Biology subjects

Qu, Y.

Publications and source records attributed to Qu, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Small molecule oxybutynin rescues proliferative capacity of complex III-defective MPCs

Mitochondrial disease encompasses a group of genetically inherited disorders hallmarked by an inability of the respiratory chain to produce sufficient ATP. These disorders present with multisystemic pathologies that predominantly impact highly energetic tissues such as skeletal muscle. There is no cure or effective treatment for mitochondrial disease. We have discovered a small molecule known as oxybutynin that can bypass Complex III mitochondrial dysfunction in primary murine and human skeletal muscle progenitor cells (MPCs). Oxybutynin administration improves MPC proliferative capacity, enhances cellular glycolytic function, and improves myotube formation. Mechanistically, results from our isothermal shift assay indicates that oxybutynin interacts with a suite of proteins involved in mRNA processing which then trigger the upregulation biological pathways to circumvent CIII mitochondrial dysfunction. Taken together, we provide evidence for the small molecule oxybutynin as a potential therapeutic candidate for the future treatment of CIII mitochondrial dysfunction.

cell biology↗

bioRxiv2024

Elongation of the nascent avian foregut requires coordination of intrinsic and extrinsic cell behaviors

The foregut tube gives rise to the lungs and upper gastrointestinal tract, enabling vital functions of respiration and digestion. How the foregut tube forms during embryonic development has historically received considerable attention, but over the past few decades this question has primarily been addressed indirectly through studies on morphogenesis of the primitive heart tube, a closely related process. As a result, many aspects of foregut development remain unresolved. Here, we exploit the accessibility of the chick embryo to study the initial formation of the foregut tube, combining embryology with fate mapping, live imaging, and biomechanical analyses. The present study reveals that the foregut forms and elongates over a narrower time window than previously thought, and displays marked dorso-ventral and left-right asymmetries early in its development. Through tissue-specific ablation of endoderm along the anterior intestinal portal, we confirm its central biomechanical role in driving foregut morphogenesis, despite not directly contributing cells to the elongating tube. We further confirm the important role of this cell population in formation of the heart tube, with evidence that this role extends to later stages of cardiac looping as well. Together, these data reveal the need for an intricate balance between intrinsic cell behaviors and extrinsic forces for normal foregut elongation, and set the stage for future studies aimed at understanding the underlying molecular cues that coordinate this balance. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/621372v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@374c2corg.highwire.dtl.DTLVardef@69ed3aorg.highwire.dtl.DTLVardef@55823aorg.highwire.dtl.DTLVardef@1d8d4fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Shared and unique lifetime stressor characteristics and brain networks predict adolescent anxiety and depression

BackgroundExposure to major life stressors and aberrant brain functioning have been related to anxiety and depression, especially during adolescence. However, whether these associations differ based on the specific characteristics of the stressors experienced, and/or the functional networks engaged, remains unclear. MethodsWe used baseline lifetime stressor exposure and resting-state functional magnetic resonance imaging data from a longitudinal sample of 150 adolescents enriched for anxiety and depressive disorders. We examined the cumulative lifetime stressor frequency and severity of five stressor characteristics: physical danger, interpersonal loss, humiliation, entrapment, and role change/disruption. Anxiety and depression symptoms were assessed at three time points: baseline, 6-month and 12-month follow-ups. Linear mixed-effect models tested if the lifetime frequency and severity of these stressor characteristics and functional connectivity within and between frontoparietal, default, and ventral attention networks at baseline predicted anxiety and depression symptoms at three time points. ResultsLifetime frequency and severity of humiliation and entrapment predicted both anxiety and depression symptoms. Lifetime frequency and severity of entrapment exposures predicted anxiety and depression symptoms after accounting for baseline depression and anxiety symptoms, respectively. Resting-state functional connectivity between default, frontoparietal and ventral attention networks did not predict either anxiety or depression symptoms after correcting for multiple comparisons. ConclusionsOur study highlights lifetime exposures to humiliation and entrapment stressors as central stressor characteristics predictive of prospective anxiety and depression symptoms in adolescence. Our results also suggest that resting-state functional connectivity within and between default, frontoparietal and ventral attention networks may be relatively weak predictors of prospective anxiety and depression symptoms in adolescence.

neuroscience↗

bioRxiv2024

LP-Micro Offers Interpretable Disease Outcome Prediction by Leveraging Microbial Biomarkers and Their Time-Varying Effects

Information generated from longitudinally-sampled microbial data has the potential to illuminate important aspects of development and progression for many human conditions and diseases. Identifying microbial biomarkers and their time-varying effects can not only advance our understanding of pathogenetic mechanisms, but also facilitate early diagnosis and guide optimal timing of interventions. However, longitudinal predictive modeling of highly noisy and dynamic microbial data (e.g., metagenomics) poses analytical challenges. To overcome these challenges, we introduce a robust and interpretable machine-learning-based longitudinal microbiome analysis framework, LP-Micro, that encompasses: (i) longitudinal microbial feature screening via a polynomial group lasso, (ii) disease outcome prediction implemented via machine learning methods (e.g., XGBoost, deep neural networks), and (iii) interpretable association testing between time points, microbial features, and disease outcomes via permutation feature importance. We demonstrate in simulations that LP-Micro can not only identify incident disease-related microbiome taxa but also offers improved prediction accuracy compared to existing approaches. Applications of LP-Micro in two longitudinal microbiome studies with clinical outcomes of childhood dental disease and weight loss following bariatric surgery yield consistently high prediction accuracy. The identified critical early predictive time points are informative and aligned with clinical expectations.

bioinformatics↗

bioRxiv2024

SAMPL-seq reveals micron-scale spatial hubs in the human gut microbiome

The local arrangement of microbes can profoundly impact community assembly, function, and stability. To date, little is known about the spatial organization of the human gut microbiome. Here, we describe a high-throughput and streamlined method, dubbed SAMPL-seq, that samples microbial composition of micron-scale sub-communities with split-and-pool barcoding to capture spatial colocalization in a complex consortium. SAMPL-seq analysis of the gut microbiome of healthy humans identified bacterial taxa pairs that consistently co-occurred both over time and across multiple individuals. These colocalized microbes organize into spatially distinct groups or "spatial hubs" dominated by Bacteroideceae, Ruminococceae, and Lachnospiraceae families. From a dietary perturbation using inulin, we observed reversible spatial rearrangement of the gut microbiome, where specific taxa form new local partnerships. Spatial metagenomics using SAMPL-seq can unlock new insights to improve the study of microbial communities. One Sentence SummaryHigh throughput micron-scale subcommunity sampling and sequencing identifies distinct spatial associations of gut bacteria within and across individuals.

systems biology↗

bioRxiv2024

Vispro improves imaging analysis for Visium spatial transcriptomics

Spatial transcriptomics (ST) enables the comprehensive analysis of gene expression while preserving the spatial context of tissues. The histological images accompanying ST data provide spatially cohesive information that is often challenging to capture through gene expression alone. However, analyzing such images is challenging due to the presence of fiducial markers and background regions, which can obscure important features and complicate downstream analysis. To address these challenges, we developed Vispro, an end-to-end, fully automated image processing tool tailored for 10x Visium data. Vispro integrates four key modules of fiducial marker detection, fiducial marker removal and image restoration, tissue region detection, and segmentation of disconnected tissue areas. We demonstrated that Vispro enhances the quality of ST images and improves the performance of downstream analyses, including tissue segmentation, cell segmentation, image registration, and histology-based gene imputation.

bioinformatics↗

bioRxiv2024

Cryo-EM structural insights into Vγ9Vδ2 TCR activation via multiple butyrophilins

Human V{gamma}9V{delta}2 T cells detect cancerous and pathogen-infected cells through an "inside-out" mechanism wherein intracellular domains of butyrophilin (BTN) proteins recognize phosphoantigens (pAgs) to prime BTN ectodomains to engage with the T cell receptor (TCR) to activate V{gamma}9V{delta}2 T cells. Here, we present cryo-electron microscopy (cryo-EM) structures, including the full-length BTN3A1-BTN3A2-BTN2A1 complex stabilized by the pAg HMBPP and an HMBPP-primed BTN multimer complex engaged with the V{gamma}9V{delta}2 TCR. The HMBPP-primed BTN3A1-BTN3A2-BTN2A1 complex confirms that this pAg bridges the intracellular B30.2 domains of BTN3A1 and BTN2A1, while also revealing an association of the ectodomains of BTN3A2 and BTN2A1. Upon TCR engagement, the TCR undergoes a substantial conformational change and BTN3A2-BTN2A1 ectodomain interaction dissociates, allowing BTN2A1 to bind to the lateral surface of the V{gamma}9 chain, while BTN3A2 binds to the apical surface of the V{delta}2 chain. Beyond demonstrating that BTN3A2 as a bona fide TCR ligand, this dissociation/binding sequence suggests a "pliers-like gripping" mechanism for TCR activation. We also obtained cryo-EM structures of BTN proteins in complex with functional antibodies, further elucidating the overall V{gamma}9V{delta}2 T cell activation process. Thus, our structural insights into how BTN proteins sense antigens and drive TCR activation lay the groundwork for developing targeted {gamma}{delta} T cell immunotherapies.

immunology↗

bioRxiv2024

AQP1- A regulatory factor associated with brown adipose tissue silencing

The activation of non-shivering thermogenesis (NST) in brown adipose tissue (BAT) by environmental cold challenge yields strong metabolic benefit in the face of diet-induced obesity (DIO). Yet, a critical barrier to leveraging brown fat NST for therapeutic use against metabolic disease is that BAT is silenced and inactive at physiological ambient temperature conditions in humans. The mechanisms that govern this silencing process remain poorly understood. Here, we identified a putative BAT-silencing factor, aquaporin-1 (AQP1), in brown fat from wild-type (WT) mice via proteomics analysis. We generated the first BAT-specific AQP1 knockout mice (AQP1-KO) and revealed that AQP1-KO could activate NST under BAT silencing environmental conditions and that the AQP1-KO mice were significantly protected against DIO and metabolic dysfunction compared to Flox controls. We found that AQP1-KO mice on high fat diet (HFD) had reduced weight gain through reductions in fat mass, improved glucose tolerance, and increased whole body energy expenditure compared to Flox control mice. Mechanistically, we show that AQP1 ablation in mice had upregulated gene expression related to the electron transport chain (ETC) and mitochondrial translation contributing to the activation of NST under BAT environmental silenced conditions. Significance StatementNovel strategies to combat obesity-associated metabolic dysfunction are urgently needed to curb the growing obesity epidemic. Investigation of brown adipose tissue (BAT) silencing mechanisms may reveal novel therapeutic targets that when ablated, can activate BAT to increase energy expenditure and protect subjects against the metabolic dysfunction associated with obesity. We have identified Aquaporin 1 (AQP1) as a putative BAT silencer regulatory factor and show through the generation of the first BAT-specific aquaporin-1 knockout (AQP1-KO) mouse that BAT can be activated under environmental silencing conditions. We further show that these mice are protected against diet-induced obesity, with improved glucose tolerance, and increased energy expenditure. These findings highlight AQP1 as a promising therapeutic target in the emerging research field of BAT silencers.

molecular biology↗

bioRxiv2024

Parallel evolution of methyltransferases leads to vobasine biosynthesis in Tabernaemontana elegans and Catharanthus roseus

Monoterpenoid indole alkaloids (MIA) are one of the largest and most complex alkaloid class in nature, boasting many clinically significant drugs such as anticancer vinblastine and antiarrhythmic ajmaline. Many MIAs undergo nitrogen N-methylation, altering their reactivity and affinity to the biological targets through a straightforward reaction. Remarkably, all known MIA N-methyltransferases (NMT) originate from the neofunctionalization of ancestral {gamma}-tocopherol C-methyltransferases ({gamma}TMTs), a phenomenon seemingly unique to the Apocynaceae family. In this study, we unveil and characterize a new {gamma}TMT-like enzyme from the plant Tabernaemontana elegans (toad tree): perivine N{beta}-methyltransferase (TePeNMT). TePeNMT and other homologs form a distinct clade in our phylogenetic study, setting them apart from other {gamma}TMTs and {gamma}TMT-like NMTs discovered to date. Enzyme kinetic experiments and enzyme homology modeling studies reveal the significant differences in enzyme active sites between TePeNMT and CrPeNMT, a previously characterized perivine N{beta}-methyltransferase from Catharanthus roseus (Madagascar periwinkle). Collectively, our findings suggest that parallel evolution of ancestral {gamma}TMTs may be responsible for the occurrence of perivine N-methylation in T. elegans and C. roseus.

biochemistry↗

bioRxiv2024

Oxidation of Four Monoterpenoid Indole Alkaloid Classes by Three Cytochrome P450 Monooxygenases from Tabernaemontana litoralis

Cytochrome P450 monooxygenases (CYPs) are well known for their ability to catalyze diverse oxidation reactions, playing a significant role in the biosynthesis of various natural products. In the realm of monoterpenoid indole alkaloids (MIAs), one of the largest groups of alkaloids in nature, CYPs are integral to reactions such as hydroxylation, epoxidation, ring opening, ring rearrangement, and aromatization, contributing to the extensive diversification of these compounds. In this study, we investigate the transcriptome, metabolome, and MIA biosynthesis in Tabernaemontana litoralis (milky way tree), a prolific producer of rare pseudoaspidosperma-type MIAs. Alongside known pseudoaspidosperma biosynthetic genes, we identify and characterize three new CYPs that facilitate regio- and stereospecific oxidation of four MIA skeletons: iboga, aspidosperma, pseudoaspidosperma, and quebrachamine. Notably, the tabersonine 14,15-{beta}-epoxidase catalyzes the formation of pachysiphine, the stereoisomer of 14,15--epoxytabersonine (lochnericine) found in Catharanthus roseus (Madagascar periwinkle) roots. The pseudovincadifformine 18-hydroxylase is the first CYP identified to modify a pseudoaspidosperma skeleton. Additionally, we demonstrate that the enzyme responsible for C10-hydroxylation of the iboga MIA coronaridine also catalyzes the same reaction on voaphylline, which bears a quebrachamine skeleton. With the discovery of a new MIA, 11-hydroxypseudovincadifformine, this study provides a comprehensive understanding of MIA biosynthesis and diversification in T. litoralis, highlighting its potential for further exploration.

biochemistry↗

bioRxiv2024

Different Roles of D1/D2 Medium Spiny Neurons in the Nucleus Accumbens in Pair Bond Formation of Male Mandarin Voles

The mesolimbic dopamine (DA) system has been implicated in pair bond formation. However, involvements of DA release, real time activities, and electrophysiological activities of D1/D2 medium spiny neurons (MSNs) in the nucleus accumbens (NAc) shell in pair bonding remain unclear. This work verified that male mandarin voles after pair bonding released higher levels of DA in the NAc shell and displayed higher levels of D1 MSNs activity and lower levels of D2 MSNs activity upon sniffing their partners compared to upon sniffing an unknown female. Moreover, pair bonding induced differential alterations in both synaptic plasticity and neuronal intrinsic excitability in both D1 MSNs and D2 MSNs. In addition, chemogenetic inhibition of ventral pallidum (VP) -projecting D2 MSNs in the NAc shell enhanced pair bond formation, while chemogenetic activation of VP-projecting D2 MSNs in the NAc shell inhibited pair bond formation. These findings suggest that different neuronal activity of NAc shell D1 MSNs / D2 MSNs regulated by increasing DA release after pair bonding may be a neurobiological mechanism underlying pair bond formation.

neuroscience↗

bioRxiv2024

Identification and Characterization of Compounds that Improve Plant Photosynthesis and Growth under Light Stress Conditions.

In order to satisfy the food and fuel demands of a growing population, global food production needs to increase by more than 50% before 2050. However, various environmental stresses in the natural environment inhibit plant growth and result in reduced yields. This is primarily caused by decreases in photosynthetic capacity. Thus, there is an urgent need to develop new strategies to improve agricultural productivity and ensure food security. In this study, a novel chemical-screening system with 96 well plates and leaf disks of tobacco was used to identify several anthraquinone derivatives that could relieve high light stress from plants. Treatments with these chemicals induced greater photosynthetic capacity after high light stress conditions for 20-72 hours (h) in tobacco and better plant growth after exposure to light stress for 96 hours in Arabidopsis and lettuces. The photoprotective effect of anthraquinone derivatives is closely related to chemical induced oxidation of PSI. Furthermore, there were no negative effects on plant growth in chemically treated plants under non-stressful conditions. Taken together, this study shows that anthraquinone derivatives can confer high light stress tolerance in plants, resulting in improved plant photosynthesis and growth in environments with light stress.

plant biology↗

bioRxiv2024

CRISPR-GPT: An LLM Agent for Automated Design of Gene-Editing Experiments

Performing effective gene-editing experiments requires a deep understanding of both the CRISPR technology and the biological system involved. Meanwhile, despite their versatility and promise, Large Language Models (LLMs) often lack domain-specific knowledge and struggle to accurately solve biological design problems. We present CRISPR-GPT, an LLM agent system to automate and enhance CRISPR-based gene-editing design and data analysis. CRISPR-GPT leverages the reasoning capabilities of LLMs for complex task decomposition, decision-making, and interactive human-artificial intelligence (AI) collaboration. This system incorporates domain expertise, retrieval techniques, external tools, and a specialized LLM fine-tuned with open-forum discussions among scientists. CRISPR-GPT assists users in selecting CRISPR systems, experiment planning, designing gRNAs, choosing delivery methods, drafting protocols, designing assays, and analyzing data. We showcase the potential of CRISPR-GPT by knocking-out four genes with CRISPR-Cas12a in a human lung adenocarcinoma cell line and epigenetically activating two genes using CRISPR-dCas9 in human melanoma cell line. CRISPR-GPT enables fully AI-guided gene-editing experiment design and analysis across different modalities, validating its effectiveness as an AI co-pilot in genome engineering.

bioinformatics↗

bioRxiv2024

CTCF mutation at R567 causes developmental disorders via 3D genome rearrangement and abnormal neurodevelopment

The three-dimensional genome structure organized by CTCF is required for development. Clinically identified mutations in CTCF have been linked to adverse developmental outcomes. Nevertheless, the underlying mechanism remains elusive. In this investigation, we explored the regulatory roles of a clinically relevant R567W point mutation, located within the 11th zinc finger of CTCF, by introducing this mutation into both murine models and human embryonic stem cell-derived cortical organoid models. Mice with homozygous CTCFR567W mutation exhibited growth impediments, resulting in postnatal mortality, and deviations in brain, heart, and lung development at the pathological and single- cell transcriptome levels. This mutation induced premature stem-like cell exhaustion, accelerated the maturation of GABAergic neurons, and disrupted neurodevelopmental and synaptic pathways. Additionally, it specifically hindered CTCF binding to peripheral motifs upstream to the core consensus site, causing alterations in local chromatin structure and gene expression, particularly at the clustered protocadherin locus. Comparative analysis using human cortical organoids mirrored the consequences induced by this mutation. In summary, this study elucidates the influence of the CTCFR567W mutation on human neurodevelopmental disorders, paving the way for potential therapeutic interventions.

molecular biology↗

bioRxiv2024

PVN-mPFC OT projections modulates pup-directed pup care or attacking in virgin mandarin voles

In many species, adult animals may exhibit caregiving or aggression towards conspecific offspring. The neural mechanisms underlying the infanticide and pup care remain poorly understood. Here, using monogamous virgin mandarin voles (Microtus mandarinus) that may exhibit pup care or infanticide, we found that more oxytocin (OT) neurons in the paraventricular nucleus (PVN) were activated during pup caring than infanticide. Optogenetic activation of OT neurons in the PVN facilitated pup-caring in male and female mandarin voles. In infanticide voles, optogenetic activation of PVN OT cells prolonged latency to approach and attack pups, whereas inhibition of these OT neurons facilitated approach and infanticide. In addition, OT release in the medial prefrontal cortex (mPFC) in pup-care voles increased upon approaching and retrieving pups, and decreased in infanticide voles upon attacking pups. Optogenetic activation of PVN OT neuron projections to the mPFC shortened the latency to approach and retrieve pups and facilitated the initiation of pup care, whereas inhibition of these projections had little effect. For pup-care females, neither activation nor inhibition of the fibers affected their behavior towards pups. In infanticide male and female voles, optogenetic activation of PVN-mPFC OT projection fibers prolonged the latency to approach and attack pups and suppressed the initiation of infanticide, whereas inhibition of these projections promoted approach and infanticide. Finally, we found that intraperitoneal injection of OT promoted pup care and inhibited infanticide behavior. It is suggested that the OT system, especially PVN OT neurons projecting to mPFC, modulates pup-directed behaviors and OT can be used to treat abnormal behavioral responses associated with some psychological diseases such as depression and psychosis.

neuroscience↗

bioRxiv2024

SARS-CoV-2 Omicron BA.2.87.1 Exhibits Higher Susceptibility to Serum Neutralization Than EG.5.1 and JN.1

As SARS-CoV-2 continues to spread and mutate, tracking the viral evolutionary trajectory and understanding the functional consequences of its mutations remain crucial. Here, we characterized the antibody evasion, ACE2 receptor engagement, and viral infectivity of the highly mutated SARS-CoV-2 Omicron subvariant BA.2.87.1. Compared with other Omicron subvariants, including EG.5.1 and the current predominant JN.1, BA.2.87.1 exhibits less immune evasion, reduced viral receptor engagement, and comparable infectivity in Calu-3 lung cells. Intriguingly, two large deletions ({Delta}15-26 and {Delta}136-146) in the N-terminal domain (NTD) of the spike protein facilitate subtly increased antibody evasion but significantly diminish viral infectivity. Collectively, our data support the announcement by the USA CDC that the public health risk posed by BA.2.87.1 appears to be low.

microbiology↗

bioRxiv2024

Cellular mechanotransduction of human osteoblasts in microgravity

Astronauts experience significant and rapid bone loss as a result of an extended stay in space, making the International Space Station (ISS) the perfect laboratory for studying osteoporosis due to the accelerated nature of bone loss on the ISS. This prompts the question, how does the lack of load due to zero-gravity propagate to bone-forming cells, human fetal osteoblasts (hFOBs), altering their maturation to mineralization? Here, we aim to study the mechanotransduction mechanisms by which bone loss occurs in microgravity. Two automated experiments, 4 microfluidic chips capable of measuring single-cell mechanics of hFOBs via aspiration and cell spheroids incubated in pressure-controlled chambers, were each integrated into a CubeLab deployed to the ISS National Laboratory. For the first experiment, we report protrusion measurements of aspirated cells after exposure to microgravity at the ISS and compare these results to ground control conducted inside the CubeLab. Our analysis revealed slightly elongated protrusions for space samples compared to ground samples indicating softening of hFOB cells in microgravity. In the second experiment, we encapsulated osteoblast spheroids in collagen gel and incubated the samples in pressure-controlled chambers. We found that microgravity significantly reduced filamentous actin levels in the hFOB spheroids. When subjected to pressure, the spheroids exhibited increased pSMAD1/5/9 expression, regardless of the microgravity condition. Moreover, microgravity reduced YAP expression, while pressure increased YAP levels, thus restoring YAP expression for spheroids in microgravity. Our study provides insights into the influence of microgravity on the mechanical properties of bone cells and the impact of compressive pressure on cell behavior and signaling in space.

cell biology↗

bioRxiv2024

Proteus: pioneering protein structure generation for enhanced designability and efficiency

Diffusion-based generative models have been successfully employed to create proteins with novel structures and functions. However, the construction of such models typically depends on large, pre-trained structure prediction networks, like RFdiffusion. In contrast, alternative models that are trained from scratch, such as FrameDiff, still fall short in performance. In this context, we introduce Proteus, an innovative deep diffusion network that incorporates graph-based triangle methods and a multi-track interaction network, eliminating the dependency on structure prediction pre-training with superior efficiency. We have validated our models performance on de novo protein backbone generation through comprehensive in silico evaluations and experimental characterizations, which demonstrate a remarkable success rate. These promising results underscore Proteuss ability to generate highly designable protein backbones efficiently. This capability, achieved without reliance on pre-training techniques, has the potential to significantly advance the field of protein design. Codes are available at https://github.com/Wangchentong/Proteus.

bioinformatics↗