Biology subjects

Li, T.

Publications and source records attributed to Li, T..

At least 289 records · Page 16Linked to original sources

bioRxiv2023

Ca2+ Oscillation in Vascular Smooth Muscle Cells Control Myogenic Spontaneous Vasomotion and Counteract Post-ischemic No-reflow

Ischemic stroke produces the highest adult disability. Despite successful recanalization, no-reflow, or the futile restoration of the cerebral perfusion after ischemia, is a major cause of brain lesion expansion. However, the vascular mechanism underlying this hypoperfusion is largely unknown, and no approach is available to actively promote optimal reperfusion to treat no-reflow. Here, by combining two-photon laser scanning microscopy (2PLSM) and a mouse middle cerebral arteriolar occlusion (MCAO) model, we found myogenic vasomotion deficits correlated with post-ischemic cerebral circulation interruptions and no-reflow. Transient occlusion-induced transient loss of mitochondrial membrane potential ({Delta}{Psi}m) permanently impaired mitochondria-endoplasmic reticulum (ER) contacts and abolished Ca2+ oscillation in smooth muscle cells (SMCs), the driving force of myogenic spontaneous vasomotion. Furthermore, tethering mitochondria and ER by specific overexpression of ME-Linker in SMCs restored cytosolic Ca2+ homeostasis, remotivated myogenic spontaneous vasomotion, achieved optimal reperfusion, and ameliorated neurological injury. Collectively, the maintaining of arteriolar myogenic vasomotion and mitochondria-ER contacts in SMCs, are of critical importance in preventing post-ischemic no-reflow.

neuroscience↗

bioRxiv2023

H7 influenza A viruses bind sialyl-LewisX, a potential intermediate receptor between species

Influenza A viruses (IAVs) can overcome species barriers by adaptation of the receptor binding site of the hemagglutinin (HA). To initiate infection, HAs bind to glycan receptors with terminal sialic acids, which are either N-acetylneuraminic acid (NeuAc) or N-glycolylneuraminic acid (NeuGc), the latter is mainly found in horses and pigs but not in birds and humans. We investigated the influence of previously identified equine NeuGc-adapting mutations (S128T, I130V, A135E, T189A, and K193R) in avian H7 IAVs in vitro and in vivo. We observed that these mutations negatively affected viral replication in chicken cells, but not in duck cells, and positively affected replication in horse cells. In vivo, the mutations reduced virus virulence and mortality in chickens. Ducks excreted high viral loads for a longer time than chickens, although they appeared clinically healthy. To elucidate why chickens and ducks were infected by these viruses despite the absence of NeuGc, we re-evaluated the receptor binding of H7 HAs using glycan microarray and flow cytometry studies. This revealed that mutated avian H7 HAs also bound to 2,3-linked NeuAc and sialyl-LewisX, which have an additional fucose moiety in their terminal epitope, explaining why infection of ducks and chickens was possible. Interestingly, the 2,3-linked NeuAc and sialyl-LewisX epitopes were only bound when presented on tri-antennary N-glycans, emphasizing the importance of investigating the fine receptor specificities of IAVs. In conclusion, the binding of NeuGc-adapted H7 IAV to sialyl-LewisX enables viral replication and shedding by chickens and ducks, potentially facilitating interspecies transmission of equine-adapted H7 IAVs. (249 words) ImportanceInfluenza A viruses cause millions of deaths and illness in birds and mammals each year. The viral surface protein hemagglutinin initiates infection by binding to host cell terminal sialic acids. Hemagglutinin adaptations affect the binding affinity to these sialic acids and therefore the potential host species targeted. While avian and human IAVs tend to bind N-acetylneuraminic acid (a form of sialic acid), equine H7 viruses prefer binding to N-glycolylneuraminic acid (NeuGc). To better understand the function of NeuGc-specific adaptations in hemagglutinin and to elucidate interspecies transmission potential NeuGc-adapted viruses, we evaluated the effects of NeuGc-specific mutations in avian H7 viruses in chickens and ducks, important economic hosts and reservoir birds, respectively. We also examined the impact on viral replication and found a binding affinity to sialyl-LewisX, another terminal epitope. These findings are important as they contribute to the understanding of the role of sialyl-LewisX in avian influenza infection. (148 words)

molecular biology↗

bioRxiv2023

Inhibition of O-GlcNAc transferase activates type I interferon-dependent antitumor immunity by bridging cGAS-STING pathway

The O-GlcNAc transferase (OGT) is an essential enzyme that mediates protein O-GlcNAcylation, a unique form of posttranslational modification of many nuclear and cytosolic proteins. Recent studies observed increased OGT and O-GlcNAcylation levels in a broad range of human cancer tissues compared to adjacent normal tissues, indicating a universal effect of OGT in promoting tumorigenesis. Here, we show that OGT is essential for tumor growth in immunocompetent hosts by repressing the cyclic GMP-AMP synthase (cGAS)-dependent DNA sensing pathway. We found that deletion of OGT (Ogt-/-) caused a marked reduction in tumor growth in both syngeneic tumor models and a genetic colorectal cancer (CRC) model induced by mutation of the Apc gene (Apcmin). Pharmacological inhibition or genetic deletion of OGT induced a robust genomic instability (GIN), leading to cGAS-dependent production of the type I interferon (IFN-I) and IFN-stimulated genes (ISGs). As a result, deletion of Cgas or Sting from Ogt-/- cancer cells restored tumor growth, and this correlated with impaired CD8+ T cell-mediated antitumor immunity. Mechanistically, we found that OGT-dependent cleavage of host cell factor C1 (HCF-1) is required for the avoidance of GIN and IFN-I production in tumors. In summary, our results identify OGT-mediated genomic stability and activate cGAS-STING pathway as an important tumor cell-intrinsic mechanism to repress antitumor immunity.

cancer biology↗

bioRxiv2023

Syncytia Formation Promotes Virus Resistance to Interferon and Neutralizing Antibodies

SARS-CoV-2, like many viruses, generates syncytia but the role of syncytia formation in viral evolution remains unknown. Using SARS-CoV-2 and SARS-CoV-2 Spike (S) replacement vesicular stomatitis (VSV), we show that S-mediated syncytia impair the antiviral effects of interferons in cultured cells, human lung cell cultures, and hACE2 transgenic mice. Amino acid substitutions that modulate syncytia formation in Delta- and Omicron-encoded S have parallel effects on viral interferon resistance. S-mediated syncytia compromise antibody-mediated virus neutralization in cultured cells. We recapitulate interferon and neutralizing antibody resistance in syncytia generated by the orthoreovirus p14 fusion-associated small transmembrane (FAST) protein in VSV, influenza virus, and seasonal coronavirus OC43 infections. These findings explain selection of SARS-CoV-2 fusogenic variants in humans and, more generally, the evolution of fusogenic viruses driven by adaptive and innate immunity.

microbiology↗

bioRxiv2023

A novel nested gene Aff3ir participates in vascular remodelling by enhancing endothelial cell differentiation in mice

Endothelial integrity in the vasculature is critically maintained by vascular stem/progenitor cells (SPCs) giving rise to endothelial cells (ECs). However, the genes significantly activated during differentiation remain incompletely understood. Based on mouse aorta and vein cDNA library, we unearthed a hitherto unidentified gene nested residing within intron 6 of Aff3, christened as Aff3 intron resident (Aff3ir), upregulated during laminar shear stress-induced ECs differentiation in mouse. Proteomic analysis substantiated the presence of a 45-amino acid(aa) peptide (AFF3IR-ORF1) and 109-aa or 151-aa protein (AFF3IR-ORF2) encoded from two transcript variants. During embryonic development, AFF3IR-ORF1 peaked at E14.5, while AFF3IR-ORF2 displayed a continuous increase until E19.5. In adult mice, AFF3IR-ORF1 was detected in the lung, liver, spleen, and kidney, while AFF3IR-ORF2 was most abundant in the aorta. Furthermore, Western blot and immunofluorescence analyses revealed a specific upregulation of AFF3IR-ORF2, but not AFF3IR-ORF1, three days after femoral artery injury or hindlimb ischemia in vivo. Overexpression of AFF3IR-ORF2 enhanced, while its knockdown attenuated, SPCs differentiation into ECs induced by shear stress or vascular endothelial growth factor in vitro. Notably, the upregulated AFF3IR-ORF2 hindered SPCs proliferation by sequestering minichromosome maintenance complex component 3 in the cytoplasm, thereby shifting the status of SPCs from a pro-proliferation to a pro-differentiation state. In conclusion, our discoveries unveil the novel protein-coding gene Aff3ir as a participant in ECs differentiation, providing fresh insights into the regulation of vascular endothelial integrity.

cell biology↗

bioRxiv2023

Dynamic floral scent profile of Epiphyllum oxypetalum and the cytosolic biosynthesis of trans-Geraniol through mevalonate pathway

O_LIEpiphyllum oxypetalum, a renowned ornamental species in Cactaceae, releases attractive fragrance during its infrequent, transient and nocturnal flowering, the nature and biosynthesis of the volatiles for this floral scent, however, remained unexplored. C_LIO_LIEmploying volatilomic, transcriptomic and biochemical approaches, we systematically characterized the composition, emission dynamics and biosynthesis of E. oxypetalum floral scent. C_LIO_LIFloral scent composition was highly dynamic, with trans-geraniol comprising 72.54% of the total emission at full bloom, followed by benzyl alcohol (12.96%) and methyl salicylate (3.75%), which predominantly emanated from petals and sepals. Transcriptomic analysis and inhibition assay using pathway-specific inhibitors revealed the mevalonate (MVA) pathway as the precursor source for trans-geraniol biosynthesis. Together with elevated expression of both cytosol-localized geraniol pyrophosphate synthase EoGDPS and geraniol synthase EoTPSa1, we elucidated an unusual cytosolic biosynthesis route for geraniol in E. oxypetalum petals. C_LIO_LIOur study on E. oxypetalum scent emission and its biosynthesis offers a comprehensive profile of cactus floral scent profiles and presents a rare case of cytosolic geraniol biosynthesis using MVA pathway-derived substrates. These findings underline the unique metabolism of cactus flower volatiles, which hold a promise to be applied in the development of novel perfumes. C_LI

plant biology↗

bioRxiv2023

Host signature as major driver of root and rhizosphere core microbiomes that differently affect plant functional traits

BackgroundPlant can evolve with a core root microbiome that maintains essential functions for host performance. However, the relative importance of plant traits and soil factors on the structure, assembly, co-occurrence networks of the core root microbiomes and their relevance for plant characteristics remain elusive. Here, we investigated how plant species identity and soil environment affect the core bacterial communities in the bulk soil, rhizosphere and root endosphere of four plants with a gradient of Cd/Zn accumulation capacity under controlled and field environments. We further tested on the role of the core bacterial isolates in plant growth and accumulation of metal and nutrients. ResultsWe identified root compartment and plant species rather than environmental parameters as the primary driver of Cd-accumulator root microbiome. Stochastic processes were more important for the assembly of endosphere generalists (58.5%) than rhizosphere counterparts (45.2%), indicating that generalists were more robust to environmental changes. Increasing host selection from epiphytes to endophytes resulted in the existence of the endosphere and rhizosphere generalist core microbiota common to different plants under varying growth environments, highlighting that shared environmental and physiological features of host plants are decisive for core microbiome establishment. Further, endophytic core microbiota conferred greater biotic connectivity within networks and was more important predictors of plant metal accumulation, whereas the rhizosphere cores were more closely linked to plant biomass and nutrient status. The divergent functions of rhizosphere and endosphere core microbes on plant characteristics were also validated by inoculating the synthetic communities comprising bacterial isolates belonging to the core microbiota. ConclusionThis study indicated the pivotal role of plant trait in the assembly of conserved and functionally important core microbiome common to different Cd-accumulators, which brings us closer to manipulating the persistent root microbial associations to accelerate the rejuvenation of metal-disturbed soils through host genetics.

microbiology↗

bioRxiv2023

De novo lipogenesis pathway is a vulnerability in IDH1 mutant glioma

Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-epileptic and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild type tumors. Surprisingly, genes upregulated by VPA showed no change in chromatin accessibility at the promoter, but there was a correlation between VPA downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decrease in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA targeted a key lipogenic gene, fatty acid synthase (FASN), via inhibition of the mTOR pathway and both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find HDACs are involved in the regulation of lipogenic genes and in particular HDAC6 is important for regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in a IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic option in IDH1 mutant gliomas.

cancer biology↗

bioRxiv2023

Reprogramming of 3D chromatin domains by antagonizing the β-catenin/CBP interaction attenuates insulin signaling in pancreatic cancer

The therapeutic potential of targeting the {beta}-catenin/CBP interaction has been demonstrated in a variety of preclinical tumor models with a small molecule inhibitor, ICG-001, characterized as a {beta}-catenin/CBP antagonist. Despite the high binding specificity of ICG-001 for the N-terminus of CBP, this {beta}-catenin/CBP antagonist exhibits pleiotropic effects. Our recent studies found global changes in three-dimensional (3D) chromatin architecture in response to disruption of the {beta}-catenin/CBP interaction in pancreatic cancer cells. However, an understanding of the functional crosstalk between antagonizing the {beta}-catenin/CBP interaction effect changes in 3D chromatin architecture and thereby gene expression and downstream effects remains to be elucidated. Here we perform Hi-C analyses on canonical and patient-derived pancreatic cancer cells before and after the treatment with ICG-001. In addition to global alteration of 3D chromatin domains, we unexpectedly identify insulin signaling genes enriched in the altered chromatin domains. We further demonstrate the chromatin loops associated with insulin signaling genes are significantly weakened after ICG-001 treatment. We finally elicit the deletion of a looping of IRS1, a key insulin signaling gene, significantly impede pancreatic cancer cell growth, indicating that looping-mediated insulin signaling might act as an oncogenic pathway to promote pancreatic cancer progression. Our work shows that targeting aberrant insulin chromatin looping in pancreatic cancer might provide a therapeutic benefit.

cancer biology↗

bioRxiv2023

A Novel Hierarchical Network-Based Approach to Unveil the Complexity of Functional Microbial Genome

Biological networks are pivotal in elucidating intricate biological processes. While substantial research has delved into interspecies environmental interactions within biological networks, intraspecific functional gene interactions within individual microbes remain relatively untapped. The burgeoning availability of microbiome datasets underscores the imperative for a refined examination of microbial genome structures and functions. We innovatively introduce the concept of "Solid Motif Structures (SMS)" through a meticulous biological network analysis of genomes from the same genus, aiming to bridge the gap between the structural and functional intricacies of microbial genomes. Harnessing publicly available data from 162 high-quality Microcystis genomes, a globally prevalent freshwater cyanobacterium instrumental in microbial ecosystems, a comprehensive genome structure network for Microcystis was delineated. Employing a state-of-the-art deep learning scheme, we discerned 27 pivotal functional subnetworks and an array of functionally-associated SMS. Incorporating metagenomic data from seven geographically diverse lakes, we embarked on an exhaustive analysis of the functional stability of Microcystis across varied environmental matrices. This culminated in the identification of distinct functional interaction models for each lake. Our research amalgamates these insights into a comprehensive resource repository, furnishing unparalleled perspectives into the functional interplay within Microcystis. Leveraging advanced biological network analysis, our study pioneers the delineation of a novel network granularity, facilitating a more lucid comprehension of the dynamic interplay between genome structure and function interactions in microorganisms of the same genus. This study shed light on the plasticity and conservation of microbial functional genomes across diverse environments, offering insights into their evolutionary trajectories.

genomics↗

bioRxiv2023

More is Different: Constructing the Most Comprehensive Human Protein High-Order Interaction Dataset

In biological systems, protein-protein interactions (PPI) weave intricate network patterns that are fundamental to the structural and functional integrity of organisms. While the majority of existing research has been anchored in the study of pairwise PPIs, the realm of high-order interactions remains relatively untapped. This oversight could potentially obscure the deeper intricacies embedded within biological networks. To address this gap, this study formulates a scientific task aimed at predicting high-order protein-protein interactions and introduces a multi-level comprehensive dataset focused on triadic high-order interactions within PPI networks. This dataset incorporates more than 80% of the known human protein interaction relationships and partitions into 60 subsets across a diverse range of functional contexts and confidence. Through meticulous evaluation using cutting-edge high-order network prediction tools and benchmark PPI prediction methodologies, our findings resonate with the principle that "more is different". Triadic high-order interactions offer a more enriched and detailed informational canvas than their pairwise counterparts, paving the way for a deeper comprehension of the intricate dynamics at play in biological systems. In summary, this research accentuates the critical importance of high-order PPI interactions in biological systems and furnishes invaluable resources for subsequent scholarly investigations. The dataset is poised to catalyze future research endeavors in protein-protein interaction networks, elucidating their pivotal roles in both health and disease states.

genomics↗

bioRxiv2023

The hidden function of nonspecifically DNA-bound RNA polymerases: a buffer of resource competition in bacteria

RNA polymerase (RNAP) is the workhorse of bacterial gene expression, transcribing rRNA and mRNA. Experiments found that a significant fraction of RNAPs in bacteria are nonspecifically bound to DNA, which is puzzling as these idle RNAPs could have produced more RNAs. Whether nonspecifically DNA-bound RNAPs have any function or are merely a consequence of passive interaction between RNAP and DNA is unclear. In this work, we propose that nonspecifically DNA-bound RNAPs buffer the free RNAP concentration and mitigate the crosstalk between rRNA and mRNA transcription. We verify our theory using mean-field models and an agent-based model of transcription, showing that the buffering effects are robust against the interaction between RNAPs and sigma factors and the spatial fluctuation and temporal noise of RNAP concentration. We analyze the relevant parameters of Escherichia coli and find that the buffering effects are significant across different growth rates at a low cost, suggesting that nonspecifically DNA-bound RNAPs are evolutionarily advantageous.

microbiology↗

bioRxiv2023

Three-dimensional visualization of blood vessels in human gliomas based on tissue clearing and deep learning

Gliomas, with their intricate and aggressive nature, call for a detailed visualization of their vasculature. While many studies lean towards 2D imaging of thin sections, this method often overlooks the full spatial heterogeneity inherent to tumors. To overcome this limitation, our study melded state-of-the-art techniques, encompassing tissue clearing technology, 3D confocal microscopy imaging, and deep learning-aided vessel extraction, resulting in a comprehensive 3D visualization of glioma vasculature in intact human tissue. Specifically, we treated formalin-fixed thick human glioma tissue sections (500 m) with OPTIClear for transparency and subsequently performed immunofluorescent labeling using CD31. Using confocal microscopy, we obtained 3D images of the glioma vasculature. For vessel extraction, we employed a specialized 3D U-Net, enriched with image preprocessing and post-processing methods, and benchmarked its performance against the Imaris software. Our findings indicated that OPTIClear-enabled tissue clearing yielded a holistic 3D representation of immunolabeled vessels in clinical human glioma samples. Impressively, our deep learning technique outshined the traditional Imaris approach in terms of accuracy and efficiency in vessel extraction. Further, discernible variations in vascular metrics, such as mean diameter, branching point count, and volume ratio, were observed between low-grade and high-grade gliomas. In essence, our innovative blend of tissue clearing and deep learning not only enables enhanced 3D visualization of human glioma vasculature but also underscores morphological disparities across glioma grades, potentially influencing pathological grading, therapeutic strategies, and prognostic evaluations.

neuroscience↗

bioRxiv2023

Identification and functional analysis of eRNA markers for hepatocellular carcinoma based on high-throughput data

Hepatocellular carcinoma (HCC) is a common type of liver cancer with a high mortality rate. enhancer RNA (eRNA) has been proved to play an important role in cancer progress and development. However, the eRNA studies in HCC are still limited. In this study, we attempted to identify some eRNA biomarkers for HCC diagnosis and analyzed their biological function. First, we identified three eRNA biomarkers (CAP2e, COLEC10e, and MARCOe), which were significant differentially expressed between tumor and normal tissues in 115 HCC patients across three datasets. CAP2e demonstrated upregulation in tumors while COLEC10e and MARCOe were downregulated. These results could be validated in TCGA-LIHC data. There were significant positive correlations between the expression of these eRNAs and their host genes. Then, functional enrichment analysis of protein-coding genes associated with the eRNA biomarkers revealed their involvement in cancer-related pathways. MARCOe was suggested to be a potential target for therapeutic drugs in HCC by a drug related study. The next, survival analysis demonstrated significant prognostic values of these eRNAs in prediction of overall survival. Immune infiltration analysis revealed a positive correlation between MARCOe expression and immune cell infiltration level. Finally, we found similar expression patterns of these eRNA biomarkers in other cancers, such as cholangiocarcinoma, through a pan-cancer comparison. CAP2e and COLEC10e in HCC were validated by other studies. However, the studies about MARCOe in HCC were limited. In conclusion, as best as our knowledge, it is the first time to identify three eRNA biomarkers for HCC diagnosis. These biomarkers are proved to be involved in HCC progress and development, have prognosis prediction values, and are potential to be therapeutic targets.

cancer biology↗

bioRxiv2023

Impact of repeated cryopreservation on embryo health and implantation potential

In IVF clinics, preimplantation genetic testing (PGT) is a common practice that involves a biopsy and cryopreservation of embryos for genetic evaluation. When testing fails - or is required for already cryopreserved embryos - multiple freeze-thaw cycles occur. Though known to impact live birth rates, the exclusive influence of cryopreservation has not been elucidated. Here, we evaluate the effect of repeated cryopreservation on embryo health and implantation potential. Blastocyst-stage murine embryos were subjected to one, two or three freeze-thaw cycles with fresh embryos serving as a control. Outcomes assessed included post-thaw survival rate, allocation of cells to the inner cell mass (ICM) vs. trophectoderm cell lineages, implantation potential and offspring health. Post-thawing, embryos that were subjected to three freeze-thaw cycles had a significantly lower survival rates compared to embryos that had undergone one cycle (P<0.001). Additionally, the number of ICM cells was significantly reduced in embryos subjected to two or three freeze-thaw cycles compared to fresh or single-cycle embryos (P<0.001). No statistically significant differences were found for pregnancy rate, number of implantations, viable fetuses or resorption sites between treatment groups. We did however, find a non-significant yet interesting trend: three freeze-thaw cycles were associated with a 20% decrease in viable fetuses and a 20% increase in resorption sites compared to one freeze-thaw cycle group. These findings demonstrate that repeated cryopreservation adversely affects embryo health and may decrease implantation potential. Consequently, caution is advised regarding the repeated application of cryopreservation in IVF clinics, underscoring the need for further research to optimise cryopreservation protocols.

developmental biology↗

bioRxiv2023

Study on the preparation of bovine milk exosomes and the stability of lyophilized powder

Bovune milk exosomes (MK-exo) have bioactive effects on the health of consumers and can also serve as excellent drug delivery vehicles. However, long-term preservation and transportation remain major challenges at present. In this report, high-quality MK-exo are prepared on a large scale. We then developed a lyophilization method belonging to MK-exo, and performed acceleration and long-term stability experiments on the lyophilized MK-exo to evaluate the effect of lyophilization. The results showed that the lyophilized MK-exo can be stored at room temperature for at least 3 months and 2-8{degrees}C for 15 months. These findings provide data support for further understanding of the properties and applications of MK-exo.

bioengineering↗

bioRxiv2023

De novo generation of antibody CDRH3 with a pre-trained generative large language model

Artificial Intelligence (AI) techniques have made great advances in assisting antibody design. However, antibody design still heavily relies on isolating antigen-specific antibodies from serum, which is a resource-intensive and time-consuming process. To address this issue, we propose a Pre-trained Antibody generative large Language Model (PALM) for the de novo generation of artificial antibodies heavy chain complementarity-determining region 3 (CDRH3) with desired antigen-binding specificity, reducing the reliance on natural antibodies. We also build a high-precision model antigen-antibody binder (A2binder) that pairs antigen epitope sequences with antibody sequences to predict binding specificity and affinity. PALM-generated antibodies exhibit binding ability to SARS-CoV-2 antigens, including the emerging XBB variant, as confirmed through in-silico analysis and in-vitro assays. The in-vitro assays validated that PALM-generated antibodies achieve high binding affinity and potent neutralization capability against both wild-type and XBB spike proteins of SARS-CoV-2. Meanwhile, A2binder demonstrated exceptional predictive performance on binding specificity for various epitopes and variants. Furthermore, by incorporating the attention mechanism into the PALM model, we have improved its interpretability, providing crucial insights into the fundamental principles of antibody design.

bioinformatics↗

bioRxiv2023

A human prenatal skin cell atlas reveals immune cell regulation of skin morphogenesis

Human prenatal skin is populated by innate immune cells including macrophages, and whether they act solely in immunity or have additional functions in morphogenesis is unclear. We assembled the first comprehensive multi-omic reference atlas of prenatal human skin (7-16 post-conception weeks), combining single cell and spatial transcriptomic data, to characterise the skins microenvironmental cellular organisation. This revealed that crosstalk between non-immune and immune cells underpins formation of hair follicles, has implications for scarless wound healing, and is critical for skin angiogenesis. We benchmarked a skin organoid model, derived from human embryonic stem (ES) and induced pluripotent stem (iPS) cells, against prenatal and adult skin, demonstrating close recapitulation of the epidermal and dermal skin components during hair follicle development. Notably, the skin organoid lacked immune cells and had markedly diminished endothelial cell heterogeneity and quantity. From our in vivo skin cell atlas data, we found that macrophages and macrophage-derived growth factors play a key role in driving endothelial development prenatally. Indeed, vascular network formation was enhanced following transfer of autologous iPS-derived macrophages into both endothelial cell angiogenesis assays and skin organoid cultures. In summary, innate immune cells moonlight as key players in skin morphogenesis beyond their conventional immune roles, a function they achieve via extensive crosstalk with non-immune cells. Finally, we leveraged our human prenatal skin cell atlas to further our understanding of the pathogenesis of genetic hair and skin disorders.

developmental biology↗