Biology subjects

Gong, Q.

Publications and source records attributed to Gong, Q..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Sensitive Transcriptomics and Genotyping reveals function of genetic variants in immunity

Advancements in genomics have revolutionized human genetics by defining the genetic architecture of disease. However, identifying causal variants and their mechanisms of action remains a challenge in translating genetics into therapeutic interventions. Here, we developed Sensitive Transcriptomics And Genotyping by sequencing (STAG-seq), a high-throughput platform designed to define mechanistic genotype-phenotype relationships through simultaneous single-cell measurements of genomic DNA and RNA transcripts. Combined with base-editing, STAG-seq enables functionalization of variants in relevant cellular contexts. We demonstrate the applicability of this approach in several settings. First, we screened genetic perturbations to identify monoallelic and biallelic variant effects in primary human macrophages treated with innate immune stimuli. Next, we phenotyped clinically relevant missense variants associated with immunodeficiency and autoimmunity. Finally, we defined a noncoding variant in a pleiotropic autoimmunity locus that governs TNRC18 expression in primary T cells. STAG-seq thus enables variant phenotyping at scale to advance functional genomics and disease biology.

genomics↗

bioRxiv2025

A synthetic chlorophagy receptor promotes plant fitness by mediating chloroplast microautophagy

Chloroplasts are major photosynthetic and protein-containing organelles in green plants and algae. Unwanted chloroplast proteins and entire chloroplasts are cleared through various degradation pathways including autophagy. Nevertheless, canonical chlorophagy receptors remain unidentified, and whether and to what extent chlorophagy can be enhanced to benefect the plants remain unknown. Here we designed and validated a synthetic chloroplast autophagy receptor using biochemical, genetical, and imaging approaches. This synthetic receptor, LIR-SNT-BFP, was constructed by fusing a fragment containing the LC3-interacting region (LIR) of the selective autophagy receptor NBR1 and the N-terminal amphipathic -helix of the chloroplast outer envelope protein SFR2. The fusion protein LIR-SNT-BFP coated the chloroplast and attracted ATG8a in planta. Upon induction, the synthetic receptor elicited vacuole-mediated microautophagy of entire chloroplasts independent of the ATG8 conjugation machinery proteins ATG5 or ATG7. Meanwhile, it induced chloroplast division; however the induced chlorophagy was independent of PDV2. Notably, moderate chlorophagy improves rosette growth, but excessive levels are detrimental. Furthermore, induced chlorophagy partially protects against herbicide-induced leaf chlorosis. This study demonstrates controlled chloroplast degradation using a synthetic chlorophagy receptor.

plant biology↗

bioRxiv2025

CDP-DAG synthases regulate plant growth and broad-spectrum disease resistance

Phosphatidic acid (PA) functions as a cell membrane component and signaling molecule in plants. PA metabolism has multiple routes, in one of which PA is converted into cytidine diphosphate diacylglycerol (CDP-DAG) by CDP-DAG synthases (CDSs). CDS genes are highly conserved in plants. Here, we found that knock-down of the CDS gene enhanced the resistance of Arabidopsis thaliana to multiple pathogens, with a growth penalty. When Arabidopsis leaves were treated with chitin or flg22, reactive oxygen species (ROS) production in cds mutants was significantly higher than that in the wild-type (WT). Similarly, phosphorylation of mitogen-activated protein kinases (MAPKs) in the cds1cds2 double mutant was significantly increased compared to the WT. By integrating lipidomics, transcriptomics, and metabolomics data, PA accumulation was observed in mutants cds1cds2, activating the jasmonic acid (JA) and salicylic acid (SA) signaling pathway, and increasing transcript levels of plant defense-related genes. Significant accumulation of the downstream metabolites including serotonin and 5-methoxyindole was also found, which plays important roles in plant immunity. In conclusion, our study indicated the role of CDSs in broad-spectrum disease resistance in Arabidopsis and that CDSs are involved in plant metabolic regulation.

plant biology↗

bioRxiv2024

Natural monoclonal autoantibodies against HERV-K102 Envelope-TM from SLE patients selectively eliminate autoreactive immune cells and cancer cells

In sharp contrast to immune dysfunction in cancer, autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit excessive immune reactions characterized by high titers of autoantibodies to HERV-K102-envelope (HERV-K102-Env) neoantigens, which are frequently found in cancer patients but seldom elicit a strong immune response. Here we aim to address whether anti-HERV-K102-Env autoantibodies in SLE can effectively eliminate autoreactive immune cells and cancer cells expressing HERV-K102-Env neoantigens. We established world-first fully human autoantibody phage display library with 3.67x108 cfu using peripheral blood mononuclear cells (PBMCs) from SLE patients. Through high-throughput screening, we identified nineteen monoclonal autoantibodies (mAbs) targeting the conserved HERV-K102 Env-TM subunit. The EC50 values of these autoantibodies binding to the HERV-K102 Env-TM subunit ranged from 0.002436 g/ml to 1.798 g/ml. Remarkably, eleven of these mAbs not only recognized the HERV-K102 Env-TM glycoprotein on the cell surface but also effectively eliminated autoreactive B, T, and natural killer (NK) cells in SLE, as well as cancer cells. Our findings provide a conceptually new immunotherapy target HERV-K102 Env-TM subunit and open the era of using natural human autoantibodies to treat autoimmune disease and cancers. Several of these monoclonal autoantibodies show promise as potential diagnostic and therapeutic agents, paving the way for innovative approaches to treating SLE and various malignancies.

immunology↗

bioRxiv2024

N1-methylpseudouridine mRNA modification enhances efficiency and specificity of gene overexpression by preventing Prkra-mediated global translation repression

In vitro transcribed messenger RNA (IVT mRNA) has emerged as a pivotal tool in mRNA-based therapies and has been extensively employed in gene function studies and genetic tool applications. However, the IVT process generates double-stranded RNA (dsRNA) by-products that are recognized by dsRNA sensors, triggering innate immune responses. In this study, we comprehensively analyzed the detrimental effects of dsRNA by-products on early zebrafish embryos, revealing that these by-products induce cell necrosis and delay maternal-zygotic transition by reducing global translation efficiency via Prkra, a recently identified dsRNA sensor in pluripotent cells. Importantly, we demonstrate that N1-methylpseudouridine (m1{varphi}) modification of IVT mRNAs effectively mitigates these adverse effects, as m1{varphi}-modified dsRNAs exhibit significantly lower binding affinity to the Prkra dimer. Our findings underscore a previously overlooked challenge in the use of IVT mRNA in early embryos and offer a robust solution to enhance the fidelity of mRNA applications. Furthermore, we elucidate that m1{varphi} modification minimizes the dsRNA-induced stress response in pluripotent cells through a distinct mechanism.

developmental biology↗

bioRxiv2024

Systemic inflammation and lymphocyte activation precede rheumatoid arthritis

Some autoimmune diseases, including rheumatoid arthritis (RA), are preceded by a critical subclinical phase of disease activity. Proactive clinical management is hampered by a lack of biological understanding of this subclinical at-risk state and the changes underlying disease development. In a cross-sectional and longitudinal multi-omics study of peripheral immunity in the autoantibody-positive at-risk for RA period, we identified systemic inflammation, proinflammatory-skewed B cells, expanded Tfh17-like cells, epigenetic bias in naive T cells, TNF+IL1B+ monocytes resembling a synovial macrophage population, and CD4 T cell transcriptional features resembling those suppressed by abatacept (CTLA4-Ig) in RA patients. Our findings characterize pathogenesis prior to clinical diagnosis and suggest the at-risk state exhibits substantial immune alterations that could potentially be targeted for early intervention to delay or prevent autoimmunity. We provide a suite of tools at https://apps.allenimmunology.org/aifi/insights/ra-progression/ to facilitate exploration and enhance accessibility of this extensive dataset. One Sentence SummaryACPA+ at-risk individuals show RA-like inflammation and multi-compartment immune dysregulation during transition to clinically active RA

immunology↗

bioRxiv2024

Craters on the melanoma surface facilitate tumor-immune interactions and demonstrate pathologic response to checkpoint blockade in humans

Immunotherapy leads to cancer eradication despite the tumors immunosuppressive environment. Here, we used extended long-term in-vivo imaging and high-resolution spatial transcriptomics of endogenous melanoma in zebrafish, and multiplex imaging of human melanoma, to identify domains that facilitate immune response during immunotherapy. We identified crater-shaped pockets at the margins of zebrafish and human melanoma, rich with beta-2 microglobulin (B2M) and antigen recognition molecules. The craters harbor the highest density of CD8+ T cells in the tumor. In zebrafish, CD8+ T cells formed prolonged interactions with melanoma cells within craters, characteristic of antigen recognition. Following immunostimulatory treatment, the craters enlarged and became the major site of activated CD8+ T cell accumulation and tumor killing that was B2M dependent. In humans, craters predicted immune response to ICB therapy, showing response better than high T cell infiltration. This marks craters as potential new diagnostic tool for immunotherapy success and targets to enhance ICB response.

cancer biology↗

bioRxiv2024

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.

immunology↗

bioRxiv2024

Recycling of trans-Golgi SNAREs is essential for apoplastic effector secretion and effective pathogenicity of Magnaporthe oryzae

Vesicle transport is an essential process that mediates the growth, development and virulence of pathogenic fungi. However, the intricate mechanisms underlying how vesicle transport regulates the secretion of effector proteins remain to be fully elucidated. Here, we unveiled a novel pathway in which retromer and trans-Golgi (TGN) SNARE proteins co-regulate the proper secretion of apoplastic effectors in the rice blast fungus Magnaporthe oryzae. A TGN-associated SNARE complex consisting of MoSnc1, MoTlg1, MoTlg2, and MoVti1 was found to be essential for growth, development and pathogenicity in the fungus. Moreover, the TGN-associated SNARE complex is indispensable for accurate secretion of apoplastic effectors. Furthermore, we have elucidated that the dynamin-like protein MoVps1, an upstream regulator of the retromer complex, regulates the fission of MoVps35-coated vesicle and the proper localization of the TGN-associated SNARE complex. Additionally, we employed prochlorperazine, which identified as a potent dynamin inhibitor, elicits a developmental response in M. oryzae akin to MoVPS1 disruption, highlighting the pivotal regulatory role of dynamin and its potential as a therapeutic target for rice blast disease management. In conclusion, the study uncovered a specific mechanism by which MoVps1 and the retromer complex regulate the positioning of TGN-associated SNARE proteins to effectively promote effector secretion. It provides a deeper understanding of the molecular mechanisms of effector secretion in fungi and underscores the importance of vesicle transport in fungal pathogenesis. ImportanceVesicle transport is essential for pathogenic fungi as it controls the secretion of effectors that modulate interactions with the host and infection processes. The detailed mechanisms of effector secretion via vesicular pathways in these fungi are not yet fully understood. In this study, we have discovered a new regulatory pathway involving the retromer complex and trans-Golgi SNARE proteins that is critical for the proper secretion of apoplast effectors in M. oryzae. We have identified an important TGN-associated SNARE complex, consisting of MoSnc1, MoTlg1, MoTlg2 and MoVti1, which is required for the development and pathogenicity of M. oryzae. Our results emphasize the importance of this SNARE complex for the precise secretion of effectors into the apoplast, a key step in pathogenesis. Additionally, we demonstrated that the dynamin-like protein MoVps1, a protein acting upstream of the retromer complex, is vital for the correct localization of the TGN-associated SNARE complex. Furthermore, our research underscores the critical regulatory role of dynamin in M. oryzae pathogenesis, with prochlorperazine serving as an inhibitor that mimics the phenotypic effects of MoVps1 disruption, thereby highlighting its potential as a biopesticide candidate for rice blast disease management. Our study has uncovered a specific regulatory mechanism in which MoVps1 and the retromer complex control the positioning and function of TGN-associated SNARE proteins, thereby facilitating effector secretion. This work not only advances our understanding of the molecular basis of effector secretion in fungi, but also has implications for the development of novel strategies to control fungal diseases.

microbiology↗

bioRxiv2024

Prkra is the double-stranded RNA sensor to mediate an embryonic integrated stress response

Double-stranded RNAs (dsRNAs), known as conserved pathogen-associated molecular patterns, are recognized by interferon-induced protein kinase R (PKR) to trigger an integrated stress response, characterized by the inhibition of global translation. However, the interferon system is inactive in pluripotent cells, thus the mechanism underlying dsRNA sensing and translational control is unclear. In this study, we utilized early zebrafish embryos as a model of pluripotent cells and discovered a PKR-independent blockage of translation initiation induced by dsRNA stimulation. Prkra dimer was identified as the genuine dsRNA sensor. Upon binding to dsRNAs, the dimerized dsRNA binding domain 3 becomes activated to sequester the eIF2 complexes from the translation machinery, leading to a hindrance in global protein synthesis. This distinctive embryonic stress response restricts RNA virus SVCV replication in zebrafish embryos but is also conserved in early mouse embryos and embryonic stem cells. Therefore, the Prkra-mediated dsRNA sensing and translation blocking mechanism potentially represents a common strategy for reestablishing physiological homeostasis in response to environmental stresses.

immunology↗

bioRxiv2024

Mutation of phosphatidate phosphohydrolase genes confers broad-spectrum disease resistance in plants

Phosphatidic acid (PA) is considered as a second messenger that interacts with protein kinases, phosphatases and NADPH oxidases, amplifying the signal to initiate plant defense signaling responses (Li and Wang, 2019). In rice, mutation of RBL1 causes the accumulation of PA, enhancing multipathogen resistance (Sha et al., 2023). In our previous study, we attempted to rescue rbl1 mutant by overexpressing phosphatidate phosphohydrolase (PAH) genes. However, overexpression of PAH2 reduced the PA level but did not affect the disease resistance, which made us to reconsider the importance of PA and PAH in rice immunity. Here, we identified that mutation of PAHs caused PA accumulation and enhanced multipathogen resistance in rice and Arabidopsis.

plant biology↗

bioRxiv2024

Excessive Dietary Fructose Aggravates Heart Failure via Impairing Myocardial Fatty Acid Oxidation Metabolism in Diet Induced Obese Mouse

BackgroundAn unhealthy diet and a sedentary lifestyle increase the prevalence of cardiometabolic syndrome. Several cardiovascular diseases (CVDs) have been highly linked to excessive added sugar intake, which alters whole-body metabolism, including heart tissue. However, whether specific added sugars can cause and aggravate severe heart dysfunction is still unknown. MethodsWe examined the association between CVDs and added sugar intake using statistical analyses and Mendelian randomization (MR). Then, we evaluated the effect of added sugar on mouse heart function employing a diet-induced obese (DIO) model with transverse aortic constriction (TAC) challenge. We measured the fatty acid and fructose metabolic flux in mouse hearts employing a mass spectrometry-based in vivo double stable isotopic labeling (DSIL) technique. The results of animal models were also confirmed in aortic stenosis (AS) patient samples. ResultsStatistical analyses and MR estimation on public databases indicated that added sugars, especially fructose, are associated with a high risk of heart failure. Feeding on either ingested or drunk fructose could aggravate heart failure and diastolic and systolic dysfunction in TAC challenged DIO mice. Mechanistically, excessive dietary intake of fructose could suppress heart fatty acid oxidation (FAO) metabolism via both shrinkage of the flux rate of FAO and inhibition of the AMPK-ACC axis. Activation of AMPK or deactivation of ACC could limit such heart dysfunction and myocardial hypertrophy. We also obtained plasma from 27 patients with AS and determined that the high fructose level instead of glucose or sucrose was linked to left ventricular ejection fractions (LVEF) and fractional shortening (FS) decline. ConclusionsFindings from epidemiological statistical analyses and investigations of animal models suggested the harmful effect of excessive fructose intake on heart function. Fructose could directly alter heart metabolism by suppressing FAO. Our results implied that targeting AMPK-ACC mediation could effectively attenuate excessive fructose-induced heart failure in DIO mice.

physiology↗

bioRxiv2024

Multivalent Targeting of Blood-Brain Barrier LRP1 for Neurovascular Recovery Therapy for Alzheimer s Disease

The blood-brain barrier (BBB) is a highly selective permeability barrier that safeguards the central nervous system (CNS) from potentially harmful substances while regulating the transport of essential molecules. Its dysfunction is increasingly recognized as a pivotal factor in the pathogenesis of Alzheimers disease (AD), contributing to the accumulation of amyloid-{beta} (A{beta}) plaques. We propose an AD therapeutic strategy targeting the BBB low-density lipoprotein receptor-related protein 1 (LRP1). We show that a multivalent scaffold with LRP1-specific peptide modulates the A{beta} transport at the BBB. We show via detailed experimentation on AD model mice that this intervention markedly reduces A{beta} deposits and prevents cognitive decline. This study marks a new approach to drug design, combining multivalent targeting with the regulation of membrane trafficking through advanced molecular engineering. Crucially, the therapeutic effects emerge from the multivalent nature of our proposed system. Furthermore, our findings underscore the paramount significance of the BBB in AD pathogenesis, particularly emphasizing the critical role of LRP1-mediated A{beta} clearance in mitigating disease progression.

neuroscience↗

bioRxiv2024

Post-death Vesicles of Senescent Bone Marrow Mesenchymal Stromal Polyploids Promote Macrophage Aging and Breast Cancer

Potential systemic factors contributing to aging-associated breast cancer (BC) remain elusive. Here, we reveal that the polyploid giant cells (PGCs) that contain more than two sets of genomes prevailing in aging and cancerous tissues constitute 5-10% of healthy female bone marrow mesenchymal stromal cells (fBMSCs). The PGCs can repair DNA damage and stimulate neighboring cells for clonal expansion. However, dying PGCs in advanced-senescent fBMSCs can form "spikings" which are then separated into membraned mtDNA-containing vesicles (Senescent PGC-Spiking Bodies; SPSBs). SPSB-phagocytosed macrophages accelerate aging with diminished clearance on BC cells and protumor M2 polarization. SPSB-carried mitochondrial OXPHOS components are enriched in BC of elder patients and associated with poor prognosis. SPSB-incorporated breast epithelial cells develop aggressive characteristics and PGCs resembling the polyploid giant cancer cells (PGCCs) in clonogenic BC cells and cancer tissues. These findings highlight an aging BMSC-induced BC risk mediated by SPSB-induced macrophage dysfunction and epithelial cell precancerous transition. SIGNIFICANCEMechanisms underlying aging-associated cancer risk remain unelucidated. This work demonstrates that polyploid giant cells (PGCs) in bone marrow mesenchymal stromal cells (BMSCs) from healthy female bone marrow donors can boost neighboring cell proliferation for clonal expansion. However, the dying-senescent PGCs in the advanced-senescent fBMSCs can form "spikings" which are separated into mitochondrial DNA (mtDNA)-containing spiking bodies (senescent PGC-spiking bodies; SPSBs). The SPSBs promote macrophage aging and breast epithelial cell protumorigenic transition and form polyploid giant cancer cells. These results demonstrate a new form of ghost message from dying-senescent BMSCs, that may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/583755v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@f07b60org.highwire.dtl.DTLVardef@33ef98org.highwire.dtl.DTLVardef@1b720c8org.highwire.dtl.DTLVardef@1c9514d_HPS_FORMAT_FIGEXP M_FIG Xie et al demonstrate that the polyploid giant cells (PGCs) in the juvenile phase expansion of female bone marrow mesenchymal stromal cells (fBMSCs) can boost neighboring cell proliferation for clonal expansion. However, when fBMSCs enter to the advanced-senescent phase, the dying-senescent PGCs form "spikings" which are then separated into membraned vesicles termed Senescent PGC spiking bodies, SPSBs). The SPSBs carrying fragmented mitochondrial elements and OXPHOS proteins can be phagocytosed by macrophage and breast epithelial cells leading to macrophage aging and breast epithelial protumorigenic transition. The SPSBs are demonstrated to be a new form of post-cell death vesicle from aging BMSCs and may serve as a systemic factor contributing to aging-associated immunosuppression and breast cancer risk. C_FIG

cancer biology↗

bioRxiv2024

Targeting GFPT2 to reinvigorate immunotherapy in EGFR-mutated NSCLC

In the evolving field of cancer immunotherapy, EGFR-mutated NSCLC presents a significant challenge, demonstrating marked innate resistance to established treatments. An effective method to counter this resistance remains elusive. Through comprehensive genetic and pharmacological analyses across various models, we have identified glutamine fructose-6-phosphate transaminase 2 (GFPT2) as a key facilitator of immune evasion in EGFR-mutated NSCLC. Mechanistically, under EGFR mutation condition, GFPT2 expression, which is typically low in normal tissues, is highly induced via EGFR/IRE1/Xbp1s signaling axis, leading to a significant increase in intracellular UDP-GlcNAc and consequently, an altered N-glycosylation profile. GFPT2 escalates the expression and glycosylation of PD-L1, PVR and CD276, bolstering their interactions with CD8+T cells, and amplifies CD73 glycosylation, thereby intensifying adenosine-mediated CD8+T cells suppression. These actions collectively reduce tumor cell vulnerability to CD8+T cell-mediated death. Moreover, GFPT2 regulates EGFR glycosylation, which consequentially modulates the EGFR-dependent secretion of CXCL10 and VEGF, thus impeding CD8+T cell infiltration within tumors. We further identified a GFPT2 isoform-specific inhibitor that potentiates PD-1 blockade therapy beyond that of existing strategy, corroborated by results in xenografts and patient-derived organoids. Together, these findings illuminate the promising therapeutic potential of GFPT2 as a metabolic checkpoint, offering an innovative approach to invigorate immunotherapy in NSCLC with EGFR mutations.

cancer biology↗

bioRxiv2024

The discovery of antimicrobial peptides from the gut microbiome of cockroach Blattella germanica using deep learning pipeline

Antimicrobial peptides (AMPs) are candidates for use against antibiotic-resistant microorganisms. However, due to high cytotoxicity and poor performance in biological contexts, most AMPs are unable to satisfy the requirements. The gut microbiomes of pathogenic species like Blattella germanica represent unexploited reservoirs of naturally evolved biocompatible AMPs. Here we developed a lightweight AI pipeline called AMPidentifer with two nine-layers Dense-Net blocks and one embedded new self-attention module to enable the discovery of biocompatible AMPs from microbiome. The core structure of AMPidentifer is simple, not requiring complexing code basis. On the independent test dataset, it showed robust performance and avoided high false-positive results. From the gut microbiome of B. germanica, new AMP candidates with potential low toxicities and antimicrobial activities were identified by AMPidentifer. The selected two AMPs demonstrated good antimicrobial effects in vitro and in vivo. The Cys residue was demonstrated to perform different action mechanisms in the antimicrobial activity of two AMPs, providing insights for future rational design. New efficient AMPs with low cytotoxicity identified by the new high-throughput AI pipeline from the gut microbiome of B. germanica successfully showed an important interdisciplinary strategy for discovering bio-safe AMPs from nature. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/580024v1_ufig1.gif" ALT="Figure 1"> View larger version (37K): org.highwire.dtl.DTLVardef@143e033org.highwire.dtl.DTLVardef@134620dorg.highwire.dtl.DTLVardef@11809forg.highwire.dtl.DTLVardef@1134ef6_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOThe Graphic AbstractC_FLOATNO C_FIG

microbiology↗

bioRxiv2023

Functional connectome through the human life span

The lifespan growth of the functional connectome remains unknown. Here, we assemble task-free functional and structural magnetic resonance imaging data from 33,250 individuals aged 32 postmenstrual weeks to 80 years from 132 global sites. We report critical inflection points in the nonlinear growth curves of the global mean and variance of the connectome, peaking in the late fourth and late third decades of life, respectively. After constructing a fine-grained, lifespan-wide suite of system-level brain atlases, we show distinct maturation timelines for functional segregation within different systems. Lifespan growth of regional connectivity is organized along a primary-to-association cortical axis. These connectome-based normative models reveal substantial individual heterogeneities in functional brain networks in patients with autism spectrum disorder, major depressive disorder, and Alzheimers disease. These findings elucidate the lifespan evolution of the functional connectome and can serve as a normative reference for quantifying individual variation in development, aging, and neuropsychiatric disorders.

neuroscience↗

bioRxiv2023

Mapping Neurophysiological Subtypes of Major Depressive Disorder Using Normative Models of the Functional Connectome

Major depressive disorder (MDD) is the most burdensome psychiatric disorder characterized by remarkably heterogeneous clinical phenotypes. It remains challenging to delineate the heterogeneity of neurobiological abnormalities underlying the clinical variance and, on this basis, to identify neurophysiological subtypes of MDD patients. Here, using a large multisite resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls, we generated lifespan normative models of functional connectivity strengths, mapped the heterogeneity of patients individual deviations, and identified neurobiological MDD subtypes. MDD patients showed positive deviations mainly in the default mode and subcortical areas, and negative deviations widely distributed over the cortex. However, there was a great inter-subject heterogeneity as indicated by that no more than 3.14% of patients deviated from the normative range for any brain region. Two neurophysiological MDD subtypes were identified. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas, and negative deviations in the sensorimotor, dorsal and ventral attention areas, while subtype 2 showed a moderate but conversed deviation pattern. The severe-deviation subtype had older age, higher medicated proportion, and higher Suicide item score, while the moderate-deviation subtype showed higher Work and Activities and Depressed Mood item scores. Moreover, the baseline deviations in the severe-deviation subtype were predictive of 6-month antidepressant treatment effects in a subsample. To our knowledge, the current study is the largest multisite analysis of neurophysiological MDD subtyping to date and the findings shed light on our understanding of the biological mechanisms underlying the intersubject heterogeneity of clinical phenotypes, which are informative for the development of personalized treatments for this disorder.

neuroscience↗