Biology subjects

Yang, Q.

Publications and source records attributed to Yang, Q..

At least 181 records · Page 10Linked to original sources

bioRxiv2024

PPARγ activation by lipolysis-generated ligands is required for cAMP dependent UCP1 induction in human thermogenic adipocytes

ObjectiveThe uncoupling protein 1 (UCP1) is induced in brown or "beige" adipocytes through catecholamine-induced cAMP signaling, which activates diverse transcription factors. UCP1 expression can also be enhanced by PPAR{gamma} agonists such as rosiglitazone (Rsg). However, it is unclear whether this upregulation results from de-novo differentiation of beige adipocytes from progenitor cells, or from the induction of UCP1 in pre-existing adipocytes. To explore this, we employed human adipocytes differentiated from progenitor cells and examined their acute response to Rsg, to the adenylate-cyclase activator forskolin (Fsk), or to both simultaneously. MethodsAdipocytes generated from primary human progenitor cells were differentiated without exposure to PPAR{gamma} agonists, and treated for 3, 6 or 78 hours to Fsk, to Rsg, or to both simultaneously. Bulk RNASeq, RNAScope, RT-PCR, CRISPR-Cas9 mediated knockout, oxygen consumption and western blotting were used to assess cellular responses. ResultsUCP1 mRNA expression was induced within 3 hours of exposure to either Rsg or Fsk, indicating that Rsgs effect is independent on additional adipocyte differentiation. Although Rsg and Fsk induced distinct overall transcriptional responses, both induced genes associated with calcium metabolism, lipid droplet assembly, and mitochondrial remodeling, denoting core features of human adipocyte beiging. Unexpectedly, we found that Fsk-induced UCP1 expression was reduced by approximately 80% following CRISPR-Cas9-mediated knockout of PNPLA2, the gene encoding the triglyceride lipase ATGL. As anticipated, ATGL knockout suppressed lipolysis; however, the associated suppression of UCP1 induction indicates that maximal cAMP-mediated UCP1 induction requires products of ATGL-catalyzed lipolysis. Supporting this, we observed that the reduction in Fsk-stimulated UCP1 induction caused by ATGL knockout was reversed by Rsg, implying that the role of lipolysis in this process is to generate natural PPAR{gamma} agonists. ConclusionUCP1 transcription is known to be stimulated by transcription factors activated downstream of cAMP-dependent protein kinases. Here we demonstrate that UCP1 transcription can also be acutely induced through PPAR{gamma}-activation. Moreover, both pathways are activated in human adipocytes in response to cAMP, synergistically inducing UCP1 expression. The stimulation of PPAR{gamma} in response to cAMP occurs as a result of the production of natural PPAR{gamma} activating ligands through ATGL-mediated lipolysis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=161 SRC="FIGDIR/small/607465v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@18675a5org.highwire.dtl.DTLVardef@95cb66org.highwire.dtl.DTLVardef@5cb189org.highwire.dtl.DTLVardef@18bac05_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Integration of immune cell-target cell conjugate dynamics changes the time scale of immune control of cancer

The human immune system can recognize, attack, and eliminate cancer cells, but cancers can escape this immune surveillance. The dynamics of these cancer control mechanisms by cells of the adaptive immune system can be captured by variants of ecological predator-prey models. These dynamical systems can describe the interaction of cancer cells and, e.g., effector T cells to form tumor cell-immune cell conjugates, cancer cell killing, immune cell activation, and T cell exhaustion. Target (tumor) cell-T cell conjugation is integral to the adaptive immune systems cancer control or immunotherapy dynamics. However, it is incompletely understood whether conjugate dynamics should be explicitly included in mathematical models of cancer-immune interactions. Here, we analyze the dynamics of a cancer-effector T cell system regarding the impact of explicitly modeling the conjugate compartment to elucidate the role of cellular conjugate dynamics. We formulate a deterministic modeling framework to compare possible equilibria and their stability, such as tumor extinction, tumor-immune coexistence (tumor control), or tumor escape. We also formulate the stochastic analog of this system to analyze the impact of demographic fluctuations that arise when cell populations are small. We find that explicit consideration of a conjugate compartment can change long-term steady-state, critically change the time to reach an equilibrium, alter the probability of tumor escape, and lead to very different extinction time distributions. Thus, we demonstrate the importance of the conjugate compartment in defining tumor-effector interactions. Accounting for transitionary compartments of cellular interactions may better capture the dynamics of tumor control and progression.

immunology↗

bioRxiv2024

A detailed protocol for generating spike trans-complemented SARS-CoV-2 replicons

Multiple approaches have been implemented for basic science studies that attempt to investigate SARS-CoV-2 biology or virology in biosafety level-2 setting. These include pseudotyped-virus based on lentivirus and vesicular stomatitis virus, virus-like particles that only contain the SARS-CoV-2 structural proteins, and single-cycle replicons. Among these, the single-cycle replicons most closely resemble the authentic virus as they essentially include the full viral genome, except for essential elements required for active virus multiplication. In this regard, we previously developed a SARS-CoV-2 replicon system where a Gaussia Dura luciferase-P2A-mNeonGreen reporter cassette replaced viral spike. In this short paper, we present an optimized protocol for the use of this reagent that overcomes previous technical limitations. We demonstrate that co-transfection of this bacmid along with spike plasmid, using the improved protocol, yields high-quality spike bearing SARS-CoV-2 virus particles with single-cycle infectivity. Due to the nature of bacmid construction, this approach is particularly useful for studying the impact of spike mutagenesis on virus evolution in BSL-2 setting.

microbiology↗

bioRxiv2024

Negatively Charged alpha-Synuclein Condensate Modulates Partitioning of Molecules

-Synuclein (Syn) aggregation via liquid-liquid phase separation has recently emerged as a crucial mechanism underlying amyloid fibril formation implicated in Parkinsons disease. However, comprehensive investigations of the physico-chemical properties of Syn condensate remains incomplete. Here, we showed that Syn condensate possesses a highly negative electrostatic potential that spans the whole condensate. This property causes differential partitioning of dye-labeled Syn as well as fluorescent molecules by an order of magnitude depending on their net charges. Consistent with this, the phase separation propensity of Syn is governed by a delicate balance between self-association of Syn and electrostatic repulsion, hence is antagonized by excess negative charge. We further demonstrated that, in differentiated neuron-like SH-SY5Y cells, Syn also forms negatively charged condensate. Our results highlighted the significant impact of Syn condensates electrostatic potential on molecular partitioning, hence calling for close examination of the electrostatic property of other biomolecular condensates.

biophysics↗

bioRxiv2024

Nuclear FAK aggravates CD8+ T cell exhaustion via the SP1-IL-6 axis in colorectal cancer

Nuclear abnormalities such as nuclear deformation are hallmarks of many diseases, including cancer. Accumulating evidence suggests that the dense and mechanically stiff tumor microenvironment promotes nuclear deformation in cancer cells. However, little is known about how nuclear deformation in neoplastic cells regulates immune exhaustion in the tumor microenvironment. Here, we found that lamin A/C-mediated nuclear stiffening in neoplastic cells promotes the nuclear translocation of phosphorylated focal adhesion kinase (pFAK), which is strongly correlated with the heterogeneity and exhaustion of CD8+ T cells within the spatial context of the tumor microenvironment in human colorectal cancer. Mechanistically, we revealed that increased nuclear tension within tumor cells promotes pFAK nuclear translocation, where nuclear pFAK was found to regulate SP1/IL-6-mediated T-cell exhaustion and the transcription of proinflammatory cytokines/chemokines. Pharmacological inhibition or disruption of pFAK nuclear translocation enhanced antitumor immune responses and synergistically potentiated PD-1 and TIM-3 immunotherapy by increasing CD8+ T-cell cytotoxicity and restoring exhaustion in preclinical models of colorectal cancer. These findings highlight the pivotal role of nuclear tension-mediated pFAK translocation into the tumor cell nucleus in regulating CD8+ T-cell exhaustion, suggesting that pFAK is a promising target for advancing cancer immunotherapy.

immunology↗

bioRxiv2024

BOOST: a robust ten-fold expansion method on hour-scale

Expansion microscopy (ExM) enhances the microscopy resolution by physically expanding biological specimens and improves the visualization of structural and molecular details. Numerous ExM techniques and labeling methods have been developed and refined over the past decade to cater to specific research needs. Nonetheless, a shared limitation among current protocols is the extensive time required for sample processing, particularly for challenging-to-expand biological specimens (e.g., formalin-fixed paraffin-embedded (FFPE) sections and large three-dimensional specimens). Here, we have developed a rapid and robust ExM workflow named BOOST, which leverages a series of novel microwave (MW)-accelerated ExM chemistry, resulting in a single-step linear expansion of [~]10x. Specifically, BOOST facilitates a [~]10-fold expansion of cultured cells, tissue sections, and even the challenging-to-expand FFPE sections under merely 90 minutes with heat and surfactant-based protein denaturation. Furthermore, BOOST employs microwave-assisted proteomic staining and immunostaining to facilitate high-resolution visualization of structural and molecular details with significantly enhanced throughput. Noteworthily, BOOST has pioneered a [~]10-fold expansion of large millimeter-sized three-dimensional specimens in approximately three hours. BOOST offers an easily adaptable workflow based on stable and common reagents, thus boosting the potential adoption of ExM methods in biological investigations.

bioengineering↗

bioRxiv2024

Substrate Rigidity Modulates Segmentation Clock Dynamics in Isolated Presomitic Mesoderm Cells

The segmentation clock, a genetic oscillator in the presomitic mesoderm (PSM), is known to be influenced by biochemical signals, yet its potential regulation by mechanical cues remains unclear. The complex PSM microenvironment has made it challenging to isolate the effects of mechanical signals on clock behavior. Here we investigated how mechanical stimuli affect clock oscillations by culturing zebrafish PSM cells on bioengineered elastic substrates (PDMS micropost arrays) with tunable rigidities ranging from 0.6 to 1,200 kPa. We observed an inverse sigmoidal relationship between substrate rigidity and the percentage of oscillating PSM cells, with a switching rigidity threshold between 3-6 kPa. The oscillation periods of oscillating PSM cells showed a consistently broad distribution across the substrate rigidity conditions tested. Moreover, these oscillatory PSM cells exhibited distinct biophysical properties, including reduced motility, contractility, and sustained circularity, compared to non-oscillating ones. These findings highlight a role of cell-substrate interactions in regulating segmentation clock behavior, providing insights into the mechanobiology of somitogenesis. HighlightsO_LIOscillatory behaviors of single PSM cells respond to substrate rigidity in a switch-like manner, transitioning from an oscillatory state to a quiescent state at a critical rigidity threshold between 2.9 kPa and 6 kPa. C_LIO_LIIncreased substrate rigidity significantly suppresses the percentage of oscillating PSM cells, while oscillation period and cycle number show no consistent rigidity-dependent trend. C_LIO_LINon-oscillating PSM cells exhibit distinct biophysical properties compared to oscillating ones, including reduced circularity, a polarized and elongated morphology, greater motility, and increased contractility. C_LIO_LIAggregates of PSM cells exhibit similar trends in response to substrate rigidity changes, except for increased oscillation percentages across different rigidity conditions, suggesting a potential interplay between cell-cell and cell-matrix communications in influencing clock oscillation behavior. C_LI

developmental biology↗

bioRxiv2024

A vacuolar invertase gene SlVI modulates sugar metabolism and postharvest fruit quality and resistance in tomato

Sugars act as signaling molecules to modulate various growth processes and enhance plant tolerance to various abiotic and biotic stresses. Moreover, sugars contribute to the post-harvest flavor in fleshy fruit crops. To date, the regulation of sugar metabolism and its effect in plant growth, fruit ripening, postharvest quality and resistance remains not fully understood. In this study, we investigated the role of tomato gene encoding a vacuolar invertase, hydrolyzing sucrose to glucose and fructose. SlVI is specifically expressed during the tomato fruit ripening process. We found that overexpression of SlVI resulted in increased leaf size and early flowering, while knockout of SlVI led to increased fruit sucrose content, enhanced fruit firmness, elevated resistance of postharvest fruit to Botrytis cinerea. Moreover, the content of naringenin and total soluble solids was significantly increased in SlVI knockout fruit at postharvest stage. Transcriptome analysis showed a negative feedback regulation triggered by sucrose accumulation in SlVI knockout fruit resulting in a downregulation of BAM3 and AMY2, which are critical for starch degradation. Moreover, genes associated with cell wall, cutin, wax, and flavonoid biosynthesis and pathogen resistance were upregulated in SlVI knockout fruit. Conversely, the expression levels of genes involved in cell wall degradation were decreased in knockout fruit. These results are consistent with the enhanced postharvest quality and resistance. Our findings not only provide new insights into the relationship between tomato fruit sucrose content and postharvest fruit quality, but also suggest new strategies to enhance fruit quality and extend postharvest shelf life.

plant biology↗

bioRxiv2024

Hair follicle-resident progenitor cells are a major cellular contributor to heterotopic subcutaneous ossifications in a mouse model of Albright hereditary osteodystrophy

Heterotopic ossifications (HOs) are the pathologic process by which bone inappropriately forms outside of the skeletal system. Despite HOs being a persistent clinical problem in the general population, there are no definitive strategies for their prevention and treatment due to a limited understanding of the cellular and molecular mechanisms contributing to lesion development. One disease in which the development of heterotopic subcutaneous ossifications (SCOs) leads to morbidity is Albright hereditary osteodystrophy (AHO). AHO is caused by heterozygous inactivation of GNAS, the gene that encodes the -stimulatory subunit (Gs) of G proteins. Previously, we had shown using our laboratorys AHO mouse model that SCOs develop around hair follicles (HFs). Here we show that SCO formation occurs due to inappropriate expansion and differentiation of HF-resident stem cells into osteoblasts. We also show in AHO patients and mice that Secreted Frizzled Related Protein 2 (SFRP2) expression is upregulated in regions of SCO formation and that elimination of Sfrp2 in male AHO mice exacerbates SCO development. These studies provide key insights into the cellular and molecular mechanisms contributing to SCO development and have implications for potential therapeutic modalities not only for AHO patients but also for patients suffering from HOs with other etiologies.

cell biology↗

bioRxiv2024

IDH1 regulates human erythropoiesis by eliciting chromatin state reprogramming in a metabolic enzyme independent manner

Isocitrate dehydrogenase 1 (IDH1) is the key enzyme that was involved in the modulation of cellular metabolism, epigenetic modification and redox states homeostasis. Gain-of-function mutations and decreased expression of IDH1 have been demonstrated to be tightly associated with the pathogenesis of various myeloid malignancies characterized by ineffective erythropoiesis, such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, the function and mechanism of IDH1 in human erythropoiesis still remains to be further explored. Here, utilizing the human erythropoiesis system, we present an evidence of IDH1-mediated chromatin state reprogramming besides its well-characterized metabolism effects. We showed that knockdown of IDH1 induced chromatin reorganization and subsequently led to abnormalities of various key biological events in erythroid precursors, which could not be rescued by addition of reactive oxygen species (ROS) scavengers or supplementation of -ketoglutarate (-KG). We further revealed that deficiency of IDH1 induces genome-wide changes in distribution and intensity of multiple histone marks, among which H3K79me3 was identified as a critical factor in chromatin state reprogramming. Integrated analysis of ChIP-seq, ATAC-seq and RNA-seq recognized that SIRT1 was the key gene affected by IDH1 deficiency. Thus, our current work provided novel insights for further clarifying fundamental biological function of IDH1 which has substantial implications for an in-depth understanding of pathogenesis of diseases with IDH1 dysfunction and accordingly development of therapeutic strategies. Key PointsO_LIIDH1 deficiency impaired terminal erythropoiesis; C_LIO_LIIDH1 deficiency leads to chromatin states reprogramming by causing aberrant accumulation and genome-wide re-distribution of H3K79me3; C_LIO_LIDyserythropoiesis is caused by upregulation of SIRT1 induced by H3K79me3 accumulation. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/599556v2_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@328986org.highwire.dtl.DTLVardef@1e2e8a0org.highwire.dtl.DTLVardef@166885org.highwire.dtl.DTLVardef@1283261_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Timed sulfonylurea modulation improves locomotor and sensory dysfunction following spinal cord injury

Traumatic injury to the spinal cord (SCI) results in immediate necrosis and delayed secondary expansion of neurological damage, often resulting in lifelong paralysis, neurosensory dysfunction, and chronic pain. Progress hemorrhagic necrosis (PHN) and excessive excitation are the primary sources of neural injury triggered by various insults, causing neuronal cytotoxicity and the gradual enlargement of lesions. Recent approaches have involved blocking TRPM4, a contributor to PHN, using the sulfonylurea (SUR) subunits regulator glibenclamide. However, since SUR subunits are expressed in both neurons and glial cells in the spinal cord and sensory neurons, forming functional KATP channels, the use of glibenclamide can exacerbate the development of SCI-induced chronic pain. In this study, we explored a treatment strategy involving the administration of glibenclamide, which suppresses PHN, and diazoxide, which protects against neuronal excitation and inflammation, at different time intervals post-SCI. Our goal is to determine whether this approach significantly enhances both sensory and motor function. Contusive SCI was induced at spinal segment T10 in adult male and female rats. Immunostaining, electrophysiological recording in vitro, spectrophotometric assay, Western blot, and behavioral tests were performed to detect the outcomes. Results showed that the timed application of glibenclamide and diazoxide at various post-SCI time points significantly improved locomotor function and mitigated the development of SCI-induced chronic pain. These preclinical studies introduce a promising treatment strategy for addressing SCI-induced dysfunction.

neuroscience↗

bioRxiv2024

Glutamate (E299) is a key residue in the evolutionarily divergence of the SAM-dependent methyltransferases DnrK and RdmB in anthracycline biosynthesis

A novel sub-class of S-adenosyl-L-methionine (SAM)-dependent methyltransferases catalyze atypical chemical transformations in the biosynthesis of anthracyclines, which include antineoplastic compounds. Intriguingly, the closely related methyltransferases DnrK and RdmB have markedly divergent functions. We investigated their catalytic activities and discovered a previously unknown 10-hydroxylation activity for DnrK and 4-O-methylation activity for RdmB. Isotope-labeling demonstrated that the 10-hydroxy group introduced by DnrK is derived from water molecules while RdmB utilizes O2. A single residue, E299, was the key modulator in the differing catalytic functions of DnrK and RdmB, especially the decarboxylative oxidation activity. Furthermore, the multifunctionality of DnrK was demonstrated to be SAM-tunable and concerted, whereas RdmB activity was cofactor-dependent and stepwise. Our findings expand the versatility and importance of methyltransferases and should aid studies to enrich the structural diversity and bioactivities of anthracyclines.

biochemistry↗

bioRxiv2024

Gra-CRC-miRTar: The pre-trained nucleotide-to-graph neural networks to identify potential miRNA targets in colorectal cancer

Colorectal cancer (CRC) is the third most diagnosed cancer and the second deadliest cancer worldwide representing a major public health problem. In recent years, increasing evidence has shown that microRNA (miRNA) can control the expression of targeted human messenger RNA (mRNA) by reducing their abundance or translation, acting as oncogenes or tumor suppressors in various cancers, including CRC. Due to the significant up-regulation of oncogenic miRNAs in CRC, elucidating the underlying mechanism and identifying dysregulated miRNA targets may provide a basis for improving current therapeutic interventions. In this paper, we proposed Gra-CRC-miRTar, a pre-trained nucleotide-to-graph neural network framework, for identifying potential miRNA targets in CRC. Different from previous studies, we constructed two pre-trained models to encode RNA sequences and transformed them into de Bruijn graphs. We employed different graph neural networks to learn the latent representations. The embeddings generated from de Bruijn graphs were then fed into a Multilayer Perceptron (MLP) to perform the prediction tasks. Our extensive experiments show that Gra-CRC-miRTar achieves better performance than other deep learning algorithms and existing predictors. In addition, our analyses also successfully revealed 172 out of 201 functional interactions through experimentally validated miRNA-mRNA pairs in CRC. Collectively, our effort provides an accurate and efficient framework to identify potential miRNA targets in CRC, which can also be used to reveal miRNA target interactions in other malignancies, facilitating the development of novel therapeutics.

bioinformatics↗

bioRxiv2024

Problem-Solving as a Language: A Computational Lens into Human and Monkey Intelligence

1Human intelligence is characterized by our remarkable ability to solve complex problems. This involves planning a sequence of actions that leads us from an initial state to a desired goal state. Quantifying and comparing problem-solving capabilities across species and finding its evolutional roots is a fundamental challenge in cognitive science, and is critical for understanding how the brain carries out this intricate process. In this study, we introduce the Language of Problem-Solving (LoPS) model as a novel quantitative framework that investigates the structure of problem-solving behavior through a language model. We adapted the classic Pac-Man game as a cross-species behavioral paradigm to test both humans and macaque monkeys. Using the LoPS model, we extracted the latent structure -- or grammar -- embedded in the agents gameplay, revealing the non-Markovian temporal structure of their problem-solving behavior. The LoPS model captured fine-grained individual differences among the players and revealed the striking differences in the complexity and hierarchical organization of problem-solving behavior between humans and monkeys, reflecting the distinct cognitive capabilities of each species. Furthermore, both humans and monkeys evolved their LoPS grammars during learning, progressing from simpler to more complex ones, suggesting that the language of problem-solving is not fixed, but rather evolves to support more sophisticated and efficient problem-solving. Through the lens of a language model, our study provides insights into how humans and monkeys break down problem-solving into compositional units and navigate complex tasks. This framework deepens our understanding of human intelligence and its evolution, and establishes a foundation for future investigations of the neural mechanisms of problem-solving.

neuroscience↗

bioRxiv2024

Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CLpro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLpro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discovered a series of novel potent non-covalent PLpro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLpro with leads revealed that the residues D164 and Q269 around the S2 site are critical for improving the inhibitors potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50 ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50 of 81.6 nM and 2.66 M, respectively. Oral administration of the compound resulted in significantly improved survival and notable reductions in lung viral loads and lesions in SARS- CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PLpro inhibitor is a promising SARS-CoV-2 therapy.

microbiology↗

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

Super Pangenome of Grapevines Empowers Improvement of the Oldest Domesticated Fruit

Grapevine (Vitis) is the oldest domesticated fruit crop with great cultural and economic importance. Here, we assemble and annotate haplotype-resolved genomes of 72 Vitis accessions including 25 wild and 47 cultivated grapevines, and a haplotype-resolved complete genome of V. vinifera. Coalescent phylogenomics of 142 haplotype genomes disentangles the mysterious hybridization history of grapevines, revealing enormous genetic diversity among species. Pangenome analysis together with phenotyping data reveals that European cultivars, more susceptible to the most destructive disease downy mildew (DM), had a smaller repertoire of disease resistance genes of NLR family. Through extensive structural variation (SV) characterization, phenotyping, transcriptome profiling of 113 Vitis accessions, and SV-eQTL analysis, we have identified over 79 SVs and their relevant genes significantly associated with DM resistance, exemplified by a lysine histidine transporter, VvLHT8. This haplotype-resolved complete genome and pangenome of Vitis genus will accelerate grapevine breeding and enrich our understanding of the evolution and biology of grapevines.

plant biology↗

bioRxiv2024

BayVarC: an ultra-sensitive ctDNA variant caller using Bayesian approach

In liquid biopsy, it is critical to detect variants of allele frequencies as low as 0.1% or even lower, especially when used to monitor secondary resistant mutations and minimal residual disease. Despite the efforts on improving experimental design, it remains challenging to distinguish low-frequency variants from technical noises in the downstream bioinformatic analysis. Here, we introduce BayVarC, a novel variant caller specifically designed for variant calling in liquid biopsy. It applies Bayesian inference to accurately quantify noise level in a locus-specific manner, enabling the discrimination between technical noise and low-frequency cancer variants. Detailed in-silico simulation and in-vitro experiments demonstrated BayVarC superior performance over existing state-of-the-art tools. BayVarC can effectively detect low frequency variants while maintaining low false positive rate (0.05 FP/KB). Meanwhile, it achieves Limit of Detection (LoD) as low as 0.1%. Furthermore, empowered by its architecture, BayVarC shows promising applicability in Minimal Residual Disease (MRD) detection. BayVarC is freely available at https://github.com/GenetronBioinfomatics/BayVarC.

bioinformatics↗