Biology subjects

Dong, Q.

Publications and source records attributed to Dong, Q..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Stathmin 1 regulates mitophagy and cellular function in hematopoietic stem cells

Stathmin 1 is a cytoplasmic phosphoprotein that regulates microtubule dynamics via promotion of microtubule catastrophe and sequestration of free tubulin heterodimers. Stathmin 1 is highly expressed in hematopoietic stem cells (HSCs), and overexpressed in leukemic cells, however its role in HSCs is not known. Herein, we found that loss of Stathmin 1 is associated with altered microtubule architecture in HSCs, and markedly impaired HSC function. Transcriptomic studies suggested alterations in oxidative phosphorylation in Stmn1-/- HSCs, and further mechanistic studies revealed defective mitochondrial structure and function in the absence of Stathmin 1 with increased ROS production. Microtubules associate with mitochondria and lysosomes to facilitate autophagosome formation and mitophagy, and indeed we found that this critical mitochondrial quality control process is impaired in Stathmin 1-deficient HSCs. Finally, stimulation of autophagy improved the colony forming ability of Stmn1-/- hematopoietic stem and progenitor cells. Together, our data identify Stathmin 1 as a novel regulator of mitophagy and mitochondrial health in HSCs. Key PointsO_LIThe microtubule regulating protein Stathmin 1 is highly expressed in HSPCs and promotes normal microtubule architecture. C_LIO_LILoss of Stathmin 1 in HSPCs leads to impaired autophagy with abnormal mitochondrial morphology, decreased respiratory capacity, and impaired cellular function. C_LI

cell biology↗

bioRxiv2025

Food pairing independently associated with cardiometabolic traits beyond dietary patterns across western and eastern populations

Cardiometabolic health is closely linked to diet. Both specific food choices and dietary indices are commonly used to guide cardiometabolic protection strategies. However, the balance between foods may also significantly impact cardiometabolic health. Here, we explore the balance and imbalance in long-term dietary food intake to quantify food pairing patterns (FPs), providing insights beyond conventional dietary indices and single-food intake frequencies. Using data from our GGMP (n = 6,994) and the NHANES (n = 7,350) cohorts, we observed that long-term food pairing patterns are independent of single food intake frequency and dietary indices. We identified 1,759 and 306 cardiometabolic-related long-term food pairing patterns from two cohorts (FDR < 0.05), respectively. Notably, around 80% of these pairing foods not individually associated with cardiometabolic traits, and food pairing pattern associations with cardiometabolic traits at hyper food group level were consistent across Eastern and Western populations. Besides, mediation analysis revealed that 72.7% of long-term food pairing patterns affected cardiometabolic traits through 31 microbial genera, with Clostridiumsensustricto1 playing a predominant role. Moreover, multi-step mediation analysis found that microbes mediated the impact of long-term food pairing patterns on cardiometabolic traits primarily through their metabolic pathways, such as pyruvate fermentation to propanoate and ergothioneine biosynthesis pathways. Our data suggest that balance between dietary foods is broadly associated with cardiometabolic traits by modulating gut microbial functionalities, in contrast to the lower occurrence when considering individual foods in isolation. These results offer a novel perspective for designing personalized dietary strategies beyond present dietary indices to enhance cardiometabolic health.

microbiology↗

bioRxiv2024

The genetic diversity and populational specificity of the human gut virome at single nucleotide resolution

Large-scale characterization of gut viral genomes provides strain-resolved insights into host-microbe interactions. However, existing viral genomes are mainly derived from Western populations, limiting our understanding of global gut viral diversity and functional variations necessary for personalized medicine and addressing regional health disparities. Here, we introduce the Chinese Gut Viral Reference (CGVR) set, consisting of 120,568 viral genomes from 3,234 deeply sequenced fecal samples collected nationwide, covering 72,751 viral species-level clusters (VSCs), nearly 90% of which are absent from current databases. Analysis of single nucleotide variations (SNVs) in 233 globally prevalent VSCs revealed that 18.9% showed significant genetic stratification between Chinese and non-Chinese populations, potentially linked to bacterial infection susceptibility. The predicted bacterial hosts of population-stratified viruses exhibit distinct genetic components associated with health-related functions, including multidrug resistance. Additionally, viral strain diversity at the SNV level correlated with human phenotypic traits, such as age and gastrointestinal issues like constipation. Our analysis also indicates that the human gut bacteriome is specifically shaped by the virome, which mediates associations with human phenotypic traits. This foundational resource underscores the unique genetic makeup of the gut virome across populations and emphasizes the importance of recognizing gut viral genetic heterogeneity for deeper insights into regional health implications.

microbiology↗

bioRxiv2024

Tumour-derived gliogenesis sustains dedifferentiation-dependent tumour growth in the Drosophila CNS

Fate-restricted cells can acquire stem cell-like properties through dedifferentiation, enabling them to gain the plasticity required for differentiation into multiple lineages. Tumour plasticity is prominently observed in brain cancers, where transient cell state changes are linked to resistance to conventional therapies. In this study, we demonstrate that a sub-population of dedifferentiated tumour neural stem cells (NSCs) in Drosophila, induced by the knockdown of prospero (pros), can generate its own glial niche. Temporal patterning, known to influence oncogenic competence and tumour malignancy, plays a key role in this process. Specifically, we show that de novo gliogenesis occurs in the more differentiated Syncrip+ (Syp+) NSC population. Modulating Syp levels alters the size of the glial niche, subsequently affecting tumour size. Furthermore, the tumour-associated glial niche expands through cell division and fails to cease proliferation on time due to dysregulated ecdysone signalling, contributing to niche expansion. Our findings reveal that tumours arising via dedifferentiation establish their own supportive glial microenvironment, which sustains tumour growth.

developmental biology↗

bioRxiv2024

Restoration of PKM1 improves functional maturation of human stem-cell derived-β cell by regulating PEP metabolism

Human stem cell-derived {beta} (SC-{beta}) cells still exhibit limited glucose response required for insulin secretion due to glycolytic bottlenecks, yet how these metabolic abnormalities impact glucose response and functional maturation of SC-{beta} cells remains unclear. In this study, we identified a metabolic checkpoint located at PEP accumulation that impeded the functional maturation, which was rescued by restoration of pyruvate kinase 1 (PKM1). Glucose-tracing metabolomics in human stem cell-derived islets revealed abnormal glycolytic PEP accumulation at resting condition, resulting in impaired calcium response and insulin secretion upon high glucose or glycolytic metabolite stimulation. Mechanistically, elevated PEP significantly raised intracellular basal calcium levels, leading to downregulated expression of genes involved in TCA cycle elucidated by single cell transcriptomics. Furthermore, the activity of pyruvate kinase, which metabolizes PEP, was notably reduced due to low PKM1 expression. By overexpressing PKM1, the impairment of TCA-related genes caused by PEP accumulation was reversed via modulating PEP metabolism, resulting in enhanced calcium responses and insulin secretion upon high glucose stimulation. Together, we discovered a novel role of PKM1-regulated PEP metabolism in mediating the functional maturation of human SC-{beta} cells. This study highlights the importance of metabolic reprogramming in human SC-{beta} cell maturation, advancing cell therapy approaches for diabetes treatment.

cell biology↗

bioRxiv2024

NOLC1 Suppresses Immuno-chemotherapy by Inhibiting p53-mediated Ferroptosis in Gastric Cancer

Gastric cancer (GC) is one of the most malignant cancers, and cisplatin (Cis)-based chemotherapy remains the main clinical treatment for GC. However, Cis resistance often occurs, largely limiting its therapeutic efficacy in tumors. Therefore, a better understanding of the drug resistance mechanism could reveal new approaches for improving GC treatment efficacy. Here, we define the integrative role of nucleolar and coiled-body phosphoprotein 1 (NOLC1), a molecular chaperone that is significantly upregulated in GC tissues and Cis-resistant GC cells. Knocking down NOLC1 increased GC sensitivity to Cis by regulating ferroptosis. Mechanistically, NOLC1 binds to the p53 DNA binding domain (DBD), decreasing p53 nuclear accumulation stimulated by Cis and suppressing p53 transcriptional functions. Then, the p53-mediated ferroptosis is suppressed. Furthermore, the silence of NOLC1 promoted ferroptosis-induced immunogenic cell death (ICD) and reprogrammed the immunosuppressive tumor microenvironment, thereby increasing sensitivity to anti-programmed cell death-1 (PD-1) therapy plus Cis. The combination of anti-PD-1 plus Cis effectively inhibited GC growth without significant side effects. In summary, our findings reveal that targeting NOLC1 may be a novel therapeutic strategy for GC and may increase the efficacy of chemotherapy combined with immune checkpoint inhibitor (ICI) therapy.

cancer biology↗

bioRxiv2024

NeuroTD: A Time-Frequency Based Multimodal Learning Approach to Analyze Time Delays in Neural Activities

Studying the temporal dynamics of neural activities is essential for understanding how neurons function. These dynamics often involve temporal delays between neurons that vary over time, revealing both their functions and how they interact within circuits. Recent techniques such as Neuropixels, depth electrodes, and Patch-seq enable time-series recordings of neural activity at various scales, ranging from single neurons to large populations. However, inferring such time-varying delays remains challenging due to noise, high sampling rates, and complex temporal patterns. To address these challenges, we developed NeuroTD, a novel computational approach based on sliding windows to align time-series datasets and infer time-varying delays. Particularly, NeuroTD integrates adaptive window-size tuning to obtain optimal and robust delay estimates. We first benchmarked NeuroTD in simulation studies, demonstrating its robustness and outperformance. Then we applied it to two emerging real-world datasets: (i) intracranial multi-channel electrophysiological recordings from depth electrodes across medial temporal lobe regions in humans, showing that hippocampal signals recorded via depth electrodes exhibited consistently significantly longer time delays than other regions during working memory tasks, and (ii) Patch-seq data in the mouse motor cortex, revealing intrinsic electro-physiological time-delays of excitatory neurons correlated with gene expression and highlighting pathways related to ion transport and neuronal excitability. Finally, NeuroTD is open-source and available at https://github.com/daifengwanglab/NeuroTD for general use.

bioinformatics↗

bioRxiv2024

Genomic diversity and underlying metabolic variations of the human gut microbiome between populations at single nucleotide resolution

BackgroundA comprehensive and representative reference database is crucial for accurate taxonomic and functional profiling of the human gut microbiome in population-level studies. However, with 70% of current microbial reference data derived from Europeans and the Americans, East Asia, especially China, remain underrepresented. MethodsWe constructed the human Gut Microbiome Reference (GMR), comprising 478,588 high-quality microbial genomes from Chinese (247,134) and non-Chinese (231,454) populations. Species-level clustering and protein annotations were performed to characterize microbial diversity and function. We further integrated novel genomes into taxonomic profiling database and validated the improvements using independent cohort data. ResultsThe GMR dataset spans 6,664 species, including 26.4% newly classified species, and encodes over 20 million unique proteins, with 47% lacking known functional annotations. Notably, we observed that 35.35% and 32.46% of species unique to Chinese and non-Chinese populations, respectively. For 2,145 species shared between populations, 74% of 304 species with balanced prevalence between populations exhibited population-specific phylogenetic stratification, involving health relevant functionalities such as antibiotic resistance. Integration of novel genomes into taxonomic improved population-level species profiling by up to 23% and uncovered replicable associations between novel species and host physiological traits. ConclusionsOur study largely expands the compositional and functional landscape of the human gut microbiome, providing a crucial resource for studying the role of gut microbiome for regional health disparities.

genomics↗

bioRxiv2024

Tanshinone IIA potentiates the therapeutic efficacy of glucocorticoid in lipopolysaccharide-treated HEI-OC1 cells through modulation of Foxp3/Nrf2 signaling pathway

Glucocorticoids (GC) are commonly used to treat sudden sensorineural hearing loss (SSNHL), although some patients show resistance to this therapeutic approach. Clinical studies demonstrate the efficacy of tanshinone IIA (TA) in combination with GC for managing various human ailments. However, it remains unclear whether TA can mitigate GC resistance in SSNHL. Aim of the studyOur aim is to elucidate the role of NRF2-induced transcriptional regulation of HDAC2 in influencing GC resistance and investigate the involvement of TA-related molecular pathways in GC resistance. Materials and MethodsHEI-OC1 cells are treated with lipopolysaccharide (LPS) to establish an in vitro model for SSNHL. Subsequently, the cells are treated with dexamethasone (DXE) or DXE+TA. RT-qPCR and western blot analyses are employed to measure mRNA and protein levels of Forkhead box P3 (FOXP3), nuclear factor erythroid 2-related factor 2 (NRF2), and histone deacetylase 2 (HDAC2). Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2-deoxyuridine (EdU) assays are conducted to assess cell proliferation. Flow cytometry analysis is performed for apoptosis evaluation. Mechanistic studies involve Chromatin immunoprecipitation (ChIP), luciferase reporter, and DNA pull-down assays. ResultsTreatment with TA+DEX significantly enhances proliferation and suppresses apoptosis in LPS-treated HEI OC1 cells. TA upregulates HDAC2 expression by activating NRF2-mediated transcription of HDAC2, with the NRF2-HDAC2 binding site located at bases 419-429 (ATGACACTCCA) in the promoter sequence of HDAC2. Furthermore, TA upregulates FOXP3 expression to activate NRF2 transcription, with the predicted FOXP3-binding site located at bases 864-870 (GCAAACA) in the promoter sequence of NRF2. ConclusionThis studys findings suggest that TA enhances the therapeutic effects of GC on proliferation and apoptosis in HEI OC1 cells by up-regulating FOXP3/Nrf2 expression. These results indicate that TA may be promising in ameliorating GC resistance in patients with SSNHL.

pharmacology and toxicology↗

bioRxiv2024

PD-1 controls differentiation, survival, and TCR affinity evolution of stem-like CD8+ T cells

Stem-like progenitors are a critical subset of cytotoxic T cells that self-renew and give rise to expanded populations of effector cells critical for successful checkpoint blockade immunotherapy. Emerging evidence suggests that the tumor-draining lymph nodes can support the continuous generation of these stem-like cells that replenish the tumor sites and act as a critical source of expanded effector populations, underlining the importance of understanding what factors promote and maintain activated T cells in the stem-like state. Using advanced 3D multiplex immunofluorescence imaging, here we identified antigen-presentation niches in tumor-draining lymph nodes that support the expansion, maintenance, and affinity evolution of a unique population of TCF-1+PD-1+SLAMF6hi stem-like CD8+ T cells. Our results show that contrary to the prevailing view that persistent TCR signaling drives terminal effector differentiation, prolonged antigen engagement well beyond the initial priming phase sustained the proliferation and self-renewal of these stem-like T cells in vivo. The inhibitory PD-1 pathway plays a central role in this process by mediating the fine-tuning of TCR and co-stimulatory signal input that enables selective expansion of high affinity TCR stem-like clones, enabling them to act as a renewable source of high affinity effector cells. PD-1 checkpoint blockade disrupts this fine tuning of input signaling, leading to terminal differentiation to the effector state or death of the most avid anti-tumor stem-like cells. Our results thus reveal an unexpected relationship between TCR ligand affinity recognition, a key negative feedback regulatory loop, and T cell stemness programming. Furthermore, these findings raise questions about whether anti-PD-1 checkpoint blockade during cancer immunotherapy provides a short-term anti-tumor effect that comes at the cost of diminishing efficacy due to progressive loss of these critical high affinity stem-like precursors.

immunology↗

bioRxiv2024

Cloud-Connected Patch-Worn Auscultation Device for Chest Sound Monitoring

In recent years, wearable electrocardiograms have risen in popularity as a solution for personal monitoring of heart activity. However, this technology has limitations in diagnostic capability and structural function monitoring. Meanwhile, auscultation of the heart remains a fundamental tool for physicians in diagnosis and monitoring of heart disease largely unaddressed in a convenient wearable format. The present work outlines a promising system currently under investigation, allowing user-initiated 10-second chest-sound recordings to be transmitted over Bluetooth-Low-Energy, with an innovative package design providing inherent noise reduction and a high signal-to-noise ratio. The device has been tested on healthy individuals, and system response has been validated against calibrated electrocardiogram recording equipment to analyze signal capture fidelity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=124 SRC="FIGDIR/small/601965v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@3605fdorg.highwire.dtl.DTLVardef@c362b3org.highwire.dtl.DTLVardef@184e799org.highwire.dtl.DTLVardef@811384_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2024

A genome-wide association study of high-sensitivity C-reactive protein in a large Korean population highlights its role in cholesterol metabolism

High-sensitivity C-reactive protein (hsCRP) is a representative biomarker of systemic inflammation and is associated with numerous complex diseases. To explore the biological pathways and functions underlying chronic inflammation, we conducted a genome-wide association study (GWAS) and several post-GWAS analyses of the hsCRP levels. This study was performed on data from 71,019 Koreans and is one of the largest East Asian studies. Overall, 69 independent single nucleotide polymorphisms (SNPs) were identified, including 12 novel variants located within SHE, RP11-740C1.2, FCRL6, STEAP1B, AC002480.5, TOMM7, SPPL3, RP11-216P16.6, RP11-209K10.2, CTC-490E21.12, CYP2F2P, CBLC, and PVRL2. The implicated genes and pathways are primarily involved in cholesterol metabolism and the immune response. A phenome-wide association study was performed based on a polygenic risk score constructed using 69 hsCRP-associated SNPs. Notably, the alleles associated with higher hsCRP levels appeared to be associated with lower low-density lipoprotein cholesterol levels (P=1.69 x 10-33, {beta}=-1.47). Our findings provide evidence of a link between hsCRP and cholesterol as well as the clinical importance of hsCRP. Specifically, we suggest that genetically determined hsCRP levels may be useful for predicting the potential risk of cardiovascular or other diseases related to lipid metabolism. Authors summaryChronic inflammation is associated with numerous complex diseases, including cancer, cardiovascular disease, and diabetes. Previous studies have shown that East Asians have lower levels of C-reactive protein (CRP), a biomarker of inflammation, than other ancestry groups. To identify East Asian-specific single nucleotide polymorphisms (SNPs) associated with chronic inflammation, we conducted a genome-wide association study and secondary genetic analyses on hsCRP in 71,019 Korean individuals. In total, 69 SNPs were identified, of which 12 were novel. A majority of the identified SNPs are located within genes (LEPR, IL6R, and APOE) that are involved in cholesterol metabolism and immune response. Notably, we found genetically determined hsCRP level may contribute to decrease cholesterol level, in contrast to previous epidemiological studies. Therefore, we suggest genetically determined hsCRP as a clinical tool for predicting the potential risk of abnormal cholesterol metabolism and its related diseases.

genomics↗

bioRxiv2024

The continuous differentiation of multiscale structural gradients from childhood to adolescence correlates with the maturation of cortical morphology and functional specialization

From childhood to adolescence, the structural organization of the human brain undergoes dynamic and regionally heterogeneous changes across multiple scales, from synaptic pruning to the reorganization of large-scale anatomical wiring. However, during this period, the developmental process of multiscale structural architecture, its association with cortical morphological changes, and its role in the maturation of functional organization remain largely unknown. Here, we utilized a longitudinal multimodal imaging dataset including 276 children aged 6 to 14 years to investigate the developmental process of multiscale cortical wiring. We used an in vivo model of cortical wiring that combines features of white matter tractography, cortico-cortical proximity, and microstructural similarity to construct a multiscale brain structural connectome. By employing the gradient mapping method, the gradient space derived from the multiscale structural connectome effectively recapitulated the sensory-association axis and anterior-posterior axis. Our findings revealed a continuous expansion of the multiscale structural gradient space during development, with the principal gradient increasingly distinguishing between primary and transmodal regions. This age-related differentiation coincided with regionally heterogeneous changes in cortical morphology. Furthermore, our study revealed that developmental changes in coupling between multiscale structural and functional connectivity were correlated with functional specialization refinement, as evidenced by changes in the participation coefficient. We also found that the differentiation of the principal multiscale structural gradient was associated with improved cognitive abilities, such as enhanced working memory and attention performance, and potentially supported by molecular processes related to synaptic functions. These findings advance our understanding of the intricate maturation process of brain structural organization and its implications for cognitive performance.

neuroscience↗

bioRxiv2024

Protection against Clostridioides difficile disease by a naturally avirulent C. difficile strain

Clostridioides difficile (C. difficile) strains belonging to the epidemic BI/NAP1/027 (RT027) group have been associated with increased transmissibility and disease severity. In addition to the major toxin A and toxin B virulence factors, RT027 strains also encode the CDT binary toxin. Our lab previously identified a toxigenic RT027 isolate, ST1-75, that is avirulent in mice despite densely colonizing the colon. Here, we show that co-infecting mice with the avirulent ST1-75 and virulent R20291 strains protects mice from colitis due to rapid clearance of the virulent strain and persistence of the avirulent strain. Although avirulence of ST1-75 is due to a mutation in the cdtR gene, which encodes a response regulator that modulates the production of all three C. difficile toxins, the ability of ST1-75 to protect against acute colitis is not directly attributable to the cdtR mutation. Metabolomic analyses indicate that the ST1-75 strain depletes amino acids more rapidly than the R20291 strain and supplementation with amino acids ablates ST1-75s competitive advantage, suggesting that the ST1-75 strain limits the growth of virulent R20291 bacteria by amino acid depletion. Since the germination kinetics and sensitivity to the co-germinant glycine are similar for the ST1-75 and R20291 strains, our results identify the rapidity of in vivo nutrient depletion as a mechanism providing strain-specific, virulence-independent competitive advantages to different BI/NAP1/027 strains. They also suggest that the ST1-75 strain may, as a biotherapeutic agent, enhance resistance to CDI in high-risk patients. ImportanceClostridioides difficile infections (CDI) are prevalent in healthcare settings and are associated with high recurrence rates. Therapies to prevent CDI, including recent FDA-approved live biotherapeutic products, are costly and have not been used to prevent primary infections. While a nontoxigenic C. difficile strain (NTCD-M3) protects against virulent CDI in animals and reduced CDI recurrence in a phase 2 clinical trial, protection against CDI recurrence in humans was variable and required high doses of the nontoxigenic strain. Here we show that an avirulent C. difficile isolate, ST1-75, efficiently outcompetes virulent C. difficile strains in mice when co-infected at a 1:1 ratio. Our data suggest that inter-strain competition results from ST1-75s more rapid depletion of amino acids than the virulent R20291 strain. Our study identifies inter-strain nutrient depletion as a potentially exploitable mechanism to reduce the incidence of CDI.

microbiology↗

bioRxiv2024

Development of the overlapping network modules in the human brain

Developmental connectomic studies have shown that the modular organization of functional networks in the human brain undergoes substantial reorganization with age to support cognitive growth. However, these studies implicitly assume that each brain region belongs to one and only one specific network module, ignoring the potential spatial overlap between functional modules. How the overlapping functional modular architecture develops and whether this development is related to structural signatures remain unknown. Using longitudinal multimodal structural, functional, and diffusion MRI data from 305 children (aged 6-14 years), we investigated the development of the overlapping modular architecture of functional networks, and further explored their structural associations. Specifically, an edge-centric network model was used to identify the overlapping functional modules, and the nodal overlap in module affiliations was quantified using the entropy measure. We showed a remarkable regional inhomogeneity in module overlap in children, with higher entropy in the ventral attention, somatomotor, and subcortical networks and lower entropy in the visual and default-mode networks. Furthermore, the overlapping modules developed in a linear, spatially dissociable manner from childhood to adolescence, with significantly reduced entropy in the prefrontal cortex and putamen and increased entropy in the parietal lobules. Personalized overlapping modular patterns capture individual brain maturity as characterized by brain age. Finally, the overlapping functional modules can be significantly predicted by integrating gray matter morphology and white matter network properties. Our findings highlight the maturation of overlapping network modules and their structural substrates, thereby advancing our understanding of the principles of connectome development.

neuroscience↗

bioRxiv2024

UNG-RPA interaction governs the choice between high-fidelity and mutagenic uracil repair

Mammalian Uracil DNA glycosylase (UNG) removes uracils and initiates high-fidelity base excision repair to maintain genomic stability. During B cell development, activation-induced cytidine deaminase (AID) creates uracils that UNG processes in an error-prone fashion to accomplish immunoglobulin (Ig) somatic hypermutation (SHM) or class switch recombination (CSR). The mechanism that governs high-fidelity versus mutagenic uracil repair is not understood. The B cell tropic gammaherpesvirus (GHV) encodes a functional homolog of UNG that can process AID induced genomic uracils. GHVUNG does not support hypermutation, suggesting intrinsic properties of UNG influence repair outcome. Noting the structural divergence between the UNGs, we define the RPA interacting motif as the determinant of mutation outcome. UNG or RPA mutants unable to interact with each other, only support high-fidelity repair. In B cells, transversions at the Ig variable region are abated while CSR is supported. Thus UNG-RPA governs the generation of mutations and has implications for locus specific mutagenesis in B cells and deamination associated mutational signatures in cancer.

immunology↗

bioRxiv2024

Normative growth modeling of brain morphology reveals neuroanatomical heterogeneity and biological subtypes in children with ADHD

BackgroundNeuroimaging studies suggest substantial individual heterogeneity in brain phenotypes in attention-deficit/hyperactivity disorder (ADHD). However, how these individual-level brain phenotypes contribute to the identification of ADHD biotypes and whether these biotypes have different treatment outcomes and neurobiological underpinnings remain largely unknown. MethodsWe collected multisite, high-quality structural magnetic resonance imaging data from 1,006 children aged 6-14 years, including 351 children with ADHD and 655 typically developing children. Normative growth models of cortical thickness were established for 219 regions in the typically developing children. Individual-level deviations from these normal references were quantified and clustered to identify ADHD biotypes. We validated the replicability and generalizability of the ADHD biotypes using two independent datasets and evaluated the associations of the biotypes with symptomatic, cognitive, and gene expression profiles, as well as follow-up treatment outcomes. FindingsNo more than 10% of children with ADHD had extreme deviations in cortical thickness in a single region, suggesting high heterogeneity among individuals with ADHD. On the basis of the brain deviation maps, we discovered two robust ADHD biotypes, an infra-normal subtype with cortical thinning associated with ADHD symptoms and a supranormal subtype with cortical thickening associated with cognition. Patients with the infra-normal subtype responded better to methylphenidate than to atomoxetine, although both subtypes showed treatment efficacy. Brain deviations in the infra-normal subtype were explained by the expression levels of genes enriched in presynaptic and axonal development and polygenic risk of ADHD. InterpretationWe identified anatomically distinct, clinically valuable, and biologically informed ADHD subtypes, providing insight into the neurobiological basis of clinical heterogeneity and facilitating a personalized medication strategy for ADHD patients. Panel: Research in contextO_ST_ABSEvidence before this studyC_ST_ABSSubstantial individual heterogeneity in brain phenotypes in attention-deficit/hyperactivity disorder (ADHD) motivates the need to discover homogeneous biotypes. We searched PubMed for research articles on ADHD biotypes using brain MRI published before December 1, 2023, using the search terms ((attention deficit hyperactivity disorder [Title/Abstract]) OR (ADHD [Title/Abstract])) AND ((subtypes [Title/Abstract]) OR (subgroups [Title/Abstract]) OR (subtyping [Title/Abstract])) AND ((MRI [Title/Abstract]) OR (neuroimaging [Title/Abstract]) OR (brain [Title/Abstract])) without language restrictions. Of the eight included studies, two identified ADHD biotypes using structural morphology, four used functional activity, and two used multimodal features. However, none of these studies considered the developmental effect of the brain phenotypes, examined treatment response, or investigated the genetic correlates of the biotypes. Added value of this studyThis study is the first to use individualized brain measures extracted from normative models to investigate ADHD biotypes in a large sample of more than 1,000 children. We identified two reproducible ADHD biotypes, characterized by distinct symptomatic, cognitive, and gene expression profiles, as well as differential treatment responses. This study advances our understanding of the neurobiological basis underlying the clinical heterogeneity of ADHD and highlights the critical need to discover ADHD biotypes using an unbiased and individualized approach. Implications of all the available evidenceThis study revealed remarkable neuroanatomical heterogeneity in ADHD patients and identified anatomically distinct, clinically valuable, and biologically informed ADHD biotypes. Our findings have potential value for the investigation of data-driven biotypes to evaluate treatment efficacy and facilitate personalized treatment. We also highlight the need for future studies to move beyond the understanding of ADHD solely based on the "average patient" perspective.

neuroscience↗

bioRxiv2024

Unique growth and morphology properties of Clade 5 Clostridioides difficile strains revealed by single-cell time-lapse microscopy

Clostridioides difficile is a gastrointestinal pathogen of both humans and agricultural animals and thus a major One Health threat. The C. difficile species consists of five main clades, with Clade 5 currently undergoing speciation from Clades 1-4. Clade 5 strains are highly prevalent in agricultural animals and can cause zoonotic infections, suggesting that these strains have evolved phenotypes that distinguish them from Clade 1-4 strains. Here, we compare the growth properties of Clade 5 strains to those of Clade 1-4 strains using anaerobic time-lapse microscopy coupled with automated image analysis. Our analyses indicate that Clade 5 strains grow faster and are more likely to form long chains of cells than Clade 1-4 strains. Using comparative genomic and CRISPRi analyses, we show that the chaining phenotype of Clade 5 strains is driven by the orientation of the invertible cmr switch sequence, with chaining strains exhibiting a bias to the cmr-ON state. Interestingly, Clade 5 strains with a bias towards the cmr-ON state shifted to a largely cmr-OFF state during murine infection, suggesting that the cmr-OFF state is under positive selection during infection. Collectively, our data reveal that Clade 5 strains have distinct growth properties, which may allow them to inhabit diverse ecological niches. Author SummaryThe Clade 5 strains of the Clostridioides difficile species are so phylogenetically divergent that they almost meet the threshold of being a distinct species. Although these strains are ubiquitously isolated from agricultural and environmental settings and an important source of zoonotic and community-acquired infections, it is unclear whether they have distinct phenotypic properties that allow them to colonize diverse hosts or persist in the environment. By combining a novel anaerobic time-lapse microscopy method with automated image analysis, we discovered that Clade 5 strains grow faster than strains from other C. difficile clades and that they frequently form long chains. These chaining properties are driven by the environmentally responsive expression of a non-canonical signal transduction system, which our analyses suggest is selected against during murine infection. Collectively, our analyses reveal that Clade 5 strains have distinct growth properties that may promote their persistence in the environment.

microbiology↗