Biology subjects

Xu, F.

Publications and source records attributed to Xu, F..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Towards anchoring evolutionary fitness for protein stability with virtual chemical environment recovery

Predicting the protein stability changes upon mutations is one of the effective ways to improve the efficiency of protein engineering. Here, we propose a dual-view ensemble learning-based framework, DVE-stability, for mutation-induced protein stability change prediction from single sequence. DVE-stability integrates the global and local dependencies of mutations to capture the intramolecular interactions from two views through ensemble learning, in which a structural microenvironment simulation module is designed to indirectly introduce the information of structural microenvironment at the sequence level. DVE-stability achieved state-of-the-art prediction performance on 7 single-point mutation benchmark datasets, and comprehensively surpassed other methods on 5 of them. Furthermore, DVE-stability outperformed other methods comprehensively through zero-shot inference on multiple-point mutation prediction task, demonstrating superior model generalizability to capture the epistasis of multiple-point mutations. More importantly, DVE-stability exhibited superior generalization performance in predicting rare beneficial mutations that are crucial for practical protein directed evolution scenarios. In addition, DVE-stability identified important intramolecular interactions via attention scores, demonstrating interpretable. Overall, DVE-stability provides a flexible and efficient tool for mutation-induced protein stability change prediction in an interpretable ensemble learning manner.

bioinformatics↗

bioRxiv2024

The Class III peroxidase OsPrx20 is a key regulator of stress response and growth in rice

In plants, reactive oxygen species maintain strictly low intracellular levels that is prerequisite for their function as second messengers. However, abiotic and biotic stresses are also long-term processes, requiring rapid scavenging of excess intracellular ROS. Plant Class III peroxidases, as multifunctional enzymes, are core enzymes in regulating intracellular ROS homeostasis and are key to regulating the complicated signaling network. Here, we found a rice Class III peroxidase OsPrx20 maintains intracellular ROS homeostasis in different conditions. OsPrx20 is a target of Ca2+/calmodulin-dependent protein kinase (OsDMI3) and phosphorylates its Thr-244 site by OsDMI3. Overexpression of OsPrx20 enhances osmotic stress tolerance but reduces blast resistance, while lack of OsPrx20 is opposite, suggesting OsPrx20 positively regulates osmotic stress tolerance but negatively regulates blast resistance in rice. Meanwhile, overexpression of OsPrx20 enlarges spike size and grain fullness, whereas lack of OsPrx20 leads to dwarfism and smaller spike. In ABA signaling, OsPrx20 Thr-244 phosphorylation is specifically dependent on OsDMI3 to reduce the sensitivity of ABA to seed germination and root growth and to enhance osmotic stress tolerance without affecting spike and grain development. Our study reveals an essential regulatory mechanism that directly activates OsPrx20 in ABA signaling, highlighting the multi-functionality of OsPrx20 in different biological processes.

plant biology↗

bioRxiv2024

Interpretable antibody-antigen interaction prediction by bridging structure to sequence

With the application of personalized and precision medicine, more precise and efficient antibody drug development technology is urgently needed. Identification of antibody-antigen interactions is crucial to antibody engineering. The time-consuming and expensive nature of wet-lab experiments calls for efficient computational methods. Taking into account the non-overlapping advantage of current structure-dependent and sequence-only computational methods, we propose an interpretable antibody-antigen interaction prediction method, S3AI. The introduction of structural knowledge, combined with explicit modeling of chemical rules, establishes a sequence-to-function route in S3AI, thereby facilitating its perception of intricate molecular interactions through providing route and priors guidance. S3AI significantly and comprehensively outperforms the state-of-the-art models and exhibits excellent generalization when predicting unknown antibody-antigen pairs, surpassing specialized prediction methods designed for out-of-distribution generalization in fair comparisons. More importantly, S3AI captures the universal pattern of antibody-antigen interactions, which not only identifies the CDRs responsible for specific binding to the antigen but also unearths the importance of CDR-H3 for the interaction. Structure-free design and superior performance make S3AI ideal for large-scale, parallelized antibody optimization and screening, enabling the rapid and precise identification of promising candidates within the extensive antibody space.

bioinformatics↗

bioRxiv2024

Brain-wide neuronal circuit connectome of human glioblastoma

Glioblastoma (GBM), a universally fatal brain cancer, infiltrates the brain and can be synaptically innervated by neurons, which drives tumor progression1-6. Synaptic inputs onto GBM cells identified so far are largely short-range and glutamatergic7-9. The extent of integration of GBM cells into brain-wide neuronal circuitry is not well understood. Here we applied a rabies virus-mediated retrograde monosynaptic tracing approach10-12 to systematically investigate circuit integration of human GBM organoids transplanted into adult mice. We found that GBM cells from multiple patients rapidly integrated into brain-wide neuronal circuits and exhibited diverse local and long-range connectivity. Beyond glutamatergic inputs, we identified a variety of neuromodulatory inputs across the brain, including cholinergic inputs from the basal forebrain. Acute acetylcholine stimulation induced sustained calcium oscillations and long-lasting transcriptional reprogramming of GBM cells into a more invasive state via the metabotropic CHRM3 receptor. CHRM3 downregulation suppressed GBM cell invasion, proliferation, and survival in vitro and in vivo. Together, these results reveal the capacity of human GBM cells to rapidly and robustly integrate into anatomically and molecularly diverse neuronal circuitry in the adult brain and support a model wherein rapid synapse formation onto GBM cells and transient activation of upstream neurons may lead to a long-lasting increase in fitness to promote tumor infiltration and progression.

cancer biology↗

bioRxiv2024

HemK2 functions for sufficient protein synthesis and RNA stability through eRF1 methylation during Drosophila oogenesis

HemK2 is a highly conserved methyltransferase spanning from yeast to humans. Despite its conservation, the identification of its genuine substrates has been controversial, and its biological importance in higher organisms remains unclear. In this study, we elucidate the role of HemK2 in the methylation of eukaryotic Release Factor 1 (eRF1), a process essential for female germline development in Drosophila melanogaster. Knockdown of hemK2 in the germline cells (hemK2-GLKD) induces apoptosis in these cells, accompanied by a pronounced decrease in both eRF1 methylation and protein synthesis. The overexpression of a methylation-deficient eRF1 variant recapitulates the defects observed in hemK2-GLKD, suggesting that eRF1 is a primary methylation target of HemK2. Furthermore, hemK2-GLKD leads to significant reduction mRNA levels in germline cell. We demonstrate that these defects in oogenesis and protein synthesis can be partially restored by inhibiting the No-Go Decay pathway. In addition, hemK2 knockdown is associated with increased disome formation, suggesting that disruptions in eRF1 methylation may provoke ribosomal stalling, which subsequently activates translation-coupled mRNA surveillance mechanisms that degrade actively-translated mRNAs. We propose that HemK2-mediated methylation of eRF1 is critical for ensuring efficient protein production and mRNA stability, which are vital for the generation of high-quality eggs.

developmental biology↗

bioRxiv2024

Long days induce adaptive secondary dormancy in seed of the Mediterranean plant Aethionema arabicum

Secondary dormancy is an adaptive trait that increases reproductive success by aligning seed germination with permissive conditions for seedling establishment. Aethionema arabicum is an annual plant and member of the Brassicaceae that grows in environments characterized by hot and dry summers. Aethionema arabicum seeds may germinate in early spring when seedling establishment is permissible. We demonstrate that long-day light regimes induce secondary dormancy in seed of Aethionema arabicum (CYP accession) repressing germination in summer when seedling establishment is riskier. Characterization of mutants screened for defective secondary dormancy demonstrated that RGL2 mediates repression of genes involved in GA signalling. Exposure to high temperature alleviates secondary dormancy, restoring germination potential. These data are consistent with the hypothesis that long-day-induced secondary dormancy and its alleviation by high temperatures, may be part of an adaptive response limiting germination to conditions permissive for seedling establishment in spring and autumn.

plant biology↗

bioRxiv2024

Hunting for peptide binders of specific targets with data-centric generative language models

Bioactive peptides have become strong candidates for a variety of clinical therapies due to their diverse advantages, which promotes the development of deep generative models for peptide design. Considering that existing methods cannot effectively deal with the conformational flexibility of peptides and are difficult to capture accurate residue-to-residue interaction dependencies, we propose a unified weakly order-dependent autoregressive language modeling architecture (PepGenWOA) for bioactive peptide generative design with tolerating out-of-order input as inductive bias. The superiority of PepGenWOA is demonstrated by generating three classes of therapeutic peptides, including antimicrobial peptides, anticancer peptides, and peptide binders. For antimicrobial and anticancer peptide generation, PepGenWOA not only comprehensively outperforms state-of-the-art baseline models, but also exhibits a significant propensity to incorporate specific types of residues that are beneficial for antimicrobial or anticancer bioactivity. For characteristic-guided peptide binder generation, the pretrained PepGenWOA is fine-tuned with Mixture-of-Experts-style plugins with lifelong learning paradigm, thereby achieving the best trade-off between memory stability for world knowledge and learning plasticity for new downstream tasks. The subsequent structure-based virtual screening anchors the 7 most promising candidates from the mega-scale synthetic sequence space, reducing the number of candidates for in vitro experimental validation by 5 orders of magnitude. A target binding rate of 28.6% with binding specificity further confirms the effectiveness of the fine-tuning strategy. Overall, PepGenWOA is a unified architecture for peptide generative design that can be flexibly customized for different task requirements, thereby harnessing generative language models to reach the "dark space" of biological language.

bioinformatics↗

bioRxiv2023

Homological landscape of human brain functional sub-circuits

Human whole-brain functional connectivity networks have been shown to exhibit both local/quasilocal (e.g., set of functional sub-circuits induced by node or edge attributes) and non-local (e.g., higher-order functional coordination patterns) properties. Nonetheless, the non-local properties of topological strata induced by local/quasilocal functional sub-circuits have yet to be addressed. To that end, we proposed a homological formalism that enables the quantification of higher-order characteristics of human brain functional sub-circuits. Our results indicated that each homological order uniquely unravels diverse, complementary properties of human brain functional sub-circuits. Noticeably, the H1 homological distance between rest and motor task were observed at both whole-brain and sub-circuit consolidated level which suggested the self-similarity property of human brain functional connectivity unraveled by homological kernel. Furthermore, at the whole-brain level, the rest-task differentiation was found to be most prominent between rest and different tasks at different homological orders: i) Emotion task (H0), ii) Motor task (H1), and iii) Working memory task (H2). At the functional sub-circuit level, the rest-task functional dichotomy of default mode network is found to be mostly prominent at the first and second homological scaffolds. Also at such scale, we found that the limbic network plays a significant role in homological reconfiguration across both task- and subject-domain which sheds light to subsequent investigations on the complex neuro-physiological role of such network. From a wider perspective, our formalism can be applied, beyond brain connectomics, to study non-localized coordination patterns of localized structures stretching across complex network fibers.

neuroscience↗

bioRxiv2023

Electron-bifurcation and fluoride efflux systems in Acetobacterium spp. drive defluorination of perfluorinated unsaturated carboxylic acids

Enzymatic cleavage of C-F bonds in per- and polyfluoroalkyl substances (PFAS) is largely unknown but avidly sought to promote systems biology for PFAS bioremediation. Here, we report the reductive defluorination of , {beta}-unsaturated per- and polyfluorocarboxylic acids by Acetobacterium spp. Two critical molecular features in Acetobacterium species enabling reductive defluorination are (i) a functional fluoride efflux transporter (CrcB) and (ii) an electron-bifurcating caffeate reduction pathway (CarABCDE). The fluoride transporter was required for detoxification of released fluoride. Car enzymes were implicated in defluorination by the following evidence: (i) only Acetobacterium spp. with car genes catalyzed defluorination; (ii) caffeate and PFAS competed in vivo; (iii) models from the X-ray structure of the electron-bifurcating reductase (CarC) positioned the PFAS substrate optimally for reductive defluorination; (iv) products identified by 19F-NMR and high-resolution mass spectrometry were consistent with the model. Defluorination biomarkers identified here were found in wastewater treatment plant metagenomes on six continents.

microbiology↗

bioRxiv2023

Evolution-guided large language model is a predictor of virus mutation trends

The increasing frequency of emerging viral infections necessitates a rapid human response, highlighting the cost-effectiveness of computational methods. However, existing computational approaches are limited by their input forms or incomplete functionalities, preventing a unified prediction of diverse viral variation drivers and hindering in-depth applications. To address this issue, we propose a unified evolution-driven framework for predicting virus variation drivers, named E2VD, which is guided by virus evolutionary traits priors. With evolution-inspired design, E2VD comprehensively and significantly outperforms state-of-the-art methods across various virus variation drivers prediction tasks. Moreover, E2VD effectively captures the fundamental patterns of virus evolution. It not only distinguishes different types of mutations but also accurately identifies rare beneficial mutations that are critical for virus to survival, while maintains generalization capabilities on different viral lineages. Importantly, with predicted biological drivers, E2VD perceives virus evolutionary trends, in which potential high-risk mutation sites are accurately recommended. Overall, E2VD represents a unified, structure-free, and interpretable approach for analyzing and predicting viral evolutionary fitness, providing an ideal alternative to costly wet-lab measurements to accelerate responses to emerging viral infections.

bioinformatics↗

bioRxiv2023

Structure of scavenger receptor SCARF1 and its interaction with lipoproteins

SCARF1 (Scavenger receptor class F member 1, SREC-1 or SR-F1) is a type I transmembrane protein that recognizes multiple endogenous and exogenous ligands such as modified low-density lipoproteins (LDL) and is important for maintaining homeostasis and immunity. But the structural information and the mechanisms of ligand recognition of SCARF1 are largely unavailable. Here we solve the crystal structures of the N-terminal fragments of human SCARF1, which show that SCARF1 forms homodimers and its epidermal growth factor (EGF)-like domains adopt a long-curved conformation. Then we examine the interactions of SCARF1 with lipoproteins and are able to identify a region on SCARF1 for recognizing modified LDLs. The mutagenesis data show that the positively charged residues in the region are crucial for the interaction of SCARF1 with modified LDLs, which is confirmed by making chimeric molecules of SCARF1 and SCARF2. In addition, teichoic acids, a cell wall polymer expressed on the surface of gram-positive bacteria, are able to inhibit the interactions of modified LDLs with SCARF1, suggesting the ligand binding sites of SCARF1 might be shared for some of its scavenging targets. Overall, these results provide mechanistic insights into SCARF1 and its interactions with the ligands, which are important for understanding its physiological roles in homeostasis and the related diseases.

biophysics↗

bioRxiv2023

Multi-region calcium imaging in freely behaving mice with ultra-compact head-mounted fluorescence microscopes

To investigate the circuit-level neural mechanisms of behavior, simultaneous imaging of neuronal activity in multiple cortical and subcortical regions is highly desired. Miniature head-mounted microscopes offer the capability of calcium imaging in freely behaving animals. However, implanting multiple microscopes on a mouse brain remains challenging due to space constraints and the cumbersome weight of equipment. Here, we present TINIscope, a Tightly Integrated Neuronal Imaging microscope optimized for electronic and opto-mechanical design. With its compact and lightweight design of 0.43 g, TINIscope enables unprecedented simultaneous imaging of behavior-relevant activity in up to four brain regions in mice. Proof-of-concept experiments with TINIscope recorded over 1000 neurons in four hippocampal subregions and revealed concurrent activity patterns spanning across these regions. Moreover, we explored potential multi-modal experimental designs by integrating additional modules for optogenetics, electrical stimulation or local field potential recordings. Overall, TINIscope represents a timely and indispensable tool for studying the brain-wide interregional coordination that underlies unrestrained behaviors.

neuroscience↗

bioRxiv2023

Systems genetics identifies the association between Enc1 and cognitive function in the hippocampus

Ectodermal-Neural Cortex 1 (ENC1) is expressed in multiple regions of the brain, including the hippocampus. However, knowledge about its function has been well explored only in the context of peroxidative stress and cancer. In this study, we investigated the association of hippocampal Enc1 with cognitive function in BXD mice. We performed Pearson correlation, phenotype-wide association analysis (PheWAS), expression-Based PheWAS, pathway enrichment, and protein interaction networks on Enc1 and BXD phenotypes/transcriptome of the hippocampus, and the results indicated that Enc1 is inextricably linked to cognitive performance. In addition, we found that most of the Enc1 co-expressed genes were highly expressed in GABAergic neuronal cells. Expression quantitative trait loci analysis indicated that Enc1 was cis-regulated in the hippocampus of mice as well as human. Genome-wide association analysis revealed ENC1 to be significantly associated with cognitive-related traits, including age-related cognitive changes etc. In conclusion, our findings demonstrated that Enc1 is involved in cognitive functions mainly in hippocampal GABAergic neuronal cells through neurogenesis, synaptic signaling, and CGMP-PKG signaling pathways, and interacts with the neurological function-related genes.

genetics↗

bioRxiv2023

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis

BackgroundChronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. MethodsSystems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE-/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE-/- mice. ResultsIn this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPAR{gamma} neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo. ConclusionOur study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

immunology↗

bioRxiv2023

Regulated Cleavage and Relocation of FERONIA Control Immunity in Arabidopsis Roots

Plant roots exhibit localized immunity (LI) specifically in the root cap and transition/elongation zone (TZ/EZ). Such immunity relies on receptor-like kinases localized at the plasma membrane (PM), which are essential for plant response to bacteria in the rhizosphere. Here, we identified a new mechanism of action for receptor kinase FERONIA (FER) in LI. In the absence of bacterial stimuli, FER is localized to the PM, maintaining plant growth. When confronted with bacterial colonization, RALF23 peptide hyper-accumulates in TZ/EZ cells and activates a metalloproteinase that cleaves FER and transfer the cytosolic kinase domain into the nucleus. The nucleus-localized kinase domain of FER contributes to LI by reducing bacterial abundance at TZ/EZ. Thus, this work uncovered a unique mechanism by which a single receptor kinase acts in two molecular forms and two distinct subcellular locations to balance growth and immunity. One Sentence SummaryBacteria induces the cleavage of FER via At2-MMP to trigger a localized immunity around TZ and EZ of Arabidopsis roots.

plant biology↗

bioRxiv2023

Hierarchy in influence but not firing patterns among forelimb motor cortices

Though hierarchy is commonly invoked in descriptions of motor cortical function, its presence and manifestation in firing patterns remain poorly resolved. Here we use optogenetic inactivation to demonstrate that short-latency influence between forelimb premotor and primary motor cortices is asymmetric during reaching in mice, demonstrating a partial hierarchy between the endogenous activity in each region. Multi-region recordings revealed that some activity is captured by similar but delayed patterns where either regions activity leads, with premotor activity leading more. Yet firing in each region is dominated by patterns shared between regions and is equally predictive of firing in the other region at the single-neuron level. In dual-region network models fit to data, regions differed in their dependence on across-region input, rather than the amount of such input they received. Our results indicate that motor cortical hierarchy, while present, may not be exposed when inferring interactions between populations from firing patterns alone.

neuroscience↗

bioRxiv2023

Pneumatic Nano-Sieve for CRISPR-based Detection of Drug-resistant Bacteria

The increasing prevalence of antibiotic-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), presents a significant public health concern. Timely detection of MRSA is crucial to enable prompt medical intervention, limit its spread, and reduce antimicrobial resistance. Here, we introduce a miniaturized nano-sieve device featuring a pneumatically-regulated chamber for highly efficient MRSA purification from human plasma samples. By using packed magnetic beads as a filter and leveraging the deformability of the nano-sieve channel, we achieve an on-chip concentration factor of 15 for MRSA. We integrated this device with recombinase polymerase amplification (RPA) and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas detection system, resulting in an on-chip limit of detection (LOD) of approximately 100 CFU/mL. This developed approach provides a rapid, precise, and centrifuge-free solution suitable for point-of-care diagnostics, with the potential to significantly improve patient outcomes in resource-limited medical conditions.

bioengineering↗

bioRxiv2023

Introducing PandaNovo for practical large-scale de novo peptide sequencing

De novo peptide sequencing is a promising approach for novel peptide discovery. We use a novel concept of complementary spectra to enhance ion information and propose a de novo sequencing model{pi} -HelixNovo based on Transformer architecture.{pi} -HelixNovo outperforms other state-of-the-art models and enhances the taxonomic resolution of gut metaproteome, taking a significant step forward in de novo sequencing.

bioinformatics↗