Biology subjects

Hu, Q.

Publications and source records attributed to Hu, Q..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Filament structures unveil the dynamic organization of human acetyl-CoA 1 carboxylase

Human acetyl-CoA carboxylases (ACCs) catalyze the carboxylation of acetyl-CoA, which is the rate-limiting step in fatty acid synthesis. The molecular mechanism underlying the dynamic organization of ACCs is largely unknown. Here, we determined the cryo-EM structure of human ACC1 in its inactive state, which forms a unique filament structure and is in complex with acetyl-CoA. We also determined the cryo-EM structure of human ACC1 activated by dephosphorylation and citrate treatment, at a resolution of 2.55 [A]. Notably, the covalently linked biotin binds to a site that is distant from the acetyl-CoA binding site when acetyl-CoA is absent, suggesting a potential coordination between biotin binding and acetyl-CoA binding. These findings provide insights into the structural dynamics and regulatory mechanisms of human ACCs. TeaserCryo-EM structures reveal how human acetyl-CoA carboxylase 1 changes shape to control its activity.

biochemistry↗

bioRxiv2024

Natural killer cell migration in HIV-infected individuals is inhibited by impairment of HIF-1alpha-mediated glycolysis

Natural killer (NK) cells serve as the first line of defense of the immune system and play a crucial role in fighting against HIV infection. The effective function of NK cells is closely related to their migration ability, but the status of NK cell migration in HIV-infected individuals and the regulation mechanism for NK cell migration remains unknown. Here, we found that NK cell migration was significantly impaired in HIV-infected individuals, lower in immune non-responders (INRs) compared with immune responders (IRs), and positively correlated with CD4+ T cell counts. Further investigations showed that the decreased NK cell migration in HIV infection was caused by the impairment of glycolysis. Mechanistically, we found that NK cell migration was regulated by HIF-1 pathway, and inhibitory receptor TIGIT restrained HIF-1 expression by inhibiting PI3K/AKT/mTORC1 or ERK signaling pathway, consequently weakening the glycolysis of NK cells in HIV-infected individuals, and ultimately leading to down-regulation of migration. Collectively, we uncovered a mechanism of reduced NK cell migration in HIV infection and provided a new insight for immunotherapy in HIV infection. In BriefThe effective function of NK cells is closely related to its migration ability. The authors show that impaired NK cell migration in HIV-infected individuals is caused by TIGIT inhibiting HIF-1-mediated glycolysis via PI3K/AKT/mTORC1 or ERK pathway.

immunology↗

bioRxiv2024

Pandemic Vibrio parahaemolyticus wave succession by gene loss

While spontaneous mutation and gene acquisition are well-established drivers of pathogen adaptation, the role of gene loss remains underexplored. Here, we investigated the emergence and diversification of the pandemic clone (PC) of Vibrio parahaemolyticus through large-scale phylogenomic analysis of 8,684 global isolates. The PC rapidly acquired multiple marker genes and genomic islands, subsequently diverging into successive sublineages mediating independent waves of cross-country transmission, as also observed in V. cholerae. Wave succession in the last two decades was driven by loss of putrescine utilization (Puu) genes, conferring phenotypic advantages for environmental adaptation (enhanced biofilm formation) and human transmission (increased cell adhesion/intestinal colonization, reduced virulence), consistent with the virulence trade-off hypothesis. We identified Puu-gene loss in multiple bacterial genera, with effects on biofilm and adhesion replicated in V. cholerae and Escherichia coli, suggesting convergent evolution and universal phenotypic effects. Our results highlight the indispensable role of gene loss in bacterial pathogen adaptation.

microbiology↗

bioRxiv2024

Structural insights into human propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC)

Propionyl-CoA carboxylase (PCC) and 3-methylcrotonyl-CoA carboxylase (MCC) are biotin-dependent carboxylases (BDCs) that catalyze the metabolism of odd-chain fatty acids, cholesterol, and specific amino acids. For human PCC and MCC, only a low-resolution (15 [A]) three-dimensional structure of human PCC has been reported. Here, we report high-resolution (2.29-3.38 [A]) cryo-EM structures of human PCC and MCC holoenzymes in their apo and acetyl-CoA and propionyl-CoA-bound states. Propionyl-CoA and acetyl-CoA bind to PCC with almost identical binding modes, indicating that the acyl-CoA specificity of PCC is largely attributed to minor differences in interactions mediated by the acyl groups. In MCC, biotin is relocated from an exo-site to an endo-site upon acetyl-CoA binding, suggesting coordination between biotin binding and acyl-CoA binding. Our work provides insights into the substrate specificity and catalytic process of BDCs.

biochemistry↗

bioRxiv2024

Granzyme B-based CAR T cells block metastasis by eliminating circulating tumor cells

Chimeric antigen receptor (CAR) T cells have limited efficacy against solid tumors due to the hostile microenvironment. Circulating tumor cells (CTCs) are essential to metastasis, which is the cause of most of cancer-related death. Here, we generated GrB-CAR T cells targeting membrane-bound HSP70 (mHSP70), a highly tumor-specific antigen detected in numerous cancers. GrB-CAR T cells exhibited potent cytotoxicity against a broad spectrum of cancer cell lines and stem-like cancer cells in vitro and effectively inhibited xenograft tumor growth in vivo. Importantly, GrB-CAR T cells markedly decreased the number of CTCs and, therefore, hindered cancer metastasis in spontaneous metastasis models with uncontrollable primary tumor growth, a scenario commonly encountered in clinical trials of CAR T therapies for solid tumors. Furthermore, despite the 100% homology between human and macaque HSP70 protein, the autotransplantation of macaque T cells expressing human GrB-CAR did not cause any obvious toxic effects. These results not only demonstrate GrB-CAR T cells as a safe and effective tactic with broad-spectrum anticancer activity, but also offer strong experimental evidence and proof-of-concept validation for CAR T cell-mediated metastasis inhibition by targeting CTCs.

immunology↗

bioRxiv2024

Navigated range expansion promotes migratory culling

Motile organisms can expand into new territories and increase their fitness, while nonmotile viruses usually depend on host migration to spread across long distances. In general, faster host motility facilitates virus transmission. However, recent ecological studies have also shown that animal host migration can reduce viral prevalence by removing infected individuals from the migratory group. Here, we use a bacteria-bacteriophage co-propagation system to investigate how host motility affects viral spread during range expansion. We find that phage spread during chemotaxis-driven navigated range expansion decreases as bacterial migration speed increases. Theoretical and experimental analyses show that the navigated migration leads to a spatial sorting of infected and uninfected hosts in the co-propagating front of bacteria-bacteriophage, with implications for the number of cells left behind. The preferential loss of infected cells in the co-propagating front inhibits viral spread. Further increase in host migration speed leads to a phase transition that eliminates the phage completely. These results illustrate that navigated range expansion of the host can promote the migratory culling of infectious diseases in the migration group. Significance StatementHost migration is commonly believed to accelerate the spread of infectious diseases. However, recent ecological studies suggest that migration may impede this spread. In our study, we developed a synthetic host-virus co-propagation model to explore the impact of host range expansion on the interplay between host mobility and virus spatial distribution. Our experimental and theoretical analysis revealed the spatial sorting of uninfected and infected hosts in the navigated propagating front leads to faster back diffusion of infected hosts. This self-organized structure allowed the migrating host population to eradicate the infectious disease, independent of intricate host-virus dynamics.

systems biology↗

bioRxiv2024

DeepPrep: An accelerated, scalable, and robust pipeline for neuroimaging preprocessing empowered by deep learning

Neuroimaging has entered the era of big data. However, the advancement of preprocessing pipelines falls behind the rapid expansion of data volume, causing significant computational challenges. Here, we present DeepPrep, a pipeline empowered by deep learning and workflow manager. Evaluated on over 55,000 scans, DeepPrep demonstrates a 11-fold acceleration, exceptional scalability, and robustness compared to the current state-of-the-art pipeline, providing a promising solution to meet the scalability requirements of neuroimaging.

neuroscience↗

bioRxiv2024

A single-cell 3D spatiotemporal multi-omics atlas from Drosophila embryogenesis to metamorphosis

The development of a multicellular organism is a highly intricate process tightly regulated by numerous genes and pathways in both spatial and temporal manners. Here, we present Flysta3D, a comprehensive multi-omics atlas of the model organism Drosophila, spanning its developmental lifespan from embryo to pupa. Our datasets encompass 3D single-cell spatial transcriptomic, single-cell transcriptomic, and single-cell chromatin accessibility information. By integrating these multi-dimensional data, we constructed cell state trajectories that uncover the detailed profiles of tissue development. With a focus on the central nervous system (CNS) and midgut, we dissected the spatiotemporal dynamics of gene regulatory networks, cell type diversity, and morphological changes from a multi-omics perspective. This extensive atlas provides an unprecedentedly rich resource and serves as a systematic platform for studying Drosophila development with integrated single-cell data at an ultra-high spatiotemporal resolution.

developmental biology↗

bioRxiv2024

Individualized functional connectivity markers associated with motor and mood symptoms of Parkinson's disease

Parkinsons disease (PD) is a complex neurological disorder characterized by many motor and non-motor symptoms. While most studies focus on the motor symptoms of the disease, it is important to identify markers that underlie different facets of the disease. In this case-control study, we sought to discover reliable, individualized functional connectivity markers associated with both motor and mood symptoms of PD. Using functional MRI, we extensively sampled 166 patients with PD (64 women, 102 men; mean age=61.8 years, SD=7.81) and 51 healthy control participants (32 women, 19 men; mean age=55.68 years, SD=7.62). We found that a model consisting of 44 functional connections predicted both motor (UPDRS-III: Pearson r=0.21, FDR-adjusted p=0.006) and mood symptoms (HAMD: Pearson r=0.23, FDR-adjusted p=0.006; HAMA: Pearson r=0.21, FDR-adjusted p=0.006). Two sets of connections contributed differentially to these predictions. Between-network connections, mainly connecting the sensorimotor and visual large-scale functional networks, substantially contributed to the prediction of motor measures, while within-network connections in the insula and sensorimotor network contributed more so to mood prediction. The middle to posterior insula region played a particularly important role in predicting depression and anxiety scores. We successfully replicated and generalized our findings in two independent PD datasets. Taken together, our findings indicate that sensorimotor and visual network markers are indicative of PD brain pathology, and that distinct subsets of markers are associated with motor and mood symptoms of PD.

neuroscience↗

bioRxiv2023

The somato-cognitive action network links diverse neuromodulatory targets for Parkinson's disease

The newly-recognized somato-cognitive action network (SCAN) is posited to be important in movement coordination. Functional disruptions in Parkinsons disease (PD) correspond with complex, non-effector-specific motor symptoms, indicating that SCAN dysfunction may underlie these symptoms. Along the same lines, the SCAN may link multiple neuromodulatory targets used for PD treatment. To investigate the role of the SCAN in PD, we leveraged resting-state precision functional mapping, analyzing data from 673 individuals across 6 independent datasets and 5 types of neuromodulation. Our findings revealed functional abnormalities within the SCAN in PD patients and the selective involvement of the SCAN in diverse neuromodulatory targets. Moreover, our data suggests causal links between SCAN connectivity changes and motor symptom alleviation following both invasive and non-invasive neuromodulation. Collectively, these findings underscore the critical role of the SCAN in the pathophysiology of PD and its brain stimulation treatments, and suggest the SCAN as a promising candidate target for neuromodulation.

neuroscience↗

bioRxiv2023

Resistance mechanisms of SARS-CoV-2 3CLpro to the non-covalent inhibitor WU-04

Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04. Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04 binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04 binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpros C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.

microbiology↗

bioRxiv2023

scCancer2: data-driven in-depth annotations of the tumor microenvironment at single-level resolution

Single-cell RNA-seq (scRNA-seq) is a powerful technique for decoding the complex cellular compositions in the tumor microenvironment (TME). As previous studies have defined many meaningful cell subtypes in several tumor types, there is a great need to computationally transfer these labels to new datasets. Also, different studies used different approaches or criteria to define the cell subtypes for the same major cell lineages. The relationships between the cell subtypes defined in different studies should be carefully evaluated. In this updated package scCancer2, designed for integrative tumor scRNA-seq data analysis, we developed a supervised machine learning framework to annotate TME cells with annotated cell subtypes from 15 scRNA datasets with 594 samples in total. Based on the trained classifiers, we quantitatively constructed the similarity maps between the cell subtypes defined in different references by testing on all the 15 datasets. Secondly, to improve the identification of malignant cells, we designed a classifier by integrating large-scale pan-cancer TCGA bulk gene expression datasets and scRNA-seq datasets (10 cancer types, 159 samples, 652,160 cells). This classifier shows robust performances when no internal confidential reference cells are available. Thirdly, this package also integrated a module to process the seq-based spatial transcriptomic data and analyze the spatial features of TME. Software availability: http://lifeome.net/software/sccancer2/.

bioinformatics↗

bioRxiv2023

Non-homologous end joining shapes the genomic rearrangement landscape of chromothripsis from mitotic errors

Errors in mitosis can generate micronuclei that entrap mis-segregated chromosomes, which are susceptible to catastrophic fragmentation through a process termed chromothripsis. The reassembly of fragmented chromosomes by error-prone DNA double-strand break (DSB) repair generates a spectrum of simple and complex genomic rearrangements that are associated with human cancers and disorders. How specific DSB repair pathways recognize and process these lesions remains poorly understood. Here we used CRISPR/Cas9 to systematically inactivate distinct DSB processing or repair pathways and interrogated the rearrangement landscape of fragmented chromosomes from micronuclei. Deletion of canonical non-homologous end joining (NHEJ) components, including DNA-PKcs, LIG4, and XLF, substantially reduced the formation of complex rearrangements and shifted the rearrangement landscape toward simple alterations without the characteristic patterns of cancer-associated chromothripsis. Following reincorporation into the nucleus, fragmented chromosomes localize within micronuclei bodies (MN bodies) and undergo successful ligation by NHEJ within a single cell cycle. In the absence of NHEJ, chromosome fragments were rarely engaged by polymerase theta-mediated alternative end-joining or recombination-based mechanisms, resulting in delayed repair kinetics and persistent 53BP1-labeled MN bodies in the interphase nucleus. Prolonged DNA damage signaling from unrepaired fragments ultimately triggered cell cycle arrest. Thus, we provide evidence supporting NHEJ as the exclusive DSB repair pathway generating complex rearrangements following chromothripsis from mitotic errors.

cell biology↗

bioRxiv2023

Tandemly duplicated MYB genes specifically in the Phaseoleae lineage are functionally diverged in the regulation of anthocyanin biosynthesis

Gene duplications have long been recognized as a driving force in the evolution of genes, giving rise to novel functions. The soybean genome is characterized by a large extent of duplicated genes. However, the extent and mechanisms of functional divergence among these duplicated genes in soybean remain poorly understood. In this study, we revealed that tandem duplication of MYB genes, which occurred specifically in the Phaseoleae lineage, exhibited a stronger purifying selection in soybean compared to common bean. To gain insights into the diverse functions of these MYB genes in anthocyanin biosynthesis, we examined the expression, transcriptional activity, metabolite, and evolutionary history of four MYB genes (GmMYBA5, GmMYBA2, GmMYBA1 and Glyma.09g235000), which were presumably generated by tandem duplication in soybean. Our data revealed that Glyma.09g235000 had become a pseudogene, while the remaining three MYB genes exhibited strong transcriptional activation activity and promoted anthocyanin biosynthesis in different soybean tissues. Furthermore, GmMYBA5 produced distinct compounds in Nicotiana benthamiana leaves compared to GmMYBA2 and GmMYBA1 due to variations in their DNA binding domains. The lower expression of anthocyanin related genes in GmMYBA5 resulted in lower levels of anthocyanins compared to GmMYBA2 and GmMYBA1. Metabolomics analysis further demonstrated the diverse and differential downstream metabolites, suggesting their functional divergence in metabolites following gene duplication. Together, our data provided evidence of functional divergence within the MYB gene cluster following tandem duplication, which shed light on the potential evolutionary direction of gene duplications during legume evolution.

evolutionary biology↗

bioRxiv2023

Natural Circulation of Tick-borne Severe Fever with Thrombocytopenia Syndrome Virus in the City Ecosystem, China

Severe fever with thrombocytopenia syndrome virus (SFTSV) is rapidly expanding its range in China, because of the accelerated spread of the parthenogenetic Haemaphysalis longicornis, Asian long-horned tick (ALT). In this letter, we report the urban circulation of SFTSV between ALTs and hedgehogs in Beijing, China. HighlightsHedgehogs and ALTs can maintain the natural circulation of SFTSV in the city ecosystem. Hedgehogs and ALTs are becoming common in Beijing. Parthenogenetic ALTs are discovered in Beijing.

microbiology↗

bioRxiv2023

High-resolution Dynamic Human Brain Neural Activity Recording Using 3T MRI

Despite extensive research over decades, a non-invasive technique capable of capturing neural activities in the human brain with high spatiotemporal resolution is still lacking. The recently proposed direct imaging of neuronal activity (DIANA) using ultrahigh-field magnetic resonance imaging (MRI) has shown promise, but the translation from anesthetized mice to awake humans poses a significant challenge. Here we present Time Resolved ImaGing of Global Electroneurophysiological Record (TRIGGER), a novel technique that enables the direct detection of neural activity in the awake human brain using 3T MRI. In 18 participants, visual responses were captured at 5-mm spatial resolution and 1.4-ms temporal resolution. Importantly, the delay in stimulus presentation reliably corresponded to the latency of neural responses on a millisecond scale. Furthermore, when stimuli were presented to one visual field, the responses in two hemispheres exhibited the expected time difference. This non-invasive mapping approach holds the potential to elucidate neural dynamics underlying human brain function and disorders.

neuroscience↗

bioRxiv2023

RNA structures and dynamics with A resolution revealed by x-ray free electron lasers

RNA macromolecules, like proteins, fold to assume shapes that are intimately connected to their broadly recognized biological functions; however, because of their high charge and dynamic nature, RNA structures are far more challenging to determine. We introduce an approach that exploits the high brilliance of x-ray free electron laser sources to reveal the formation and ready identification of [A] scale features in structured and unstructured RNAs. New structural signatures of RNA secondary and tertiary structures are identified through wide angle solution scattering experiments. With millisecond time resolution, we observe an RNA fold from a dynamically varying single strand through a base paired intermediate to assume a triple helix conformation. While the backbone orchestrates the folding, the final structure is locked in by base stacking. In addition to understanding how RNA triplexes form and thereby function as dynamic signaling elements, this new method can vastly increase the rate of structure determination for these biologically essential, but mostly uncharacterized macromolecules.

biophysics↗

bioRxiv2023

An autoinhibited state of 53BP1 revealed by chemical probes and protein engineering

The recruitment of 53BP1 to chromatin, mediated by its recognition of histone H4 dimethylated at lysine 20 (H4K20me2), is important for DNA double-strand break repair. Using a series of small molecule antagonists, we demonstrate a conformational equilibrium between an open and a pre-existing lowly populated closed state of 53BP1 in which the H4K20me2 binding surface is buried at the interface between two interacting 53BP1 molecules. In cells, these antagonists inhibit the chromatin recruitment of wild type 53BP1, but do not affect 53BP1 variants unable to access the closed conformation despite preservation of the H4K20me2 binding site. Thus, this inhibition operates by shifting the conformational equilibrium toward the closed state. Our work therefore identifies an auto-associated form of 53BP1 -- autoinhibited for chromatin binding -- that can be stabilized by small molecule ligands encapsulated between two 53BP1 protomers. Such ligands are valuable research tools to study the function of 53BP1 and have the potential to facilitate the development of new drugs for cancer therapy.

biochemistry↗