Biology subjects

Gao, H.

Publications and source records attributed to Gao, H..

At least 91 records · Page 5Linked to original sources

bioRxiv2024

Transcranial focused ultrasound activates feedforward and feedback cortico-thalamo-cortical pathways by selectively activating excitatory neurons

Transcranial focused ultrasound stimulation (tFUS) has been proven capable of altering focal neuronal activities and neural circuits non-invasively in both animals and humans. The abilities of tFUS for cell-type selection within the targeted area like somatosensory cortex have been shown to be parameter related. However, how neuronal subpopulations across neural pathways are affected, for example how tFUS affected neuronal connections between brain areas remains unclear. In this study, multi-site intracranial recordings were used to quantify the neuronal responses to tFUS stimulation at somatosensory cortex (S1), motor cortex (M1) and posterior medial thalamic nucleus (POm) of cortico-thalamo-cortical (CTC) pathway. We found that when targeting at S1 or POm, only regular spiking units (RSUs, putative excitatory neurons) responded to specific tFUS parameters (duty cycle: 6%-60% and pulse repetition frequency: 1500 and 3000 Hz ) during sonication. RSUs from the directly connected area (POm or S1) showed a synchronized response, which changed the directional correlation between RSUs from POm and S1. The tFUS induced excitation of RSUs activated the feedforward and feedback loops between cortex and thalamus, eliciting delayed neuronal responses of RSUs and delayed activities of fast spiking units (FSUs) by affecting local network. Our findings indicated that tFUS can modulate the CTC pathway through both feedforward and feedback loops, which could influence larger cortical areas including motor cortex.

neuroscience↗

bioRxiv2024

An Investigation of Parameter-Dependent Cell-Type Specific Effects of Transcranial Focused Ultrasound Stimulation Using an Awake Head-Fixed Rodent Model

Transcranial focused ultrasound (tFUS) is a promising neuromodulation technique able to target shallow and deep brain structures with high precision. Previous studies have demonstrated that tFUS stimulation responses are both cell-type specific and controllable through altering stimulation parameters. Specifically, tFUS can elicit time-locked neural activity in regular spiking units (RSUs) that is sensitive to increases in pulse repetition frequency (PRF), while time-locked responses are not seen in fast spiking units (FSUs). These findings suggest a unique capability of tFUS to alter circuit network dynamics with cell-type specificity; however, these results could be biased by the use of anesthesia, which significantly modulates neural activities. In this study, we develop an awake head-fixed rat model specifically designed for tFUS study, and address a key question if tFUS still has cell-type specificity under awake conditions. Using this novel animal model, we examined a series of PRFs and burst duty cycles (DCs) to determine their effects on neuronal subpopulations without anesthesia. We conclude that cell-type specific time-locked and delayed responses to tFUS as well as PRF and DC sensitivity are present in the awake animal model and that despite some differences in response, isoflurane anesthesia is not a major confound in studying the cell-type specificity of ultrasound neuromodulation. We further determine that, in an awake, head-fixed setting, the preferred PRF and DC for inducing time-locked excitation with our pulsed tFUS paradigm are 1500 Hz and 60%, respectively.

neuroscience↗

bioRxiv2024

Terrestrial ecosystems enhance root zones in response to intensified drought

Adaptation of ecosystems root zones to climate change critically affects drought resilience and vegetation productivity. However, a global quantitative assessment of this mechanism is missing. Therefore, we analyzed observation-based data and found that the global average root zone water storage capacity (SR) increased by 11%, from 182 to 201 mm in 1982-2020. This increase amounts to 1657 billion m3 over the past four decades, affecting hydrological and ecological processes worldwide. SR increased in 9 out of 12 land cover types, while three relatively dry types experienced decreasing trends, potentially suggesting the crossing of ecosystem tipping points. Our results underscore the importance of considering root zone dynamics while analysing floods, droughts and carbon sequestration under climate change.

ecology↗

bioRxiv2024

MDF regulates both auxin-dependent and -independent pathways of adventitious root regeneration in Arabidopsis.

Plants exhibit strong plasticity in growth and development, seen clearly in lateral and adventitious root development from differentiated tissues in response to environmental stresses. Previous studies have demonstrated the role of both auxin-dependent and auxin-independent signalling pathways in regulating the de novo formation of adventitious roots (ARs) from differentiated tissues, such as leaf petiole in Arabidopsis. One important question is how the auxin-dependent and -independent pathways are coordinated. To investigate this question, we used a combined approach of inducible gene expression, mutant, and signalling reporter gene analysis during AR regeneration in the Arabidopsis petiole to understand regulatory relationships. Auxin signalling components AXR1 and AXR3, and the PIN trafficking protein VAMP714, are each required for AR initiation, as is the ethylene signalling repressor POLARIS, but not EIN2. We identify the RNA splicing regulator MDF and the transcription factor RAP2.7 as new positive regulators of both the auxin-independent and auxin-dependent pathways, and show that MDF regulates RAP2.7, WOX5 and NAC1; while RAP2.7 regulates WOX5 but not NAC1 or YUC1. NAC1 is required for de novo root formation in a pathway independent of YUC1, WOX5 or RAP2.7. We propose a model in which MDF represents a point of molecular crosstalk between auxin-dependent and -independent regeneration processes.

plant biology↗

bioRxiv2024

Microbiota from young mice counteracts susceptibility to age-related gout through modulating butyric acid levels in aged mice

Gout is a prevalent form of inflammatory arthritis that occurs due to high levels of uric acid in the blood leading to the formation of urate crystals in and around the joints, particularly affecting the elderly. Recent research has provided evidence of distinct differences in the gut microbiota of patients with gout and hyperuricemia when compared to healthy individuals. However, the link between gut microbiota and age-related gout remained underexplored. Our study found that gut microbiota plays a crucial role in determining susceptibility to age-related gout. Specifically, we observed that age-related gut microbiota regulated the activation of the NLRP3 inflammasome pathway and modulated uric acid metabolism. More scrutiny highlighted the positive impact of "younger" microbiota on the gut microbiota structure of old or aged mice, enhancing butanoate metabolism and butyric acid content. Experimentation with butyrate supplementation indicated that butyric acid exerts a dual effect, inhibiting inflammation in acute gout and reducing serum uric acid levels. These insights emphasize the potential of gut microbiome rejuvenation in mitigating senile gout, unraveling the intricate dynamics between microbiota, aging, and gout. It potentially serves as a therapeutic target for senile gout-related conditions.

microbiology↗

bioRxiv2024

The segmented flavivirus Alongshan virus reduces mitochondrial mass via degrading STAT2 to suppress innate immune response

Alongshan virus (ALSV) is a newly discovered pathogen of the Flaviviridae family, characterized by a multi-segmented genome distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of the emerging segmented flavivirus is crucial for the development of intervention strategies. Here we show that ALSV can infect multiple mammalian cells and induces the expression of antiviral genes. Moreover, ALSV is sensitive to IFN-{beta} and possesses the ability to counteract type I IFN response. Mechanistically, ALSVs nonstructural protein NSP1 binds to and degrades human STAT2 through an autophagy pathway in a species-dependent manner, resulting in direct inhibition of the expression of interferon-stimulated genes (ISGs). Specifically, NSP1 methyltransferase domain binds to the key sites of F175/R176 located in coiled-coil domain of STAT2. Moreover, NSP1-mediated degradation of STAT2 results in a reduction in mitochondrial mass by disrupting mitochondrial dynamics to induce mitophagy and inhibiting mitochondrial biogenesis, thereby suppressing the innate immune response. Interestingly, inhibiting mitophagy using 3-Methyladenine and enhancing mitochondrial biogenesis using the PPAR{gamma} agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass presents an effective antiviral strategy. Our findings elucidate the intricate regulatory crosstalk between ALSV and the hosts innate immune response, providing valuable insights into the pathogenesis and intervention strategy of emerging segmented flavivirus.

microbiology↗

bioRxiv2024

Brain preparedness: The cortisol awakening response proacts dynamic organization of large-scale brain networks across emotional and executive functions

Emotion and cognition involve an intricate crosstalk of neural and endocrine systems that support allostatic processes for maintenance of dynamic equilibrium and rapid adaptation for upcoming challenges. As a hallmark of human endocrine activity, the cortisol awakening response (CAR) is recognized to play a critical role in modulating emotional and executive functions. Yet, the underlying mechanisms of such effects remain elusive. By leveraging pharmacological neuroimaging technique and Hidden Markov Modeling of brain state dynamics, we show that the CAR proactively modulates rapid reconfigurations (state) of large-scale brain networks across multi-task demands. Behaviorally, suppression of CAR proactively and selectively impaired accuracy for emotional discrimination task but not for working memory (WM). In parallel, suppressed CAR led to a decrease in the occurrence rate of brain state dominant to emotional processing, but an increase in brain state linking to executive control under high WM demand. Further energy-based analyses revealed an increase in transition frequency and sequence complexity along with an increased entropy during emotional tasks when suppressed CAR, suggesting a decreased energy supply. Moreover, an increased transition frequency was observed when shifting from neutral to emotional conditions, but an opposite pattern during WM task, with n decreased transition frequency shifts from low to high-executive demands. Our findings establish a causal link between CAR and dynamic allocation of neural resources for emotional and executive functions, suggesting a cognitive neuroendocrine account for CAR-mediated proactive effects and human allostasis.

neuroscience↗

bioRxiv2024

Metabolic shift to serine pathway induced by lipids confers oncogenic properties in non-transformed breast cells

A lipid metabolism gene signature is associated with the risk of estrogen negative breast cancer (ER-BC). In vitro, lipid exposure alters histone methylation affecting gene expression and increasing flux through various metabolic reactions; but little is known about the mechanism(s) linking lipids and epigenetic reprogramming with the genesis of ER-BC. Here we show that the metabolism of the medium-chain fatty acid Octanoic Acid (OA) in preference to glucose and glutamine results in a metabolic shift toward the serine pathway increasing the production of SAM, glutathione, and 2-HG, with implications for oncogenesis: SAM production results in epigenetic fostered plasticity leading to reprogramming/selecting cells that express Neural, EMT and BC related genes. 2-HG exposure results in appearance of DNA breaks, potentially consequent to the inhibition of essential demethylases for HR repair. ROS increases shortly after OA exposure and is mitigated by antioxidant defenses, which favors/enables the survival of specific cell subtypes.

cancer biology↗

bioRxiv2024

Ndufs4 knockout induces transcriptomic signatures of Alzheimer's Diseases that are partially reversed by mitochondrial complex I inhibitor

Mitochondrial dysfunction is well documented in Alzheimers Disease (AD). However, whether it instigates the onset of AD remains unclear. We demonstrate that a reduction of complex I activity in wild type (WT) mice caused by a global knockout of Ndufs4, an accessory mitochondrial complex I subunit, was sufficient to induce transcriptomic changes in the brain reminiscent of those observed in AD patients and familial mouse models of AD. Reduced complex I activity affected expression of genes in the networks related to mitochondrial homeostasis, neuronal and synaptic function. Transcriptomic signatures in male and female Ndufs4-/-mice reflected a different severity of AD phenotype. Unexpectedly, these changes were partially rescued by a neuroprotective small molecule mild complex I inhibitor CP2. Consistent with studies in AD mice, CP2 treatment in Ndufs4-/- mice augmented the expression of genes associated with mitochondrial biogenesis and turnover, synaptic activity, autophagy, redox balance, and reduced expression of genes related to inflammation. Female Ndufs4-/- mice demonstrated a greater reversal of gene expression toward WT mice. These studies provide further support for mitochondria as a causative factor of AD pathophysiology and complex I as a putative therapeutic target.

neuroscience↗

bioRxiv2024

Mosaic sarbecovirus vaccination elicits cross-reactive responses in pre-immunized animals

Immunization with mosaic-8b [60-mer nanoparticles presenting 8 SARS-like betacoronavirus (sarbecovirus) receptor-binding domains (RBDs)] elicits more broadly cross-reactive antibodies than homotypic SARS-CoV-2 RBD-only nanoparticles and protects against sarbecoviruses. To investigate original antigenic sin (OAS) effects on mosaic-8b efficacy, we evaluated effects of prior COVID-19 vaccinations in non-human primates and mice on anti-sarbecovirus responses elicited by mosaic-8b, admix-8b (8 homotypics), or homotypic SARS-CoV-2 immunizations, finding greatest cross-reactivity for mosaic-8b. As demonstrated by molecular fate-mapping in which antibodies from specific cohorts of B cells are differentially detected, B cells primed by WA1 spike mRNA-LNP dominated antibody responses after RBD-nanoparticle boosting. While mosaic-8b- and homotypic-nanoparticles boosted cross-reactive antibodies, de novo antibodies were predominantly induced by mosaic-8b, and these were specific for variant RBDs with increased identity to RBDs on mosaic-8b. These results inform OAS mechanisms and support using mosaic-8b to protect COVID-19 vaccinated/infected humans against as-yet-unknown SARS-CoV-2 variants and animal sarbecoviruses with human spillover potential.

immunology↗

bioRxiv2024

Global neural encoding of model-free and inference-based strategies in mice

When a simple model-free strategy does not provide sufficient outcomes, an inference-based strategy estimating a hidden task structure becomes essential for optimizing choices. However, the neural circuitry involved in inference-based strategies is still unclear. We developed a tone frequency discrimination task in head-fixed mice in which the tone category of the current trial depended on the category of the previous trial. When the tone category was repeated every trial, the mice continued to use the default model-free strategy, as well as when tone was randomly presented, to bias the choices. In contrast, the default strategy gradually shifted to an inference-based strategy when the tone category was alternated in each trial. Brain-wide electrophysiological recording during the overtrained phase suggested that the neural activity of the frontal and sensory cortices, hippocampus, and striatum was correlated with the reward expectation of both the model-free and inference-based strategies. These results suggest the global encoding of multiple strategies in the brain.

neuroscience↗

bioRxiv2024

Functional 3'-UTR Variants Identify Regulatory Mechanisms Impacting Alcohol Use Disorder and Related Traits

Although genome-wide association studies (GWAS) have identified loci associated with alcohol consumption and alcohol use disorder (AUD), they do not identify which variants are functional. To approach this, we evaluated the impact of variants in 3 untranslated regions (3-UTRs) of genes in loci associated with substance use and neurological disorders using a massively parallel reporter assay (MPRA) in neuroblastoma and microglia cells. Functionally impactful variants explained a higher proportion of heritability of alcohol traits than non-functional variants. We identified genes whose 3-UTR activities are associated with AUD and alcohol consumption by combining variant effects from MPRA with GWAS results. We examined their effects by evaluating gene expression after CRISPR inhibition of neuronal cells and stratifying brain tissue samples by MPRA-derived 3-UTR activity. A pathway analysis of differentially expressed genes identified inflammation response pathways. These analyses suggest that variation in response to inflammation contributes to the propensity to increase alcohol consumption.

genomics↗

bioRxiv2024

Architecture of intact mammalian pyruvate dehydrogenase complex revealed by in-situ structural analysis

The multi-enzyme pyruvate dehydrogenase complex (PDC) links glycolysis to the citric acid cycle by converting pyruvate into acetyl-coenzyme A and is essential for cellular energy metabolism. Although individual components have been characterized, the structure of intact PDC remains unclear, hampering our understanding of its composition and multi-step catalytic reactions. Here, we report the in-situ architecture of intact PDC within mammalian mitochondria by cryo-electron tomography. The organization of peripheral E1 and E3 multimers varies substantially among PDCs. We discovered 1-46 E1 heterotetramers surrounding each PDC core, and up to 12 E3 dimers locating primarily along the pentagonal openings. Furthermore, we observed dynamic interactions of the substrate translocating lipoyl domains (LDs) with both E1 and E2, implicating the mechanism of substrate channeling. Our findings reveal the intrinsic dynamics of PDC peripheral compositions, suggesting an additional model in which the number of assembled E1 heterotetramer, E3 dimer, and functional LDs of PDC may be regulated to further control its catalytic activity.

cell biology↗

bioRxiv2024

Human Amniotic Epithelial Cells Promote Chx10-/Pax6+ Muller Glia Subpopulation Reprogramming into Photoreceptor-like Cells

Reprogramming Muller glia to regenerate neurons is a promising strategy for treating retinal degeneration, but whether Muller glia contain subpopulations with different regenerative fates remains unclear. Here, using single-cell RNA-seq analysis and Muller glia lineage-tracing mice with retinal degeneration, we reveal that Muller glia were heterogeneous and identify a specific Muller glial subpopulation (Chx10-/Pax6+) in healthy retinas that is activated and migrate to the outer nuclear layer (ONL) during photoreceptor degeneration. Transplantation of human amniotic epithelial cells (hAECs) facilitates the activation and extensive migration of the Chx10-/Pax6+ Muller glial subpopulation to the ONL, where they are reprogrammed into photoreceptor-like cells. Mechanistically, hAECs degrade the inhibitory extracellular matrix through regulating matrix metalloproteinases, which probably induces remodeling of the microenvironment of Muller glia and contributes to cell reprogramming. Consequently, hAEC transplantation improves visual function in rd10 mice. Our findings uncover a distinctive Muller glial subpopulation with the potential for reprogramming into photoreceptors.

cell biology↗

bioRxiv2024

Identification of a distinct cluster of GDF15high macrophages exhibiting anti-inflammatory activities

Macrophage-mediated inflammatory response may have crucial roles in the pathogenesis of a variety of human diseases. Growth differentiation factor 15 (GDF15) is a cytokine of the transforming growth factor-{beta} superfamily, with potential anti-inflammatory activities. Previous studies observed in human lungs some macrophages which expressed a high level of GDF15. In the present study, we employed multiple techniques, including immunofluorescence, flow cytometry, and single-cell RNA sequencing, in order to further clarify the identity of such GDF15high macrophages. We demonstrated that macrophages derived from human peripheral blood mononuclear cells and rat bone marrow mononuclear cells by in vitro differentiation with granulocyte-macrophage colony stimulating factor contained a minor population ([~]1%) of GDF15high cells. GDF15high macrophages did not exhibit a typical M1 or M2 phenotype, but had a unique molecular signature as revealed by single-cell RNA sequencing. Functionally, GDF15high macrophages were associated with reduced responsiveness to pro-inflammatory activation; furthermore, GDF15high macrophages could inhibit the pro-inflammatory functions of other macrophages via a paracrine mechanism. We further confirmed that GDF15 per se was a key mediator of the anti-inflammatory effects of GDF15high macrophage. Also, we provided direct evidence showing that GDF15high macrophages were also present in other macrophage-residing human tissues in addition to the lungs. Our results suggest that the GDF15high macrophage may represent a distinct cluster of macrophage cells with intrinsic anti-inflammatory functions. The (patho)physiological importance of these cells in vivo warrants further investigation.

immunology↗

bioRxiv2023

The ICF2 gene Zbtb24 specifically regulates the differentiation of B1 cells via promoting heme synthesis

Loss-of-function mutations of ZBTB24 cause the Immunodeficiency, Centromeric Instability and Facial Anomalies syndrome 2 (ICF2). ICF2 is a rare autosomal recessive disorder with immunological defects in serum antibodies and circulating memory B cells, indicating an essential role of ZBTB24 in the terminal differentiation of B cells. Here we generated B-cell specific Zbtb24-deficient mice and systemically investigated its role in B cell development and function both in vivo and in vitro. Zbtb24 is dispensable for B cell development & maintenance in naive mice. Surprisingly, B-cell specific deletion of Zbtb24 does not evidently compromise germinal center reactions and the resulting primary & secondary antibody responses induced by T-cell dependent antigens, but significantly inhibits T-cell independent antigen-elicited antibody productions in vivo. At the cellular level, Zbtb24-deficiency specifically impedes the plasma cell differentiation of B1 cells without impairing their survival, activation and proliferation in vitro. Mechanistically, Zbtb24-ablation attenuates heme biosynthesis partially through mTORC1 in B1 cells, and addition of exogenous hemin abrogates the differentiation defects of Zbtb24-null B1 cells. Our study suggests that the defected B1 functions may contribute to recurrent infections in ICF2 patients, and discloses a B1-specific role of Zbtb24 in regulating plasma cell differentiation and antibody production, which is relevant for barrier defenses against invading pathogens.

immunology↗

bioRxiv2023

Exploration of the intricacies of low light-induced changes in cigar tobacco leaf anticlinal growth: A holistic approach from anatomical and hormonal levels to gene expression

Cigar tobacco stands as a pivotal economic crop, with its leaf growth and development profoundly influenced by light intensity. It specifically aims to investigate how leaf morphology and anticlinal growth respond to varying light intensities, including normal light intensity (NL-300 mol m-2 s-1) and lower light intensity (LL-100 mol m-2 s-1). The research elucidates significant morphological shifts in cigar tobacco leaves under LL, revealing notable alterations in leaf area, leaf length, and leaf width. Early reductions in leaf dimensions, ranging from 30% to 48%, were succeeded by a substantial enhancement in expansion rates from day 9 to day 26, contributing to expanded leaf surfaces at later stages. Upper epidermis thickness declined by 29-19%, with a notably slower expansion rate in the initial 20 days. Palisade cell length consistently decreased by 52-17%, corresponding with upper epidermis trends. Spongy tissue thickness was reduced by 31-12%, with a slower expansion rate in LL for the initial 14 days, and leaf thickness dropped by 34-11%. LL resulted in slower leaf anticlinal expansion, leading to reduced leaf thickness (LT). LL significantly influenced phytohormones in cigar tobacco leaves. Gibberellic acid (41% to 16%) and auxin (20% to 35%) levels were found in higher amounts, while cytokinin levels (19% to 5%) were lowered compared to NL, indicating the intricate regulatory role of light in hormonal dynamics. The observed increase in LT and different cell layers at specific time points (day 8, day 12, day 24, and day 28) under LL, although lower than NL, may be attributed to elevated expression of genes related to cell expansion, including GRF1, XTH, and SAUR19 at those time points. This comprehensive understanding elucidates the intricate mechanisms by which light intensity orchestrates the multifaceted processes governing leaf anatomy and anticlinal expansion in cigar tobacco plants.

physiology↗

bioRxiv2023

metaExpertPro: a computational workflow for metaproteomics spectral library construction and data-independent acquisition mass spectrometry data analysis

BackgroundAnalysis of mass spectrometry-based metaproteomic data, in particular large-scale data-independent acquisition MS (DIA-MS) data, remains a computational challenge. Here, we aim to develop a software tool for efficiently constructing spectral libraries and analyzing extensive datasets of DIA-based metaproteomics. ResultsWe present a computational pipeline called metaExpertPro for metaproteomics data analysis. This pipeline encompasses spectral library generation using data-dependent acquisition MS (DDA-MS), protein identification and quantification using DIA-MS, functional and taxonomic annotation, as well as quantitative matrix generation for both microbiota and hosts. To enhance accessibility and ease of use, all modules and dependencies are encapsulated within a Docker container. By integrating FragPipe and DIA-NN, metaExpertPro offers compatibility with both Orbitrap-based and PASEF-based DDA and DIA data. To evaluate the depth and accuracy of identification and quantification, we conducted extensive assessments using human fecal samples and benchmark tests. Performance tests conducted on human fecal samples demonstrated that metaExpertPro quantified an average of 45,000 peptides in a 60-minute diaPASEF injection. Notably, metaExpertPro outperformed three existing software tools by characterizing a higher number of peptides and proteins. Importantly, metaExpertPro maintained a low factual False Discovery Rate (FDR) of less than 5% for protein groups across four benchmark tests. Applying a filter of five peptides per genus, metaExpertPro achieved relatively high accuracy (F-score = 0.67-0.90) in genus diversity and demonstrated a high correlation (rSpearman = 0.73-0.82) between the measured and true genus relative abundance in benchmark tests. Additionally, the quantitative results at the protein, taxonomy, and function levels exhibited high reproducibility and consistency across the commonly adopted public human gut microbial protein databases IGC and UHGP. In a metaproteomic analysis of dyslipidemia patients, metaExpertPro revealed characteristic alterations in microbial functions and potential interactions between the microbiota and the host. ConclusionsmetaExpertPro presents a robust one-stop computational solution for constructing metaproteomics spectral libraries, analyzing DIA-MS data, and annotating taxonomic as well as functional data.

microbiology↗