthy individuals, in both the discovery and validation cohorts. Thus, the decreased presence of Faecalibacterium, Dorea, and Fusicatenibacter in CD-R likely contributed to disease relapse through reduced SCFA production, highlighting their potential as diagnostic markers and therapeutic targets for CD.

pathology↗

bioRxiv2024

Targeting resident astrocytes attenuates neuropathic pain after spinal cord injury

Astrocytes derive from different lineages and play a critical role in neuropathic pain after spinal cord injury (SCI). Whether selective eliminating these main origins of astrocytes in lumbar enlargement could attenuate SCI-induced neuropathic pain remains unclear. Through transgenic mice injected with an adeno-associated virus vector and diphtheria toxin, astrocytes in lumbar enlargement were lineage traced, targeted and selectively eliminated. Pain-related behaviors were measured with an electronic von Frey apparatus and a cold/hot plate after SCI. RNA sequencing, bioinformatics analysis, molecular experiment and immunohistochemistry were used to explore the potential mechanisms after astrocyte elimination. Lineage tracing revealed that the resident astrocytes but not ependymal cells were the main origins of astrocytes-induced neuropathic pain. SCI induced mice to obtain significant pain symptoms and astrocyte activation in lumbar enlargement. Selective resident astrocytes elimination in lumbar enlargement could attenuate neuropathic pain and activate microglia. Interestingly, the type I interferons (IFNs) signal was significantly activated after astrocytes elimination, and the most activated Gene Ontology terms and pathways were associated with the type I IFNs signal which was mainly activated in microglia and further verified in vitro and in vivo. Furthermore, different concentrations of interferon and Stimulator of interferon genes (STING) agonist could activate the type I IFNs signal in microglia. These results elucidate that selectively eliminating resident astrocytes attenuated neuropathic pain associated with type I IFNs signal activation in microglia. Targeting type I IFNs signal is proven to be an effective strategy for neuropathic pain treatment after SCI.

neuroscience↗

bioRxiv2023

Fluorescent Chiral Quantum Dots to Unveil Origin-Dependent Exosome Uptake and Cargo Release

Exosomes are promising nanocarriers for drug delivery. Yet, it is challenging to apply exosomes in clinical use due to the limited understanding of their physiological functions. While cellular uptake of exosomes is generally known through endocytosis and/or membrane fusion, the mechanisms of origin-dependent cellular uptake and subsequent cargo release of exosomes into recipient cells are still unclear. Herein, we investigated the intricate mechanisms of exosome entry into recipient cells and the intracellular cargo release. In this study, we utilized chiral graphene quantum dots (GQDs) as representatives of exosomal cargo, taking advantage of the superior permeability of chiral GQDs into lipid membranes, as well as their excellent optical properties for tracking analysis. We observed a higher uptake rate of exosomes in their parental recipient cells. However, these exosomes were predominantly entrapped in lysosomes through endocytosis (intraspecies endocytic uptake). On the other hand, in non-parental recipient cells, exosomes exhibited a greater inclination for cellular uptake through membrane fusion, followed by direct cargo release into the cytosol (cross-species direct fusion uptake). We revealed the underlying mechanisms involved in the cellular uptake and the subsequent cargo release of exosomes depending on their cell-of-origin and recipient cell types. This study envisions valuable insights into further advancements in the effective drug delivery using exosomes, as well as a comprehensive understanding of cellular communication, including disease pathogenesis.

bioengineering↗

bioRxiv2023

Class A capsid assembly modulator apoptotic elimination of hepatocytes with high HBV core antigen level in vivo is dependent on de novo core protein translation

Background and aimsCapsid assembly (CA) is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the viral core protein. CA is the target for various new anti-viral candidate therapeutics known as capsid assembly modulators (CAMs) of which the CAM-aberrant (CAM-A) class induces aberrant shaped core protein structures and lead to hepatocyte cell death. The aim of the studies was to identify the mechanism of action of the CAM-A modulators leading to HBV infected hepatocyte elimination. MethodsThe CAM-A mediated mechanism of HBsAg reduction was evaluated in vitro in a stable HBV replicating cell line and in vivo in AAV-HBV transduced C57BL/6, C57BL/6 SCID and HBV-infected chimeric mice with humanized livers. ResultsIn vivo treatment with CAM-A modulators induced pronounced reductions in HBe- and HBsAg which were associated with a transient increase in ALT. Both HBs- and HBeAg reduction and ALT increase were delayed in C57BL/6 SCID and chimeric mice, suggesting that adaptive immune responses may indirectly contribute to this phenotype. However, depletion of CD8+ T-cells in transduced wild-type mice did not have a negative impact on antigen reduction, indicating that CD8+ T-cell responses are not essential. Coinciding with the transient ALT elevation in AAV-HBV transduced mice, we observed a transient increase in markers related to endoplasmic reticulum stress and apoptosis as well as cytokines related to apoptosis pathways, followed by the detection of a proliferation marker. Pathway enrichment analysis of microarray data revealed that antigen presentation pathway (MHC-I) was upregulated, overlapping with observed apoptosis. Combination treatment with HBV-specific siRNA demonstrated that CAM-A mediated HBsAg reduction is dependent on de novo core protein translation and that the effect is dependent on high levels of core protein expression, which will likely focus the CHB sub-population that could respond. ConclusionCAM-A treatment eradicates HBV infected hepatocytes with high core protein levels through the induction of apoptosis a promising approach as part of a regimen to achieve functional cure. Lay summaryTreatment with hepatitis B virus (HBV) capsid assembly modulators that induce the formation of aberrant HBV core protein structures (CAM-A) leads to programmed cell death, apoptosis, of HBV-infected hepatocytes and subsequent reduction of HBV antigens, which differentiates CAM-A from other CAMs. The effect is dependent on the de novo synthesis and high levels of core protein.

microbiology↗