Biology subjects

Liang, X.

Publications and source records attributed to Liang, X..

At least 127 records · Page 7Linked to original sources

bioRxiv2022

Polyphasic circadian neural circuits drive differential activities in multiple downstream rhythmic centers

Circadian clocks align various behaviors such as locomotor activity, sleep/wake, feeding, and mating to times of day that are most adaptive. How rhythmic information in pacemaker circuits is translated to neuronal outputs is not well understood. Here we used brain-wide, 24-hr in vivo calcium imaging in the Drosophila brain and searched for circadian rhythmic activity among identified clusters of dopaminergic (DA) and peptidergic neuroendocrine (PNE) neurons. Such rhythms were widespread and imposed by the PERIOD-dependent clock activity within the [~]150 cell circadian pacemaker network. The rhythms displayed either a Morning, an Evening, or Mid-Day phase. Different sub-groups of circadian pacemakers imposed neural activity rhythms onto different downstream non-clock neurons. Outputs from the canonical M and E pacemakers converged to regulate DA-PPM3 and DA-PAL neurons. E pacemakers regulate the Evening-active DA-PPL1 neurons. In addition to these canonical M and E oscillators, we present evidence for a third dedicated phase occurring at Mid-Day (MD): the l-LNv pacemakers present the MD activity peak and they regulate the MD-active DA-PPM1/2 neurons and three distinct PNE cell types. Thus, the Drosophila circadian pacemaker network is a polyphasic rhythm generator. It presents dedicated M, E and MD phases that are functionally transduced as neuronal outputs to organize diverse daily activity patterns in downstream circuits.

neuroscience↗

bioRxiv2022

A conserved role for stomatin domain genes in olfactory behavior

The highly-conserved stomatin domain has been identified in genes throughout all classes of life. In animals, different stomatin domain-encoding genes have been implicated in the function of the kidney, red blood cells, and specific neuron types, though the underlying mechanisms remain unresolved. In one well-studied example of stomatin domain gene function, the C. elegans gene mec-2 and its mouse homologue Stoml3 are required for the function of mechanosensory neurons, where they modulate the activity of mechanosensory ion channels on the plasma membrane. Here we identify an additional shared function for mec-2 and Stoml3 in a very different sensory context, that of olfaction. In worms, we find that a subset of stomatin domain genes are expressed in olfactory neurons, but only mec-2 is strongly required for olfactory behavior. mec-2 acts cell-autonomously and does not have any observable effect on olfactory neuron development or morphology, but modestly reduces olfactory neuron activity. We generate a Stoml3 knockout mouse and demonstrate that, like its worm homologue mec-2, it is required for olfactory behavior. In mice, Stoml3 is not required for odor detection, but is required for odor discrimination. Therefore, in addition to their shared roles in mechanosensory behavior, mec-2 and Stoml3 also have a shared role in olfactory behavior.

neuroscience↗

bioRxiv2022

Developmental reprogramming mediates aberrant cell state plasticity in colorectal cancer initiation

Cell state (phenotypic) plasticity is a carefully regulated feature of adult epithelial cells that enables adaptive responses to injury, inflammation, and other forms of stress. Aberrant expansion of the normally restricted capability for cell state plasticity to escape terminal differentiation is a critical aspect of neoplasia. The nongenetic factors and specific programs that mediate aberrant cell state plasticity and impaired differentiation require deeper characterization to understand this elusive aspect of cancer pathogenesis. Using genetically engineered and carcinogen-induced murine models of intestinal neoplasia, we demonstrate that impaired differentiation is a conserved event preceding cancer development. Single cell RNA-sequencing (scRNA-seq) of neoplastic intestinal lesions from both mouse models and a patient with familial adenomatous polyposis revealed that cancer initiates by adopting an aberrant transcriptional state characterized by nonoverlapping expression of a regenerative pathway, marked by Ly6a (Sca-1), and a fetal intestinal program, positive for Tacstd2 (Trop2). Genetic inactivation of Sox9 prevented adenoma formation in ApcKO mice, obstructed emergence of aberrant regenerative and fetal intestinal programs, and restored multi-lineage differentiation by scRNA-seq. Expanded chromatin accessibility at regeneration and fetal genes upon Apc inactivation was reduced by concomitant Sox9 suppression. These studies indicate that aberrant cell state plasticity mediated by unabated regenerative activity and developmental reprogramming precedes cancer development.

cancer biology↗

bioRxiv2022

Global genomic analysis reveals the genetic origin and secondary invasion of fall armyworm in the Eastern hemisphere

The major plant pest fall armyworm (FAW), Spodoptera frugiperda, is native to the Americas and has colonized African and Asian countries in the Eastern hemisphere since 2016, causing severe damage to multiple agricultural crop species. However, the genetic origin of these invasive populations require more in-depth exploration. We analyzed genetic variation across FAW genomes of 153 newly sequenced individuals from Eastern hemisphere and 127 individuals mostly originating from the Americas. The global genetic structure of FAW shows that the FAW in American has experienced deep differentiation, largely consistent with the Z-chromosomal Tpi haplotypes commonly used to differentiate "corn-strain" and "rice-strain" populations. Results indicate that the invasive Eastern hemisphere populations are different from the American ones and have relatively homogeneous population structure, consistent with the common origin and recent spreading from Africa to Asia. Our analyses suggest that north-and central American "corn-strain" FAW are the most likely sources of the invasion into the Eastern hemisphere. Furthermore, evidence based on genomic, transcriptomic and mitochondrial haplotype network analysis suggest that there has been an earlier independent introduction of FAW into Africa that introgressed into the recent invasive population.

molecular biology↗

bioRxiv2022

Systematic mutagenesis reveals critical effector functions in the assembly and dueling of the H1-T6SS in Pseudomonas aeruginosa

Pseudomonas aeruginosa is an important human pathogen that can cause severe wound and lung infections. It employs the type VI secretion system (H1-T6SS) as a molecular weapon to carry out a unique dueling response to deliver toxic effectors to neighboring sister cells or other microbes after sensing an external attack. However, the underlying mechanism for such dueling is not fully understood. Here, we examined the role of all H1-T6SS effectors and VgrG proteins in assembly and signal sensing by ectopic expression, combinatorial deletion and point mutations, and imaging analyses. Expression of effectors targeting the cell wall and membrane resulted in increased H1-T6SS assembly. Deletion of individual effector and vgrG genes had minor- to-moderate effects on H1-T6SS assembly and dueling activities. The dueling response was detectable in the P. aeruginosa mutant lacking all H1-T6SS effector activities. In addition, double deletions of vgrG1a with either vgrG1b or vgrG1c and double deletions of effector genes tse5 and tse6 severely reduced T6SS assembly and dueling activities, suggesting their critical role in T6SS assembly. Collectively, these data highlight the diverse roles of effectors in not only dictating antibacterial functions but also their differential contributions to the assembly of the complex H1-T6SS apparatus.

microbiology↗

bioRxiv2022

Resting fMRI-guided TMS evokes subgenual anterior cingulate response in depression

Depression alleviation following treatment with repetitive transcranial magnetic stimulation (rTMS) tends to be more effective when TMS is targeted to cortical areas with high resting state functional connectivity (rsFC) with the subgenual anterior cingulate cortex (sgACC). However, it has not yet been confirmed that rsFC-guided TMS coil placement leads to TMS modulation of the sgACC. For each participant (N=115, 34 depressed patients), a peak rsFC cortical hotspot for the sgACC and control targets were prospectively identified. Single pulses of TMS interleaved with fMRI readouts were then administered to these targets and established significant downstream fMRI BOLD responses in the sgACC. We then marked an association between TMS-evoked BOLD responses in the sgACC and rsFC between the stimulation site and sgACC. This effect was qualified by a difference between healthy and patient participants: only in depressed patients, positively connected sites of stimulation led to the strongest evoked responses in the sgACC. Our results highlight rsFC-based targeting as a viable strategy to causally modulate sgACC subcortical targets and further suggest that cortical sites with high positive rsFC to the sgACC might represent an alternative target for the treatment of depression.

neuroscience↗

bioRxiv2022

A dueling-competent signal-sensing module guides precise delivery of cargo proteins into target cells by engineered Pseudomonas aeruginosa

To recognize and manipulate a specific microbe of a crowded community is a highly challenging task in synthetic biology. Here, we introduce a highly-selective protein delivery platform, termed DUEC, which responds to direct contact of attacking cells by engineering the tit-for-tat/dueling response of H1-T6SS (type VI secretion system) in Pseudomonas aeruginosa. Using a Cre-recombinase-dependent reporter, we screened H1-T6SS secreted substrates and developed Tse6N as the most effective secretion tag for Cre delivery. DUEC cells can discriminately deliver the Tse6N-Cre cargo into the cytosol of T6SS+ but not T6SS- Vibrio cholerae cells in a mixed population. These data demonstrate that the DUEC cell is not only a prototypical physical-contact sensor and delivery platform but also may be coupled with recombination-based circuits with the potential for complex tasks in mixed microbial communities.

microbiology↗

bioRxiv2022

Analysis of the mechanism of castor tolerance to Cd metal based on proteomics and metabolomics

The pollution of soil with heavy metals is an increasingly serious worldwide problem, and cadmium (Cd) has attracted attention because of its high toxicity to almost all plants. Since castor tolerates the accumulation of heavy metals, it has the potential for heavy metal soil remediation. We studied the mechanism of the tolerance of castor to Cd stress treatments at three doses: 300 mg/L, 700 mg/L, and 1,000 mg/L. Our research provides new ideas for revealing the defense and detoxification mechanisms of Cd-stressed castor. By combining the results of physiology, differential proteomics and comparative metabolomics, we conducted a comprehensive analysis of the networks that regulate the response of castor to Cd stress. The physiological results mainly emphasize the super-sensitive responses of castor plant roots to Cd stress and the effects of Cd stress on plants antioxidant system, ATP synthesis and ion homeostasis. We confirmed these results at the protein and metabolite levels. At the same time, proteomics and metabolomics show that castor plants mainly block the root systems absorption of Cd2+ by enhancing the strength of the cell wall, and inducing programmed cell death in response to the three different doses of Cd stress. In addition, the plasma membrane ATPase encoding gene (RcHA4), which was significantly upregulated in our differential proteomics and RT-qPCR studies, was transgenically overexpressed in wild type Arabidopsis thaliana for functional verification. The results indicated that this gene plays an important role in improving plant Cd tolerance.

molecular biology↗

bioRxiv2022

A point mutation in Chl biosynthesis gene Mg-chelatase I subunit influences on leaf color and metabolism in strawberry

Magnesium chelatase catalysis the insertion of magnesium into protoporphyrin IX is a vital step in chlorophyll biogenesis. It consists of three subunits, CHLI, CHLD and CHLH. The CHLI subunit is an ATPase and hydrolysis ATP in the catalysis. However, its key point on influencing flavonoid biosynthesis and chlorophyll accumulation under different light density was still unknown. In this study, we identified an N-Ethyl-N-nitrosourea (ENU) mutant, p240 from strawberry Fragaria pentaphylla that has yellow-green leaves and lower chlorophyll level. We verified the mutation occurs in the 186th amino acid of CHLI subunit, which is conserved in most photosynthetic organism. Mutants generated from RNAi and CRISPR/Cas9 gene editing confirmed this phenotype. In addition, we found that FpCHLI was localized in chloroplast and its subcellular location have not been changed by mutation. Further study showed that the interaction between FpCHLI and FpCHLD were not affected by mutagenesis. In contrast, all types of mutants showed reduced ATPase and magnesium chelatase activity indicating mutagenesis decreased enzymatic activities. Furthermore, mutagenesis suppressed the biosynthesis of Mg-proto IX. Metabolites analysis of gene knock-out mutant and WT revealed that CHLI may help to keep stabilizing the flavonoid level in leaves. Furthermore, both p240 and chli mutants are light sensitive, which has yellow leaves under high light but pale green leaves under poor light. The photosynthesis ability of mutants was also increased under shade. Moreover, stomatal apertures of mutants were wider than WT. Taken together, these results suggest that CHLI plays an important role in both leaf coloration and metabolism.

plant biology↗

bioRxiv2022

A common mechanism of temperature-sensing in thermoTRP channels

Detecting temperature is crucial for the survival of living organisms. Though the thermo transient receptor potential (thermoTRP) channels, such as TRPV1 or TRPM8, have been identified as prototypic heat or cold sensors, respectively, how they detect temperature remains elusive. Here we first identified groups of clustered residues in these channels that undergo burial/exposure conformational rearrangements during temperature activation by analyzing available protein structures or hydroxyl radical footprinting-mass spectroscopy (HRF-MS). By systematically perturbing water-protein interactions at these residues, we found that the temperature sensitivity in these channels were modulated in accordance with the sidechain hydrophobicity. The changes in energy associated with changes in water-protein interactions were sufficient for thermo activation. Therefore, our study has established that the water-protein interactions as a common mechanism underlying temperature sensing in TRPM8 and TRPV1.

biophysics↗

bioRxiv2022

KDM4A promotes NEPC progression through regulation of MYC expression

Neuroendocrine prostate cancer (NEPC) represents one of the most lethal forms of prostate cancer (PCa) and lacks life-prolonging treatment. The incidence of NEPC is increased due to the widespread use of AR pathway inhibitors (ARPIs) in the treatment of non-metastatic CRPC and hormone-sensitive metastatic tumors. Here, we identified histone lysine demethylase KDM4A as a key player in NEPC progression and an effective therapeutic target. We found that KDM4A mRNA and protein are overexpressed in human and mouse NEPC compared to prostate adenocarcinoma. Knockdown (KD) or knockout (KO) of KDM4A in NEPC cell lines suppressed cancer cell growth in vitro and in vivo. Mechanistically, we found that KDM4A promotes NEPC progression, in part, through direct transcriptional regulation of MYC. We showed that MYC is hyper-activated in human and mouse NEPC. KDM4A KD led to suppression of MYC signaling. MYC KD or inhibition profoundly suppressed NEPC cell proliferation. Furthermore, a potent pan-KDM4 inhibitor QC6352 significantly reduced NEPC cell growth in vitro and in vivo. Taken together, we demonstrated that KDM4A is an important regulator of NEPC progression and targeting KDM4A may potentially be an effective therapeutic strategy for NEPC. SignificanceNeuroendocrine prostate cancer (NEPC) is a highly aggressive prostate cancer subtype that is resistant to potent androgen receptor pathway inhibitors (ARPIs) and currently lacks effective therapeutic options. Histone lysine demethylase KDM4A is an important epigenetic regulator of gene expression in development and cancer. In this study, we show that KDM4A is highly expressed in NEPC and is required for NEPC proliferation, anchorage-independent growth, and in vivo growth, which is in part mediated through the regulation of MYC expression. Importantly, we demonstrate that inhibition of KDM4A significantly impairs NEPC growth in preclinical models. Thus, our findings provide valuable insights into the molecular mechanisms underlying NEPC progression and offer a rationale for clinical trials with KDM4 inhibitor in NEPC patients.

cancer biology↗

bioRxiv2022

Extensive diversity of RNA viruses in ticks revealed by metagenomics in northeastern China

Recently, several emerging tick-borne viruses have been identified to be associated with human diseases in northeastern China. Here, we used metagenomics to investigate the virome diversity in Haemaphysalis japonica, H. conicinna, Dermacentor silvarum, and Ixodes persulcatus ticks in northeastern China. A total of 22 RNA viruses were identified and belonged to more eight viral families, including four each in Nairoviridae and Phenuiviridae, three each in Flaviviridae, Rhabdoviridae, and Solemoviridae, two in Chuviridae, and one each in Partitiviridae, Tombusviridae, and unclassified. Of them, eight viruses were novel species, belonging to Nairoviridae (Jian nairovirus and Yichun nairovirus), Phenuiviridae (Mudanjiang phlebovirus), Rhabdoviridae (Tahe rhabdovirus 1-3), Chuviridae (Yichun mivirus), and Tombusviridae (Yichun tombus-like virus), and five members were established human pathogens, including Alongshan virus, tick-borne encephalitis virus, Songling virus, Beiji nairovirus, and Nuomin virus. I. persulcatus ticks had significant higher viral species than those in H. japonica, H. concinna, and D. silvarum ticks. Significant differences in tick viromes were observed among Daxingan, Xiaoxingan and Changbai mountains. These findings showed an extensive diversity of RNA viruses in ticks in northeastern China, revealed potential public health threats from the emerging tick-borne viruses. Further studies are needed to explain the natural circulation and pathogenicity of these viruses.

microbiology↗

bioRxiv2022

Ultra-high-throughput microbial single-cell whole genome sequencing for genome-resolved metagenomics

Microbes exist widely in nature. However, less than 1% of the species of microorganisms have been discovered so far, and more than 99% of microorganisms still remain unknown, which is called microbial dark matter. Unravelling microbial dark matter is not only helpful for exploring the unknown microbial world, but also of great significance for human health research. Ever since a long time ago, due to technical limitations, the microbiome, to a great extent, is still a black box. The traditional population-based metagenomic analysis tools are without single microbial resolution and they are stretched when studying rare and unknown microbial species. Here, we use high-throughput microdroplet technology to achieve the whole genome amplification of microbial single-cell genomes in pico-litter sized microdroplets, and develop subsequent library preparation steps such as indexing of the genome, to achieve the development of ultra-high-throughput microbial single-cell whole genome sequencing for genome-resolved metagenomics, aiming to provide a powerful new weapon for exploring microbial dark matter and other microbiological studies.

microbiology↗

bioRxiv2022

Structural insights into the viral proteins binding by TRIM7 reveal a general C-terminal glutamine recognition mechanism

The E3 ligase TRIM7 has emerged as a critical player in viral infection and pathogenesis. A recent study found that TRIM7 inhibits human enteroviruses through ubiquitination and proteasomal degradation of viral 2BC protein by targeting the 2C moiety of 2BC protein. Here, we report the crystal structures of TRIM7 in complex with 2C, where the C-terminal region of 2C is inserted into a positively charged groove of the TRIM7 PRY-SPRY domain. Structure-guided biochemical studies revealed the C-terminus glutamine residue of 2C as the primary determinant for TRIM7 binding. Such a glutamine-end motif binding mechanism can be successfully extended to other substrates of TRIM7. More importantly, leveraged by this finding, we were able to identify norovirus and SARS-CoV-2 proteins, and physiological proteins, as new TRIM7 substrates. We further show that TRIM7 may function as a restriction factor to promote the degradation of the viral proteins of norovirus and SARS-CoV-2, thereby restoring the Type I interferon immune response and inhibiting viral infection. Several crystal structures of TRIM7 in complex with SARS-CoV-2 proteins are also determined, and a conserved C-terminus glutamine-specific interaction is observed. These findings unveil a common recognition mode by TRIM7, providing the foundation for further mechanistic characterization of antiviral and cellular functions of TRIM7.

biochemistry↗

bioRxiv2022

HCLC-FC: a novel statistical method for phenome-wide association studies

The emergence of genetic data coupled to longitudinal electronic medical records (EMRs) offers the possibility of phenome-wide association studies (PheWAS). In PheWAS, the whole phenome can be divided into numerous phenotypic categories according to the genetic architecture across phenotypes. Currently, statistical analyses for PheWAS are mainly univariate analyses, which test the association between one genetic variant and one phenotype at a time. In this article, we derived a novel and powerful multivariate method for PheWAS. The proposed method involves three steps. In the first step, we apply the bottom-up hierarchical clustering method to partition a large number of phenotypes into disjoint clusters within each phenotypic category. In the second step, the clustering linear combination method is used to combine test statistics within each category based on the phenotypic clusters and obtain p-values from each phenotypic category. In the third step, we propose a new false discovery rate (FDR) control approach. We perform extensive simulation studies to compare the performance of our method with that of other existing methods. The results show that our proposed method controls FDR very well and outperforms other methods we compared with. We also apply the proposed approach to a set of EMR-based phenotypes across more than 300,000 samples from UK Biobank. We find that the proposed approach not only can well-control FDR at a nominal level but also successfully identify 1,244 significant SNPs that are reported to be associated with some phenotypes in the GWAS catalog. Our open-access tools and instructions on how to implement HCLC-FC are available at https://github.com/XiaoyuLiang/HCLCFC. Author summaryAs a complementary approach to genome-wide association studies, phenome-wide association studies (PheWAS) have been an efficient tool for testing associations between genetic variations and a wide range of phenotypes utilizing all available phenotypic information. For instance, the first PheWAS has demonstrated that rs3135388 on HLA-DRB1 associated with atrial fibrillation and multiple sclerosis. A challenging step in performing large-scale multiple testing of PheWAS is to control the false discovery rate (FDR). In this work, we propose a novel and powerful multivariate method, HCLC-FC, to test the association between a genetic variant with a large number of phenotypes simultaneously controlling FDR. Within each phenotypic category, a newly proposed method clusters phenotypes into different groups and the combined test statistic within each category based on the phenotypic clusters has an asymptotic distribution which avoids the computational burden of simulation. Furthermore, the newly developed FDR controlling process is based on p-values and does not depend on test statistics. Therefore, it is more general and can be applied to other multiple testing procedures to control FDR.

bioinformatics↗

bioRxiv2022

Gene selection by incorporating genetic networks into case-control association studies

Large-scale genome-wide association studies (GWAS) have been successfully applied to a wide range of genetic variants underlying complex diseases. The network-based penalized regression approach has been developed to overcome the challenges caused by the computational efficiency for analyzing high-dimensional genomic data by incorporating a biological genetic network. In this paper, we propose a gene selection approach by incorporating genetic networks into case-control association studies for DNA sequence data or DNA methylation data. Instead of using traditional dimension reduction techniques such as principal component analyses and supervised principal component analyses, we use a linear combination of genotypes at SNPs or methylation values at CpG sites in each gene to capture gene-level signals. We develop three approaches for the linear combination: optimally weighted sum (OWS), LD-adjusted polygenic risk score (LD-PRS), and beta-based weighted sum (BWS). OWS and LD-PRS are supervised approaches that depend on the effect of each SNP or CpG site on the case-control status, while BWS can be extracted without using the case-control status. After using one of the linear combinations of genotypes or methylation values in each gene to capture gene-level signals, we regularize them to perform gene selection based on the biological network. Simulation studies show that the proposed approaches have higher true positive rates than using traditional dimension reduction techniques. We also apply our approaches to DNA methylation data and UK Biobank DNA sequence data for analyzing rheumatoid arthritis. The results show that the proposed methods can select potentially rheumatoid arthritis related genes that are missed by existing methods. Author SummaryThere is strong evidence showing that when genes are functionally related to each other in a genetic network, statistical methods utilizing prior biological network knowledge can outperform other methods that ignore genetic network structures. Therefore, statistical methods that can incorporate genetic network information into association analysis in human genetic association studies have been widely used since 2008. Here, we take advantage of recently developed methods to capture the gene-level signals in network-based penalized regression of high-dimensional genetic data. We have shown that the selection performance of our proposed methods can outperform three traditional principal component-based dimension reduction techniques in several simulation scenarios in terms of true positive rates. Meanwhile, by applying our methods in both DNA methylation data and DNA sequence data, the genes identified by our proposed methods can be significantly enriched into the rheumatoid arthritis pathway, such as genes HLA-DMA, HLA-DPB1, and HLA-DQA2 in the HLA region.

bioinformatics↗

bioRxiv2022

E. coli can eat DNA as excellent nitrogen source to grow quickly

Is DNA or RNA a good nutrient? Although scientists have raised this question for dozens of years, few textbooks mention the nutritional role of nucleic acids. Paradoxically, mononucleotides are widely added to infant formula milk and animal feed for improving Intestinal health. Here, found that E. coli can grow well in the medium with DNA as carbon and nitrogen sources. More interestingly, in the presence of glucose and DNA, bacteria grew more rapidly, showing that bacteria can use DNA as an excellent nitrogen source. Surprisingly, the amount of DNA in culture media decreased but its length remained unchanged, demonstrating that E. coli ingested long DNA directly. The gene expression study shows that E. coli mainly ingests DNA before digestion and digests it in the periplasm. Bifidobacterium bifidum can also use DNA as the nitrogen source for growth but not efficiently as E. coli. This study is of great significance to study DNA metabolism and utilization in organisms. It also lays a foundation to understand the nutritional function of DNA for intestinal flora and human health.

microbiology↗

bioRxiv2022

Highly Connected and Highly Variable: A Core Brain Network during Resting State Supports Propofol-induced Unconsciousness

Leading theories of consciousness make diverging predictions for where and how neural activity gives rise to subjective experience. The Global Neuronal Workspace theory (GNW) states that consciousness is instantiated through global broadcasting of information across the prefrontal-parietal regions, whereas the integrated information theory (IIT) postulates that consciousness requires the posterior cortex to produce maximally irreducible integrated information. As both theories seem to partially agree on that the neural correlates of consciousness (NCC) require globally integrated brain activity across a network of functionally specialized modules, it is not known yet whether brain regions with such functional configurations would align with the NCC distribution predicted by the GNW or the IIT. We scanned resting-state fMRI data from 21 subjects during wakefulness, propofol-induced sedation and anesthesia. Graph-theoretical analysis were conducted on awake fMRI data to search for the NCC candidates as brain regions that exhibit both high rich-clubness and high modular variability. Another independent dataset of 10 highly-sampled subjects were used to validate the NCC distribution at individual-level. Brain module-based dynamic analysis was conducted to estimate temporal stability of the NCC candidates. Alterations in functional connectivity and modular variability from awake to propofol-induced anesthesia were assessed to test the involvement of the NCC candidates in conscious processing. NCC candidates that are characterized by both high functional interconnectivity and high modular variability were identified to locate in prefrontal and temporoparietal cortices, which covered brain structures predicted by the GNW as well as the IIT. The identified NCC was found to mainly attributed to higher-order cognitive functions, and associated with genes enriched in synaptic transmission. Dynamic analysis revealed two discrete reoccurring brain states, which were characterized by their difference in temporal stability -- the state dominated by the NCC candidates appearred to be temporally more stable than the other state predominately composed of primary sensory/motor regions, suggesting that the identified NCC members could sustain conscious contents as metastable network representations. Finally, we showed that the prefrontal GNW regions and posterior IIT regions within the identified NCC was differentially modulated in terms of functional connectedness and modular variability in response to loss of consciousness induced by propofol anesthesia. This work offers a framework to search for neural correlates of consciousness by charting the brain network topology, and provides new insights in understanding the distinct roles of the frontoparietal and posterior network in underpinning human consciousness. HighlightsStudies suggest that there are neural correlates of consciousness (NCC) we experience subjectively everyday. By overlapping regions with both high functional interconnectivity (rich-clubness) and high modular variability, we identified the putative NCC distributed in prefrontal and temporoparietal cortices, attributed to higher-order cognitive functions, and associated with genes enriched in synaptic transmission. We further revealed that the NCC members appeared to sustain conscious contents as metastable network representations in a reoccurring NCC dominant state. The identified NCC architecture was significantly modulated in terms of functional connectedness and modular varibility during propofol anesthesia, demonstrating its critical role in supporting consciousness. These findings testify to the NCCs abilities in information integration and differentiation, and provide novel insights in reconciling the ongoing discussion of the contribution of anterior versus posterior regions in supporting human consciousness.

neuroscience↗