Biology subjects

Chen, Q.

Publications and source records attributed to Chen, Q..

At least 271 records · Page 15Linked to original sources

bioRxiv2023

SPADE: Spatial Deconvolution for Domain Specific Cell-type Estimation

The advent of spatial transcriptomics technology has allowed for the acquisition of gene expression profiles with multi-cellular resolution in a spatially resolved manner, presenting a new milestone in the field of genomics. However, the aggregate gene expression from heterogeneous cell types obtained by these technologies poses a significant challenge for a comprehensive delineation of cell type-specific spatial patterns. Here, we propose SPADE (SPAtial DEconvolution), an in-silico method designed to address this challenge by incorporating spatial patterns during cell type decomposition. SPADE utilizes a combination of single-cell RNA sequencing data, spatial location information, and histological information to computationally estimate the proportion of cell types present at each spatial location. In our study, we showcased the effectiveness of SPADE by conducting analyses on synthetic data. Our results indicated that SPADE was able to successfully identify cell type-specific spatial patterns that were not previously identified by existing deconvolution methods. Furthermore, we applied SPADE to a real-world dataset analyzing the developmental chicken heart, where we observed that SPADE was able to accurately capture the intricate processes of cellular differentiation and morphogenesis within the heart. Specifically, we were able to reliably estimate changes in cell type compositions over time, which is a critical aspect of understanding the underlying mechanisms of complex biological systems. These findings underscore the potential of SPADE as a valuable tool for analyzing complex biological systems and shedding light on their underlying mechanisms. Taken together, our results suggest that SPADE represents a significant advancement in the field of spatial transcriptomics, providing a powerful tool for characterizing complex spatial gene expression patterns in heterogeneous tissues.

bioinformatics↗

bioRxiv2023

Multidimensional responses of ecological stability to eutrophication in grasslands

Eutrophication usually impacts biodiversity, species composition, and functioning of grassland communities. Whether such effects propagate to influence the stability of these community aspects is unknown. Using standardized experiments across 55 global grasslands, we quantified the effects of nutrient addition on five stability facets (i.e., temporal invariability and resistance during and recovery after dry and wet growing seasons) for three community aspects (i.e., aboveground biomass, community composition, and species richness). Nutrient addition reduced the temporal invariability and resistance of species richness and community composition, but not biomass, during dry and wet growing seasons. Temporal invariability and resistance during, but not recovery after, dry and wet growing seasons were strongly positively correlated in both ambient and eutrophic conditions. This indicates that maintaining and restoring the stability of plant communities requires increasing resistance rather than recovery. Harnessing the complexity of ecological stability provides new insights for grassland ecosystem sustainability in a changing world.

ecology↗

bioRxiv2023

Genetic and environmental contributions to ancestry differences in gene expression in the human brain

Ancestral differences in genomic variation are determining factors in gene regulation; however, most gene expression studies have been limited to European ancestry samples or adjusted for ancestry to identify ancestry-independent associations. We instead examined the impact of genetic ancestry on gene expression and DNA methylation (DNAm) in admixed African/Black American neurotypical individuals to untangle effects of genetic and environmental factors. Ancestry-associated differentially expressed genes (DEGs), transcripts, and gene networks, while notably not implicating neurons, are enriched for genes related to immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinsons disease, and 30% of heritability for Alzhemiers disease. Ancestry-associated DEGs also show general enrichment for heritability of diverse immune-related traits but depletion for psychiatric-related traits. The cell-type enrichments and direction of effects vary by brain region. These DEGs are less evolutionarily constrained and are largely explained by genetic variations; roughly 15% are predicted by DNAm variation implicating environmental exposures. We also compared Black and White Americans, confirming most of these ancestry-associated DEGs. Our results highlight how environment and genetic background affect genetic ancestry differences in gene expression in the human brain and affect risk for brain illness. SummaryWe examine the impact of genetic ancestry on gene expression and DNA methylation of admixed African/Black Americans, highlighting how genetic and environmental background affect risk for brain illness.

genetics↗

bioRxiv2023

Lepidoptera proboscis pollens are mainly derived from nectar

The pollens which are rejected or ignored by the dry stigma cant germinate since they havent acquired sugar solution from dry stigmas. But almost all research has ignored the participation of insects which may transport pollens from the nectar to stigmas, and that pollens may germinate on the dry stigma since they have soaked in the nectar. So, the key question is that whether insects carry pollens from nectar to the stigma. Since the adult Lepidoptera are important to the plant pollination and there is a general consensus that pollens are mainly deposited on the proboscis of adult Lepidoptera, and pollens are ubiquitous in the nectar of field flowers, we simulated the flower environment to conduct several groups of behavioral experiments in the adult Mythimna separata by controlling the presence, absence or movement of pollens in nectar, then counted and compared the proboscis pollens. We found that the pollens on the proboscis were mainly derived from the nectar. Our conclusion may contributes to the research of pollen germination on stigmas, especially the dry stigma, and also shows the importance of adult Lepidoptera to pollination, even supports the coevolution of Lepidoptera and angiosperm.

zoology↗

bioRxiv2023

A meta-analysis of immune cell fractions at high resolution reveals novel associations with common phenotypes and health outcomes

AbstractO_ST_ABSBackgroundC_ST_ABSChanges in cell-type composition of complex tissues are associated with a wide range of diseases, environmental risk factors and may be causally implicated in disease development and progression. However, these shifts in cell-type fractions are often of a low magnitude, or involve similar cell-subtypes, making their reliable identification challenging. DNA methylation profiling in a tissue like blood is a promising approach to discover shifts in cell-type abundance, yet studies have only been performed at a relatively low cellular resolution and in isolation, limiting their power to detect these shifts in tissue composition. MethodsHere we derive a DNA methylation reference matrix for 12 immune cell-types in human blood and extensively validate it with flow-cytometric count data and in whole-genome bisulfite sequencing data of sorted cells. Using this reference matrix and Stouffers method, we perform a meta-analysis encompassing 25,629 blood samples from 22 different cohorts, to comprehensively map associations between the 12 immune-cell fractions and common phenotypes, including health outcomes. ResultsOur meta-analysis reveals many associations with age, sex, smoking and obesity, many of which we validate with single-cell RNA-sequencing. We discover that T-regulatory and naive T-cell subsets are higher in women compared to men, whilst the reverse is true for monocyte, natural killer, basophil and eosinophil fractions. In a large subset encompassing 5000 individuals we find associations with stress, exercise, sleep and health outcomes, revealing that naive T-cell and B-cell fractions are associated with a reduced risk of all-cause mortality independently of age, sex, race, smoking, obesity and alcohol consumption. We find that decreased natural killer cell counts are associated with smoking, obesity and stress levels, whilst an increased count correlates with exercise, sleep and a reduced risk of all-cause mortality. ConclusionsThis work derives and extensively validates a high resolution DNAm reference matrix for blood, and uses it to generate a comprehensive map of associations between immune cell fractions and common phenotypes, including health outcomes. AvailabilityThe 12 immune cell-type DNAm reference matrices for Illumina 850k and 450k beadarrays alongside tools for cell-type fraction estimation are freely available from our EpiDISH Bioconductor R-package http://www.bioconductor.org/packages/devel/bioc/html/EpiDISH.html

bioinformatics↗

bioRxiv2023

Coupling of Slack and NaV1.6 sensitizes Slack to quinidine blockade and guides anti-seizure strategy development

Quinidine has been used as an anticonvulsant to treat patients with KCNT1-related epilepsy by targeting gain-of-function KCNT1 pathogenic mutant variants. However, the detailed mechanism underlying quinidines blockade against KCNT1 (Slack) remains elusive. Here, we report a functional and physical coupling of the voltage-gated sodium channel NaV1.6 and Slack. NaV1.6 binds to and highly sensitizes Slack to quinidine blockade. Homozygous knockout of NaV1.6 reduces the sensitivity of native sodium-activated potassium currents to quinidine blockade. NaV1.6-mediated sensitization requires the involvement of NaV1.6s N-and C-termini binding to Slacks C-terminus, and is enhanced by transient sodium influx through NaV1.6. Moreover, disrupting the Slack-NaV1.6 interaction by viral expression of Slacks C-terminus can protect against SlackG269S-induced seizures in mice. These insights about a Slack-NaV1.6 complex challenge the traditional view of "Slack as an isolated target" for anti-epileptic drug discovery efforts, and can guide the development of innovative therapeutic strategies for KCNT1-related epilepsy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/532982v3_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1127858org.highwire.dtl.DTLVardef@19ad9f4org.highwire.dtl.DTLVardef@15b5542org.highwire.dtl.DTLVardef@13a86b4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Beta bursts correlate with synchronization of movements to rhythmic sounds

Accumulating evidence indicates transient beta bursts play an important role in the representation of temporal information and prediction. However, the role of beta bursts in sensorimotor synchronization (SMS) involving active interactions between motor and sensory systems to synchronize predictive movements to periodic events remains unclear. To answer this question, 15 participants were invited to complete a finger-tapping task whilst high-density EEG (128 channels) was recorded. Participants tapped with their right index finger in synchrony with 1 Hz and 0.5 Hz tone trains. In line with previous findings, we found a negative mean asynchrony between tone and tap time, i.e., taps preceded tones for both tone frequencies (1 and 0.5 Hz). In the EEG data, beta bursts were detected and their timing in relationship with tapping and auditory tracking was examined. Results revealed that beta bursts tracked tapping and were modulated by the low frequency phase of the tone frequency (i.e., 1 Hz or 0.5 Hz). Importantly, the locking of beta bursts to the phase of auditory tracking correlated with the behavioural variance on a single trial level that occurred while tapping to the tones. These results demonstrate a critical role for an interplay between beta bursts and low frequency phase in coordinating rhythmic behaviour.

neuroscience↗

bioRxiv2023

Atypical Chemokine Receptor 3 'Senses' CXC Chemokine Receptor 4 Activation Through GPCR Kinase Phosphorylation

Atypical chemokine receptor 3 (ACKR3) is an arrestin-biased receptor that regulates extracellular chemokine levels through scavenging. The scavenging action mediates the availability of the chemokine CXCL12 for the G protein-coupled receptor (GPCR) CXCR4 and requires phosphorylation of the ACKR3 C-terminus by GPCR kinases (GRKs). ACKR3 is phosphorylated by GRK2 and GRK5, but the mechanisms by which these kinases regulate the receptor are unresolved. Here we mapped the phosphorylation patterns and determined that GRK5 phosphorylation of ACKR3 dominates {beta}-arrestin recruitment and chemokine scavenging over GRK2. Co-activation of CXCR4 significantly enhanced phosphorylation by GRK2 through the liberation of G{beta}{gamma}. These results suggest that ACKR3 senses CXCR4 activation through a GRK2-dependent crosstalk mechanism. Surprisingly, we also found that despite the requirement for phosphorylation, and the fact that most ligands promote {beta}-arrestin recruitment, {beta}-arrestins are dispensable for ACKR3 internalization and scavenging, suggesting a yet to be determined function for these adapter proteins.

biochemistry↗

bioRxiv2023

Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression

Activation of heterotrimeric G-proteins (G{beta}{gamma}) by G-protein-coupled receptors (GPCRs) is a quintessential mechanism of cell signaling widely targeted by clinically-approved drugs. However, it has become evident that heterotrimeric G-proteins can also be activated via GPCR-independent mechanisms that remain untapped as pharmacological targets. GIV/Girdin has emerged as a prototypical non-GPCR activator of G proteins that promotes cancer metastasis. Here, we introduce IGGi-11, a first-in-class smallmolecule inhibitor of non-canonical activation of heterotrimeric G-protein signaling. IGGi-11 binding to G-protein -subunits (Gi) specifically disrupted their engagement with GIV/Girdin, thereby blocking non-canonical G-protein signaling in tumor cells, and inhibiting pro-invasive traits of metastatic cancer cells in vitro and in mice. In contrast, IGGi-11 did not interfere with canonical G-protein signaling mechanisms triggered by GPCRs. By revealing that small molecules can selectively disable non-canonical mechanisms of G-protein activation dysregulated in disease, these findings warrant the exploration of therapeutic modalities in G-protein signaling that go beyond targeting GPCRs.

biochemistry↗

bioRxiv2023

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification

NAT10 is dysregulated and plays an essential role in various types of cancers. However, the exact machenism of how NAT10 regulates cancer progression remains debatable. In this report, we show that NAT10 affects tumorigeneis mainly based on its acetylation function on tRNA. In addition, we found NAT10 regulate the ac4C of tRNA in cancer via interaction with RNPS1, which in turn protect NAT10 from degradation by E3 ubiquitin ligase ZSWIM6. We developed TRMC-seq method to compreshensively profile tRNA ac4C sites and uncovered the presence of ac4C in a broader range of tRNA isoacceptors than previous studies. Multi-omics analysis identified AP-1 signaling pathway as a major downstream mediator of NAT10. Mechanistically, we found NAT10 is responsible for the translation efficiency genes which contain higher ac4C-tRNA codon. Importantly, our genetic mouse model validated our in vitro findings of NAT10 in cancer. Our study highlights a role of NAT10 in mediating tRNA ac4C to regulate the translation and tumorigenesis of cancer.

molecular biology↗

bioRxiv2023

Discovery of a unique pathway for glutathione utilization in Francisella

Glutathione (GSH) is an abundant metabolite that can act as a signal, a nutrient source, or serve in a redox capacity for intracellular pathogens. For Francisella, GSH is thought to be a critical in vivo source of cysteine; however, the cellular pathways permitting GSH utilization by Francisella differ between strains and have remained poorly understood. Using genetic screening, we discovered a unique pathway for GSH utilization in Francisella spp. Whereas prior work suggested GSH catabolism initiates in the periplasm, the pathway we define consists of a major facilitator superfamily member that transports intact GSH and a previously unrecognized bacterial cytoplasmic enzyme that catalyzes the first step of GSH degradation. Interestingly, we find that the transporter gene for this pathway is pseudogenized in pathogenic Francisella, explaining phenotypic discrepancies in GSH utilization among Francisella spp. and revealing a critical role for GSH in the environmental niche of these bacteria.

microbiology↗

bioRxiv2023

Structure of alpha-synuclein fibrils derived from human Lewy body dementia tissue

The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. We developed and validated a novel method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and used solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise two protofilaments with pseudo-21 helical screw symmetry, very low twist and an interface formed by antiparallel beta strands of residues 85-93. The fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural landscape of LBD Asyn fibrils and inform further studies of disease mechanisms, imaging agents and therapeutics targeting Asyn.

neuroscience↗

bioRxiv2022

Glyco-engineered pentameric SARS-CoV-2 IgMs show superior activities compared to IgG1 orthologues

Immunoglobulin M (IgM) is the largest antibody isotype with unique features like extensive glycosylation and oligomerization. Major hurdles in characterizing its properties are difficulties in the production of well-defined multimers. Here we report the expression of two SARS-CoV-2 neutralizing monoclonal antibodies in glycoengineered plants. Isotype switch from IgG1 to IgM resulted in the production of pentameric IgMs, comprising of correctly assembled 21 human protein subunits. All four recombinant monoclonal antibodies carried a highly reproducible human-type N-glycosylation profile, with a single dominant N-glycan species at each glycosite. Both pentameric IgMs exhibited increased antigen binding and virus neutralization potency, up to 390-fold, compared to the parental IgG1. Collectively, the results may impact on the future design of vaccines, diagnostics and antibody-based therapies and emphasize the versatile use of plants for the expression of highly complex human proteins with targeted posttranslational modifications.

molecular biology↗

bioRxiv2022

Hypothalamic supramammillary neurons that project to the medial septum control wakefulness

The hypothalamic supramammillary nucleus (SuM) plays a key role in controlling wakefulness, but the downstream target regions participating in this control process remain unknown. Here, using circuit-specific fiber photometry and single-neuron electrophysiology together with electroencephalogram, electromyogram and behavioral recordings, we find approximately half of SuM neurons that project to the medial septum (MS) are wake-active. Optogenetic stimulation of axonal terminals of SuM-MS projection induces a rapid and reliable transition to wakefulness from NREM or REM sleep, and chemogenetic activation of SuMMS projecting neurons significantly increases wakefulness time and prolongs latency to sleep. Consistently, chemogenetically inhibiting these neurons significantly reduces wakefulness time and latency to sleep. Therefore, these results identify the MS as a functional downstream target of SuM and provide evidence for a causal role for this hypothalamic-septal projection in wakefulness control.

neuroscience↗

bioRxiv2022

Low-intensity transcranial focused ultrasound changes pain-associated behaviors by modulating pain processing brain circuits

There is an urgent and unmet clinical need to develop non-pharmacological interventions for chronic pain management due to the critical side effects of opioids. Low-intensity transcranial focused ultrasound is an emerging non-invasive neuromodulation technology with high spatial specificity and deep brain penetration. Here, we developed a tightly-focused 128-element ultrasound transducer to specifically target small mouse brains, employing dynamic focus steering. We demonstrate that transcranial focused ultrasound stimulation at pain processing brain circuits can significantly alter pain-associated behaviors in mouse models in vivo. Our findings indicate that a single-session focused ultrasound stimulation to the primary somatosensory cortex (S1) significantly attenuates heat pain sensitivity in wild-type mice and modulates heat and mechanical hyperalgesia in a humanized mouse model of chronic pain in sickle cell disease. Results further revealed a sustained behavioral change associated with heat hypersensitivity by targeting deeper cortical structures (e.g., insula) and multi-session focused ultrasound stimulation to S1 and insula. Analyses of brain electrical rhythms through electroencephalography demonstrated a significant change in noxious heat hypersensitive- and chronic hyperalgesia-associated neural signals following focused ultrasound treatment. Validation of efficacy was carried out through control experiments, tuning ultrasound parameters, adjusting inter-experiment intervals, and investigating effects on age, gender, genotype, and in a head-fixed awake model. Importantly, transcranial focused ultrasound was shown to be safe, causing no adverse effects on motor function and brain neuropathology. In conclusion, the rich experimental evidence validates the ability of novel focused ultrasound neuromodulation to suppress pain, presenting significant translational potential for next-generation chronic pain treatment without adverse effects. Key pointsO_LINovel non-invasive neuromodulation of brains pain processing circuits with submillimeter spatial precision for pain management C_LIO_LITranscranial focused ultrasound significantly modulates pain-related behaviors and brain electrical rhythms of pain in humanized SCD mice C_LI

bioengineering↗

bioRxiv2022

Structure of Toxoplasma gondii glideosome-associated connector suggests a role as an elastic element in actomyosin force generation for gliding motility

Toxoplasma gondii glideosome-associated connector (GAC) is a giant armadillo-repeat protein, essential for parasite motility and conserved across Apicomplexa. It connects actin filaments to the plasma membrane via interactions with phosphatidic acid and membrane-spanning adhesins. It is unclear how GAC contributes to gliding motility and invasion and why such a large connector is needed. We determined the crystal structure of full-length T. gondii GAC at 2.3 [A] resolution and explored its conformational space in solution using small-angle X-ray scattering and cryogenic electron microscopy. The crystal structure reveals a compact conformation but, in solution, GAC adopts both compact and extended forms. The PH domain stabilizes the compact form and may act as a switch triggered by membrane sensing. Based on its spring-like architecture, we suggest a role for GAC as an elastic element in actomyosin force generation during gliding motility and invasion.

biochemistry↗

bioRxiv2022

Regulatory heterogeneity of Vegf- and Wnt7-dependent angiogenesis drives phenotypic diversity of brain vasculature

Fenestrated and blood-brain barrier (BBB)-forming endothelial cells constitute major brain capillaries, and this vascular heterogeneity is crucial for region-specific neural function and brain homeostasis. How these capillary types emerge in a brain region-specific manner and subsequently establish intrabrain vascular heterogeneity remains unclear. Here, we show a core angiogenic mechanism critical for fenestrated brain capillary development via a comparative analysis of the zebrafish choroid plexuses (CPs) and circumventricular organs (CVOs), demonstrating capillary-type-selective vascularization mechanisms. We found that zebrafish deficient for Gpr124, Reck, or Wnt7aa exhibit severely-impaired BBB angiogenesis without any apparent defect in fenestrated capillary formation in the CPs and CVOs. Conversely, simultaneous genetic loss of various Vegf combinations revealed remarkable heterogeneity of endothelial requirements for Vegfs-dependent angiogenesis within and across these organs, identifying unexpected interplay of Vegfc/d and Vegfa in fenestrated brain capillary formation. Expression analysis and paracrine activity-deficient vegfc mutant characterization suggest that endothelial cells and non-neuronal specialized cell types present in the CPs and CVOs are major sources of Vegfs responsible for regionally-restricted angiogenic interplay. Thus, local presentations and interplay of Vegfc/d and Vegfa control brain region-specific emergence of fenestrated capillaries, providing insight into fenestrated capillary formation in other organs and also how intra-organ vascular heterogeneity arises.

developmental biology↗

bioRxiv2022

Structural basis for Fc receptor recognition of immunoglobulin M

FcR is the IgM-specific Fc receptor involved in the survival and activation of B cells. Using cryo-EM, we reveal eight binding sites for the human FcR Ig domain on the IgM pentamer, one of which overlaps with the receptor binding site for the transcytosis receptor pIgR, but a different mode of binding explains Ig isotype specificity. The complex explains engagement with polymeric serum IgM and the monomeric IgM B cell receptor.

molecular biology↗