Biology subjects

Xu, N.

Publications and source records attributed to Xu, N..

At least 55 records · Page 3Linked to original sources

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↗

bioRxiv2022

Spatial and Spectral Components of the BOLD Global Signal in Rat Resting-State Functional MRI

In resting-state fMRI (rs-fMRI), the global signal average captures widespread fluctuations related to unwanted sources of variance such as motion and respiration, and has long been used as a regressor to reduce noise during data preprocessing. However, coherent neural activity in spatially-extended functional networks can also contribute to the global signal. The relative contributions of neural and non-neural sources to the global signal remain poorly understood. This study sought to tackle this problem through the comparison of the blood oxygenation level dependent (BOLD) global signal to an adjacent non-brain tissue signal from the same scan in rs-fMRI obtained from anesthetized rats. In this dataset motion was minimal and ventilation was phase-locked to image acquisition to minimize respiratory fluctuations. In addition to contrasting the spatial and spectral components of these two signals, we also observed these differences across the use of three different anesthetics: isoflurane, dexmedetomidine, and a combination of dexmedetomidine and light isoflurane. Here, we report differences in the spectral composition of the two signals as evaluated by a power spectral density (PSD) estimate and a fractional amplitude of low-frequency fluctuations (fALFF) calculation. Additionally, we show spatial selectivity for specific brain structures that show an increased correlation to the global signal both statically and dynamically, through Pearsons correlation and co-activation pattern analysis, respectively. All of the observed differences between the BOLD global signal and the adjacent non-brain tissue signal were maintained across all three anesthetic conditions, showing that the global signal is distinct from the noise contained in the tissue signal. This study provides a unique perspective to the contents of the global signal and their origins.

bioengineering↗

bioRxiv2022

The effect of random and systematic visual stimulation on entrained infraslow quasi-periodic global waves in human brain activity

One prominent feature of the infraslow BOLD signal during rest or task is quasi-periodic spatiotemporal pattern (QPP) of signal changes that involves an alternation of activity in key functional networks and propagation of activity across brain areas, and that is known to tie to the infraslow neural activity involved in attention and arousal fluctuations. This ongoing whole-brain pattern of activity might potentially modify the response to incoming stimuli or be modified itself by the induced neural activity. To investigate this, we presented checkerboard sequences flashing at 6Hz to subjects. This is a salient visual stimulus that is known to produce a strong response in visual processing regions. Two different visual stimulation sequences were employed, a systematic stimulation sequence in which the visual stimulus appeared every 20.3 secs and a random stimulation sequence in which the visual stimulus occurred randomly every 14~62.3 secs. Three central observations emerged. First, the two different stimulation conditions affect the QPP waveform in different aspects, i.e., systematic stimulation has greater effects on its phase and random stimulation has greater effects on its magnitude. Second, the QPP was more frequent in the systematic condition with significantly shorter intervals between consecutive QPPs compared to the random condition. Third, the BOLD signal response to the visual stimulus across both conditions was swamped by the QPP at the stimulus onset. These results provide novel insights into the relationship between intrinsic patterns and stimulated brain activity.

neuroscience↗

bioRxiv2022

A novel pathway of functional microRNA uptake and mitochondria delivery

Extracellular miRNAs serve as signal molecules in the recipient cells. Uptake of extracellular miRNAs by the recipient cells and their intracellular transport, however, remains elusive. Here we show RNA phase separation as a novel pathway of miRNA uptake. In the presence of serum, synthetic miRNAs rapidly self-assembly into [~]110nm discrete nanoparticles which enable miRNAs entry into different cells. Depleting serum cationic proteins prevents the formation of such nanoparticles and thus blocks miRNA uptake. Different from lipofectamine-mediated miRNA transfection in which the majority of miRNAs are in lysosomes of transfected cells, nanoparticles-mediated miRNA uptake predominantly delivers miRNAs into mitochondria in a polyribonucleotide nucleotidyltransferase 1-dependent manner. Functional assays further show that the internalized miR-21 via miRNA phase separation enhances mitochondrial translation of Cytochrome b, leading to increase in ATP and ROS reduction in HEK293T cells. Our findings reveal a previously unrecognized mechanism for uptaking and delivering functional extracellular miRNAs into mitochondria. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/515397v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@1b83cd8org.highwire.dtl.DTLVardef@a29f54org.highwire.dtl.DTLVardef@8a6b1aorg.highwire.dtl.DTLVardef@17d9d2a_HPS_FORMAT_FIGEXP M_FIG C_FIG RNA phase separation-based extracellular miRNA uptake and PNPT1-mediated mitochondrial delivery of internalized miRNAs O_LImiRNAs can self-assembly into [~]110nm nanoparticles to enter various cells in the presence of serum C_LIO_LImiRNA phase separation is mediated by serum cationic proteins C_LIO_LIInternalized miRNAs via this nanoparticle pathway are predominantly delivered to mitochondria C_LIO_LIMitochondrial delivery of the internalized miRNAs is mediated by PNPT1 C_LI

cell biology↗

bioRxiv2022

Evaluation of antibody kinetics and durability in health subjects vaccinated with inactivated COVID-19 vaccine (CoronaVac): A cross-sectional and cohort study in Zhejiang, China

BackgroundAlthough inactivated COVID-19 vaccines are proven to be safe and effective in the general population, the dynamic response and duration of antibodies after vaccination in the real world should be further assessed. MethodsWe enrolled 1067 volunteers who had been vaccinated with one or two doses of CoronaVac in Zhejiang Province, China. Another 90 healthy adults without previous vaccinations were recruited and vaccinated with three doses of CoronaVac, 28 days and 6 months apart. Serum samples were collected from multiple timepoints and analyzed for specific IgM/IgG and neutralizing antibodies (NAbs) for immunogenicity evaluation. Antibody responses to the Delta and Omicron variants were measured by pseudovirus-based neutralization tests. ResultsOur results revealed that binding antibody IgM peaked 14-28 days after one dose of CoronaVac, while IgG and NAbs peaked approximately 1 month after the second dose then declined slightly over time. Antibody responses had waned by month 6 after vaccination and became undetectable in the majority of individuals at 12 months. Levels of NAbs to live SARS-CoV-2 were correlated with anti-SARS-CoV-2 IgG and NAbs to pseudovirus, but not IgM. Homologous booster around 6 months after primary vaccination activated anamnestic immunity and raised NAbs 25.5-fold. The NAb inhibition rate subsequently rose to 36.0% for Delta (p=0.03) and 4.3% for Omicron (p=0.004), and the response rate for Omicron rose from 7.9% (7/89) to 17.8% (16/90). ConclusionsTwo doses of CoronaVac vaccine resulted in limited protection over a short duration. The homologous booster slightly increased antibody responses to the Delta and Omicron variants; therefore, the optimization of booster procedures is vital. FundingKey Research and Development Program of Zhejiang Province; Key Program of Health Commission of Zhejiang Province/ Science Foundation of National Health Commission; Major Program of Zhejiang Municipal Natural Science Foundation.

immunology↗

bioRxiv2022

Dissecting the genetic basis of the heterosis of Y900, an elite super-hybrid rice

Y900 is one of the top hybrid rice varieties with a yield exceeding 15 t/hm2. To dissect the mechanism of heterosis, the male parent line R900 and female parent line Y58S were sequenced using long-read and Hi-C technology. High-quality reference genomes of sizes of 396.41 Mb and 398.24 Mb were obtained for R900 and Y58S, respectively. Genome-wide variations between the parents were systematically identified, including 1,367,758 SNPs and 299,149 Indels. No megabase level structural variations exist. >75% of genes exhibited variation between the two parents. Compared with other two-line hybrids sharing the same female parent, the Geng/japonica-type genetic components from different male parents showed an increasing trend from phase 2-4 super-hybrid rice; Transcriptome analysis revealed that additive and dominance effects are the main genetic effects that constitute the heterosis of Y900. Allele-specific expression patterns and expression regulation patterns are quite dynamic in different tissues. For young panicle tissues, cis-regulation is dominant, while trans-regulation is more popular in leaf issues. Overdominance is more likely regulated by the trans-regulation mechanism. The differential gene expression and regulation pattern are closely related to Geng/japonica introgression. Additionally, R900 contained several excellent japonica haplotypes, such as NAL1, OsSPL13, Ghd8, OsBRI1, and DTH2, which make a good complement to Y58S. The fine tune mechanism through dynamic expression or regulation pattern change, especially on some key functional genes, is the base for heterosis.

plant biology↗

bioRxiv2021

Two Stages of Speech Envelope Tracking in Human Auditory Cortex Modulated by Speech Intelligibility

The envelope is essential for speech perception. Recent studies have shown that cortical activity can track the acoustic envelope. However, whether the tracking strength reflects the extent of speech intelligibility processing remains controversial. Here, using stereo-electroencephalogram (sEEG) technology, we directly recorded the activity in human auditory cortex while subjects listened to either natural or noise-vocoded speech. These two stimuli have approximately identical envelopes, but the noise-vocoded speech does not have speech intelligibility. We found two stages of envelope tracking in auditory cortex: an early high-{gamma} (60-140 Hz) power stage (delay {approx} 49 ms) that preferred the noise-vocoded speech, and a late {theta} (4-8 Hz) phase stage (delay {approx} 178 ms) that preferred the natural speech. Furthermore, the decoding performance of high-{gamma} power was better in primary auditory cortex than in non-primary auditory cortex, consistent with its short tracking delay. We also found distinct lateralization effects: high-{gamma} power envelope tracking dominated left auditory cortex, while {theta} phase showed better decoding performance in right auditory cortex. In sum, we suggested a functional dissociation between high-{gamma} power and {theta} phase: the former reflects fast and automatic processing of brief acoustic features, while the latter correlates to slow build-up processing facilitated by speech intelligibility.

neuroscience↗

bioRxiv2021

Asymmetrical choice-related ensemble activity in direct and indirect-pathway striatal neurons drives perceptual decisions

Sensory-guided decision-making is a vital brain function critically depending on the striatum, a key brain structure transforming sensorimotor information into actions. However, how the two opposing striatal pathways work in concert to select actions during decision-making remains controversial. Here, using cell-type specific two-photon imaging and optogenetic perturbations from the posterior dorsal striatum during decision-making behavior in mice, we uncover the population coding and causal mechanisms of the direct- and indirect-pathway spiny projection neurons (dSPNs and iSPNs) in decision-related action selection. Unexpected from prevailing models, we found that both dSPNs and iSPNs contain divergent subpopulations representing competing choices, and exhibit ensemble-level asymmetry: stronger contralateral dominance in dSPNs than in iSPNs. Such multi-ensemble competition/cooperation causally contributes to decision-related action selection, as supported by systematic optogenetic manipulations and verified by computational modeling. Our results unravel a multi-ensemble coordination mechanism in the striatum for action selection during decision-making.

neuroscience↗

bioRxiv2021

De novo assembly of 20 chickens reveals the undetectable phenomenon for thousands of core genes on sub-telomeric regions

The gene numbers and evolutionary rates of birds were assumed to be much lower than that of mammals, which in sharp contrast to the huge species number and morphological diversity of birds. It is very necessary to construct a complete avian genome and analyze its evolution.We constructed a chicken pan-genome from 20 de novo genome assemblies with high sequencing depth, newly identified 1,335 protein-coding genes and 3,011 long noncoding RNAs. The majority of these novel genes were detected across most individuals of the examined transcriptomes but were accidentally measured in each of the DNA sequencing data regardless of Illumina or PacBio technology. Furthermore, different from previous pan-genome models, most of these novel genes were overrepresented on chromosomal sub-telomeric regions, surrounded with extremely high proportions of tandem repeats, and strongly blocked DNA sequencing. These hidden genes were proved to be shared by all chicken genomes, included many housekeeping genes, and enriched in immune pathways. Comparative genomics revealed the novel genes had three-fold elevated substitution rates than known ones, updating the evolutionary rates of birds. Our study provides a framework for constructing a better chicken genome, which will contribute towards the understanding of avian evolution and improvement of poultry breeding.

genomics↗

bioRxiv2021

Extrasynaptic NMDA receptors bidirectionally modulate intrinsic excitability of inhibitory neurons

The NMDA subtype glutamate receptors (NMDARs) play important roles in both physiological and pathological processes in the brain. Comparing to their critical roles in synaptic modifications and excitotoxicity in the excitatory neurons, much less is understood about the functional contributions of NMDARs to the inhibitory/GABAergic neurons. By using selective NMDAR inhibitors and potentiators, we here show that NMDARs bi-directionally modulate the intrinsic excitability (defined as spontaneous/evoked spiking activity and EPSP-spike coupling) in the inhibitory/GABAergic neurons. This modulation depends on GluN2C/2D-but not GluN2A/2B-containing NMDARs. We further show that NMDAR modulator EU1794-4 mostly enhances extrasynaptic NMDAR activity, and by using it we demonstrate a significant contribution of extrasynaptic NMDARs to the modulation of intrinsic excitability in the inhibitory neurons. Altogether, this bidirectional modulation of intrinsic excitability reveals a previously less appreciated importance of NMDARs in the second-to-second functioning of inhibitory/GABAergic neurons.

neuroscience↗

bioRxiv2021

The endoplasmic reticulum-resident protein TMEM-120/TMEM120A promotes fat storage in C. elegans and mammalian cells

The synthesis of triacylglycerol (TAG) is essential for the storage of excess fatty acids, which can subsequently be used for energy or cell growth. A series of enzymes act in the endoplasmic reticulum (ER) to synthesize TAG, prior to its transfer to lipid droplets (LDs), which are conserved organelles for fat storage. Here, we report that the deficiency of TMEM-120/TMEM120A, a protein with 6-transmembrane helices, retards TAG synthesis and LD expansion in C. elegans. A missense mutation near the predicted coenzyme A binding site of TMEM-120 confers strong loss of function phenotypes. GFP fusion proteins of TMEM-120, expressed at the endogenous level in live worms, were observed throughout the ER network. Using Stimulated Raman Scattering, we discovered a specific requirement of TMEM-120 in the storage of exogenous fatty acids in LDs. Knockdown of TMEM120A impedes adipogenesis of pre-adipocytes in vitro, while its over-expression is sufficient to promote LD expansion. Pharmacological studies indicate that TMEM120A most likely acts upstream of diacylglycerol O-acyltransferase 1 (DGAT1). Our results suggest that TMEM-120/TMEM120A plays a conserved role in increasing the efficiency of TAG synthesis.

cell biology↗

bioRxiv2021

CRISPRa screen on a genetic risk locus shared by multiple autoimmune diseases identifies a dysfunctional enhancer that affects IRF8 expression through cooperative lncRNA and DNA methylation machinery

Dysregulated transcription factors represent a major class of drug targets that mediate the abnormal expression of many critical genes involved in SLE and other autoimmune diseases. Although strong evidence suggests that natural human genetic variation affects basal and inducible gene expression, it is still a considerable challenge to establish a biological link between GWAS-identified non-coding genetic risk variants and their regulated gene targets. Here, we combine genetic data, epigenomic data, and CRISPR activation (CRISPRa) assays to screen for functional variants regulating IRF8 expression. Using CRISPR-mediated deletion and 3D chromatin structure analysis, we demonstrate that the locus containing rs2280381 is a cell-type-specific distal enhancer for IRF8 that spatially interacts with the IRF8 promoter. Further, rs2280381 mediates IRF8 expression through enhancer RNA AC092723.1, which recruits TET1 to the IRF8 promoter to modulate IRF8 expression by affecting methylation levels. The alleles of rs2280381 modulate PU.1 binding and chromatin state to differentially regulate AC092723.1 and IRF8 expression. Our work illustrates a strategy to define the functional genetic variants modulating transcription factor gene expression levels and identifies the biologic mechanism by which autoimmune diseases risk genetic variants contribute to the pathogenesis of disease.

genetics↗

bioRxiv2021

Multiple nucleotide polymorphism DNA markers for the accurate evaluation of genetic variations

DNA markers are an essential tool for the detection and evaluation of genetic variations, a central theme in genetics and biology. Effective markers must be highly reproducible, polymorphic, accurate and efficient to profile. We developed multiple dispersed nucleotide polymorphism (MNP) DNA marker and an efficient MNP genotyping method called MNP-Seq. The MNP marker was 17.48% more polymorphic than the highly polymorphic marker of microsatellites on a collection of hybrid rice plants. When applied to genotype more than 80,000 individual MNP markers of diploid rice and polyploidy hybrid cotton varieties which were notoriously difficult to genotype accurately, MNP-Seq finished in two days and achieved accuracies of 99.999% and 99.988%, respectively. We adopted MNP-Seq to reveal the ubiquitous, albeit subtle and neglected, genetic heterogeneities in homonyms of Nipponbare rice, a popular model organism for plant biology. This result raised a question on the consistency of the published results using the model plant. We also used MNP-Seq to accurately and efficiently determine the identities of plant varieties, a key but difficult problem for the protection of plant intellectual property rights. While being applied to plants in the current study, the MNP marker and MNP-Seq are general and readily applicable to similar problems in animals and micro-organisms.

molecular biology↗

bioRxiv2020

Nuclear receptor NHR-49 promotes peroxisome proliferation to compensate for aldehyde dehydrogenase deficiency in C. elegans

The intracellular level of fatty aldehydes is tightly regulated to minimize the formation of toxic aldehyde adducts of cellular components. Accordingly, deficiency of a fatty aldehyde dehydrogenase FALDH causes the neurologic disorder Sjogren-Larsson syndrome (SLS) in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Based on lipidomic and imaging analysis, we report that the loss of endoplasmic reticulum-, mitochondria- and peroxisomes-associated ALH-4, the C. elegans FALDH ortholog, increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are not viable. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels, and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy for SLS.

cell biology↗

bioRxiv2020

A cortical circuit mechanism for coding and updating task structural knowledge in inference-based decision-making

Making decisions based on knowledge about causal environmental structures is a hallmark of higher cognition in mammalian brains. Despite mounting work in psychological and cognitive sciences, how the brain implements knowledge-based decision-making at neuronal circuit level remains a terra incognita. Here we established an inference-based auditory categorization task, where mice performed within-session re-categorization of stimuli by inferring the changing task rules. Using a belief-state reinforcement learning (BS-RL) model, we quantified the hidden variable associated with task knowledge. Using simultaneous two-photon population imaging and projection-specific optogenetics, we found that a subpopulation of auditory cortex (ACx) neurons encoded the hidden task-rule variable, which depended on the feedback input from orbitofrontal cortex (OFC). Chemogenetic silencing of the OFC-ACx projection specifically disrupted re-categorization performance. Finally, imaging from OFC axons within ACx revealed task state-related value signals in line with the modeled updating mechanism. Our results provide a cortical circuit mechanism underlying inference-based decision-making.

neuroscience↗

bioRxiv2020

Altered N-glycan composition impacts flagella mediated adhesion in Chlamydomonas reinhardtii

For the unicellular alga Chlamydomonas reinhardtii, the presence of N-glycosylated proteins on the surface of two flagella is crucial for both cell-cell interaction during mating and flagellar surface adhesion. It is unknown whether the composition of N-glycans attached to respective proteins is important for these processes. To this end, we examined several C. reinhardtii insertional mutants and a CRIPSR/Cas9 knockout mutant of xylosyltransferase 1A, all possessing altered N-glycan compositions. Taking advantage of atomic force microscopy and micropipette force measurements, our data revealed that reduction in N-glycan complexity impedes the adhesion force required for binding the flagella to surfaces. In addition, polystyrene bead binding and transport is impaired. Notably, assembly, Intraflagellar Transport and FMG-1B transport into flagella are not affected by altered N-glycosylation. Thus, we conclude that proper N-glycosylation of flagellar proteins is crucial for adhering C. reinhardtii cells onto surfaces, indicating that N-glycans mediate surface adhesion via direct surface contact.

plant biology↗

bioRxiv2020

SLE non-coding Genetic Risk Variant Determines the Epigenetic Dysfunction of an Immune Cell Specific Enhancer that Controls Disease-critical microRNA Expression

The human genome contains millions of putative regulatory elements, which regulate gene expression. We are just beginning to understand the functional consequences of genetic variation within these regulatory elements. Since the bulk of common genetic variation impacting polygenic disease phenotypes localizes to these non-coding regions of the genome, understanding the consequences will improve our understanding of the mechanisms mediating genetic risk in human disease. Here, we define the systemic lupus erythematosus (SLE) risk variant rs2431369 as likely causal for SLE and show that it is located in a functional regulatory element that modulates miR-146a expression. We use epigenomic analysis and genome-editing to show that the rs2431697-containing region is a distal enhancer that specifically regulates miR-146a expression in a cell-type dependent manner. 3D chromatin structure analysis demonstrates physical interaction between the rs2431697-containing region and the miR-146a promoter. Further, our data show that NF-kB binds the disease protective allele in a sequence-specific manner, leading to increased expression of this immunoregulatory microRNA. Our work provides a strategy for using disease-associated variants to define the functional regulatory elements of non-coding RNA molecules such as miR-146a and provides mechanistic links between autoimmune disease risk genetic variation and disease etiology.

genetics↗

bioRxiv2020

Spatiotemporal functional interactivity among large-scale brain networks

The macro-scale intrinsic functional network architecture of the human brain has been well characterized. Early studies revealed robust and enduring patterns of static connectivity, while more recent work has begun to explore the temporal dynamics of these large-scale brain networks. Little work to date has investigated directed connectivity within and between these networks, or the temporal patterns of afferent (input) and efferent (output) connections between network nodes. Leveraging a novel analytic approach, prediction correlation, we investigated the causal interactions within and between large-scale networks of the brain using resting-state fMRI. This technique allows us to characterize information transfer between brain regions in both the spatial (direction) and temporal (duration) scales. Using data from the Human Connectome Project (N=200) we applied prediction correlation techniques to four resting state fMRI runs (total TRs = 4800). Three central observations emerged. First, the strongest and longest duration connections were observed within the somatomotor, visual and dorsal attention networks. Second, the short duration connections were observed for high-degree nodes in the visual and default networks, as well as in hippocampus. Specifically, the connectivity profile of the highest-degree nodes was dominated by efferent connections to multiple cortical areas. Moderate high-degree nodes, particularly in hippocampal regions, showed an afferent connectivity profile. Finally, multimodal association nodes in lateral prefrontal brain regions demonstrated a short duration, bidirectional connectivity profile, consistent with this regions role in integrative and modulatory processing. These results provide novel insights into the spatiotemporal dynamics of human brain function.

bioinformatics↗