Biology subjects

Xu, N.

Publications and source records attributed to Xu, N..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Intraguild parasitism promotes the persistence of facultative hyperparasitoids by extending temporal host availability

Intraguild predation (IGP) is pervasive in natural food webs, although theoretical models predict restricted parameter space for the coexistence of IG-prey and IG-predators. One potential mechanism is that IGP persistence might be increased when IG-prey extend resource availability for IG-predators. Here we test this hypothesis using manipulative experiments in combination with mathematical modeling. Our experiment system includes Drosophila flies (Drosophila melanogaster, basal resources), primary larval parasitoids (Asobara leveri, IG-prey) and facultative pupal hyperparasitoid (Pachycrepoideus vindemiae, IG-predator). We measured the performance of facultative pupal parasitoids with and without the primary larval parasitoid. Our study revealed that larval parasitoids significantly increased the number of pupal parasitoids emerged from limited host resources, due to the extended resource availability to facultative hyperparasitoid. Specifically, immature primary parasitoids within Drosophila pupae can be explored by facultative hyperparasitoids for up to 14 days, while the healthy fly pupae are available to hyperparasitoids for only 5 days. Despite a significant reduction in offspring fitness of the facultative hyperparasitoids when reared on larval parasitoids versus healthy Drosophila pupae, adult female facultative hyperparasitoids showed no significant preference for healthy fly pupae over immature primary parasitoids. Our theoretical models demonstrated that an extended development period of the primary parasitoid can promote the persistence of the facultative hyperparasitoids and allow their coexistence with the primary parasitoid, although too prolonged development could drive the extinction of the primary parasitoid. As IG-prey often take longer time to develop after consuming the shared resources, extension of temporal resource availability could be a general mechanism contribute to the persistence of intraguild predators. Open research statementData are not yet available, but all of the original experimental data has been displayed in figures 2[~]4. The data will be made publicly available upon manuscript acceptance and archived in the Dryad Digital Repository.

ecology↗

bioRxiv2025

Targeting Non-Catalytic Sites of SRC Sensitizes the Efficacy of SRC Kinase Inhibitors in Solid Tumors

The non-receptor tyrosine kinase SRC promotes the progression of hematologic malignancies and numerous solid tumors. Several SRC kinase inhibitors have been approved for the treatment of hematologic malignancies. However, drug resistance to sole ATP pocket-targeted kinase inhibition, coupled with low potency for solid tumors and insufficient selectivity, has limited the clinical application of SRC kinase inhibitors. The non-catalytic functions of kinases have provided crucial mechanisms underlying kinase inhibitor resistance, thereby presenting new opportunities for discovery SRC-targeted strategies. In this study, we discovered that upon abrogation of phosphorylation by SRC kinase inhibitors, non-catalytic SRC promotes the transcription of the oncogenes TRIB3 and SPC24 transcription by binding to their promoter sequence. Simultaneously, it interacts with TRIB3 and prevents their proteasome-mediated degradation by the E3 ligase CHIP, ultimately inducing resistance to SRC kinase inhibitors. The peptide TS1-2, blocking SRC/TRIB3 interaction in non-catalytic regions, inhibits the tumor progression of pancreatic ductal adenocarcinoma (PDAC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and breast invasive carcinoma (BRCA), and enhances the efficacy of SRC kinase inhibitors in solid tumors. This study provides the insights of non-catalytic functions of SRC, validates the tumor-promoting function and mechanism of nuclear accumulation of SRC/TRIB3 following SRC kinase inhibitor treatment, identifies SRC/TRIB3 interaction as a potential non-catalytic target, and offers the candidate peptide TS1-2 as a potential combination strategy for overcoming SRC kinase inhibitor resistance. SignificanceThe scaffolding functions of SRC reduced the efficacy of SRC kinase inhibitors, and targeting SRC/TRIB3 non-catalytic functions synergizes the therapeutic effects of SRC kinase inhibitors in SRC-dependent solid tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/638389v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@17aa618org.highwire.dtl.DTLVardef@12e86eeorg.highwire.dtl.DTLVardef@19c8d82org.highwire.dtl.DTLVardef@10e6c46_HPS_FORMAT_FIGEXP M_FIG C_FIG SRC kinase inhibitors block myristoylation-dependent membrane location and catalytic phosphorylation of SRC. Phosphorylated SRC activates STAT1 and thereby represses TRIB3 transcription. Accumulated non-catalytic SRC promotes TRIB3, SPC24 transcription. Upregulated TIRB3 interacts with SRC to reduce CHIP-mediated ubiquitin-proteasomal degradation. The peptide TS1-2 disrupts TRIB3/SRC complex by targeting Non-kinase regions of SRC, consequently enhancing the therapeutic efficacy of SRC kinase inhibitors.

cancer biology↗

bioRxiv2025

Ether Rhodamines with Enhanced Hydrophilicity, Fluorogenicity, and Brightness for Super-Resolution Imaging

Rhodamine dyes are widely used fluorophores in super-resolution fluorescence imaging due to their exceptional optical properties and "aggregation-disaggregation" induced fluorogenic activation. However, their excessive lipophilicity often reduces brightness in aqueous environments and causes off-target staining, limiting their effectiveness in high-resolution imaging. To address these challenges, we introduce an ether-decorated N-terminal modification strategy for rhodamine and silicon-rhodamine (Si-rhodamine), replacing conventional N-alkyl groups. The ether chains enhance water solubility, decrease aggregate size, and improve fluorogenicity across a wide concentration range. Their flexible, hydrophilic structure forms a protective shield around the xanthene core, minimizing dye-water interactions and reducing fluorescence quenching. Additionally, the inductive effect of the ether chains decreases the electron-donating strength of the amino groups, suppressing quenching caused by twisted intramolecular charge transfer (TICT). These modifications collectively increase the quantum yields of ER and ESiR in water from 0.35 and 0.19 (for tetraethyl-substituted analogs) to 0.70 and 0.41, respectively. Probes derived from ER and ESiR exhibit outstanding fluorogenicity, enhanced signal-to-noise ratios, and improved resolution in complex aqueous environments, demonstrating superior performance in advanced super-resolution imaging techniques such as structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single-molecule localization microscopy (SMLM). This work introduces an innovative strategy for fluorophore design, offering significant advancements for super-resolution imaging applications.

biochemistry↗

bioRxiv2024

A General Strategy to Endow Dyes with Genic Fluorescence for Wash-Free Imaging of Proteins in Living Cells

Fluorescent dyes are the main fluorophore for protein labeling and fluorescent imaging in living cells. However, due to the inevitable nonspecific binding of the dye to non-targets within the cell, background signals are generated, which severely affect the imaging quality. Here, we endow the dye with genic fluorescence by introducing a fluorescent proteins FRET pair, such that only the dye bound to the target protein emits fluorescence ({lambda}ex = FPs, {lambda}em = Dyes), while nonspecifically bound dye remains non-fluorescent. This significantly improves the signal-to-noise ratio (SNR) in wash-free imaging. This strategy is achieved by fusing the Halo-tag to fluorescent proteins (sfGFP, mCherry) that can generate FRET with Halo dyes O-Rho and Si-Rho. The FPs serve as the donor, and the FRET mechanism imparts genic fluorescence property to O-Rho and Si-Rho. Since the excitation wavelength of the donor ({lambda}ex = FPs) cannot excite the unspecifically dye fluorescence, background fluorescence interference is reduced. We further improved the SNR by increasing the FRET efficiency between the FPs and dyes. The system was used for four-color super-resolution imaging of target proteins and dynamic SIM tracking of mitochondria. In addition, the genic FRET fluorophore constructed with the ultra-stable mStayGold showed significant photobleaching resistance and can be used for long-term dynamic super-resolution imaging. Theoretically, by selecting appropriate FRET pairs, this method can improve the SNR of any fluorophore, providing a new labeling strategy for live-cell wash-free imaging.

biochemistry↗

bioRxiv2024

NMI induces chemokine release and recruits neutrophils through the activation of NF-kappaB pathway

Neutrophils are essential components of the innate immune system, playing a pivotal role in immune responses. These cells rapidly migrate to sites of inflammation or tissue injury, facilitating pathogen clearance and tissue repair. The chemotactic signaling network regulating neutrophil recruitment is complex and not fully understood, particularly regarding damage-associated molecular patterns (DAMPs). In our previous research, we identified NMI as a DAMP that activates dendritic cells and macrophages, amplifying inflammatory responses and contributing to both acute and chronic inflammation. In this study, we investigated the role of NMI in neutrophil recruitment. We purified and characterized a recombinant murine NMI protein, ensuring endotoxin removal while preserving biological activity. In vivo experiments demonstrated that NMI enhances neutrophil recruitment in both a murine air pouch model and an acute peritonitis model, mediated by macrophage-derived chemokines. In vitro assays revealed a concentration-dependent increase in neutrophil migration induced by NMI, facilitated by chemokine secretion and subsequent migration through the CXCR2 receptor. Importantly, we established that NMI activates chemokine expression via the NF-{kappa}B signaling pathway. These findings provide insights into the mechanisms of NMI-induced neutrophil migration, enhancing our understanding of neutrophil recruitment during inflammation.

immunology↗

bioRxiv2024

Cholinergic signaling differentially regulates song premotor circuits to stabilize songs in songbirds

Cholinergic modulation plays an important role in motor skill performance, including vocal control. In songbirds, song motor nucleus RA simultaneously receives inputs from song nuclei HVC and LMAN, and then its projection neurons (RAPNs) generate song motor control output. Using electrophysiological and pharmacological methods, we found that cholinergic signaling can enhance song stability by reducing HVC-RAPN excitatory synaptic transmission in adult male zebra finches, mediated by mAChRs. Although nAChRs are not effective overall, cholinergic signaling can also decrease LMAN-RAPN excitatory synaptic transmission induced by electrical stimulation via nAChRs, suggesting the potential role of cholinergic regulation in song behavior through LMAN-RA pathway. On the contrary, in adult female zebra finches, only LMAN-RAPN synaptic transmission was reduced by cholinergic signaling via mAChRs. The role of differential cholinergic regulation of song premotor circuits in songbirds singing provides insights into the neural control mechanism of motor skill performance.

neuroscience↗

bioRxiv2024

DEK-rRNA interactions regulate ribosome biogenesis and stress response

DNA/chromatin-based functions of the DEK oncogene, a unique nucleic acid-interacting factor in metazoans, have been widely investigated, yet its role in cellular RNA biology is under-studied. Herein we employed CLIP-seq alongside mutational, biochemical, and cellular approaches to gain deeper insights into the cellular DEK-RNA interplay. We confirm interaction of DEK with coding RNA, yet also report association with ribosomal RNA (rRNA) and thereby establishing a robust link between DEK and ribosome biology. Indeed, cells lacking DEK showed marked deficits in cytoplasmic ribosome quality and function. This phenotype was exclusively rescued by C-terminal DEK, harboring two RNA interaction domains, but not by an rRNA-binding deficient mutant. Mechanistically, we uncovered pleiotropic involvement of DEK in RNA polymerase I-mediated rRNA transcription and processing pathways. More specifically, we found direct interaction of DEK with RNA polymerase III-transcribed 5S rRNA and identified DEK as a regulator of the Impaired Ribosome Biogenesis Checkpoint (IRBC). Within this ribosomal stress pathway, DEK depletion results in free 5S RNP, triggering stabilization of p53 via inhibition of MDM2. In summary, our multilayer analysis revealed DEK as a potent cellular RNA binding protein and provides first evidence of DEK as a regulator of ribosome biogenesis and stress response via the 5S RNP-MDM2-p53 axis.

biochemistry↗

bioRxiv2024

OsAAI1-OsMADS25 module orchestrates root morphogenesis by fine-tuning IAA in drought stressed rice

Indole-3-acetic acid (IAA) plays a critical role as a plant hormone in regulating the growth and development of the root system in plants, particularly in enhancing their ability to withstand abiotic stress. In this study, we found that overexpression of OsAAI1 promoted the growth of rice root system. The length of primary root, the number of lateral roots, the density of lateral roots, and the number of adventitious roots of overexpression of OsAAI1 (OE19) were significantly better than those of the wild type (ZH11) and the mutant line (osaai1), and the IAA content of OE19 was significantly higher than those of ZH11 and osaai1. We also found that exogenous application of IAA could compensate for the root growth defect caused by the osaai1 mutation. OE19 had the highest number and widest distribution of total roots under the water-cut drought treatment, and exogenous application of IAA attenuated the growth inhibitory effect of drought stress on osaai1. Our study also revealed that OsAAI1 interacts with the MADS-box family transcription factor OsMASD25. Additionally, the application of IAA helped alleviate the growth inhibitory effects of drought stress on osmads25.Importantly, OsMADS25 interaction with OsAAI1 was found to enhance the transcriptional expression of its downstream target genes LAX1 and OsBAG4, which are crucial genes in rices response to drought stress. These findings suggest that OsAAI1 and OsMADS25 are crucial in rices drought acclimation process by regulating downstream gene expression and influencing the IAA signaling pathway. Author summaryThe root system is a crucial organ for crop plants as it facilitates the absorption of water and nutrients, contributing to their drought resistance. Indole-3-acetic acid (IAA) plays a pivotal role in the growth of various types of roots in plants. Under drought stress conditions, changes in IAA levels and transport can impact the morphology of plant roots. This research illustrates that OsAAI1 positively influences rice root development and enhances the plants response to drought stress through the auxin signaling pathway. The study reveals a physical interaction between OsAAI1 and the transcription factor OsMADS25. This interaction boosts the expression of the auxin synthesis gene OsYUC4 and suppresses the auxin inhibitory factor OsIAA14, thereby promoting the auxin signaling pathway, stimulating rice root growth, and enhancing the plants ability to withstand drought. Furthermore, the interaction between OsAAI1 and OsMADS25 has been found to also positively affect the expression of the genes LAX1 and OsBAG4, which is associated with activated drought resistance in rice plants.

plant biology↗

bioRxiv2024

The Effects of Locus Coeruleus Optogenetic Stimulation on Global Spatiotemporal Patterns in Rats

Whole-brain intrinsic activity as detected by resting-state fMRI can be summarized by three primary spatiotemporal patterns. These patterns have been shown to change with different brain states, especially arousal. The noradrenergic locus coeruleus (LC) is a key node in arousal circuits and has extensive projections throughout the brain, giving it neuromodulatory influence over the coordinated activity of structurally separated regions. In this study, we used optogenetic-fMRI in rats to investigate the impact of LC stimulation on the global signal and three primary spatiotemporal patterns. We report small, spatially specific changes in global signal distribution as a result of tonic LC stimulation, as well as regional changes in spatiotemporal patterns of activity at 5 Hz tonic and 15 Hz phasic stimulation. We also found that LC stimulation had little to no effect on the spatiotemporal patterns detected by complex principal component analysis. These results show that the effects of LC activity on the BOLD signal in rats may be small and regionally concentrated, as opposed to widespread and globally acting.

neuroscience↗

bioRxiv2024

Variation in the Distribution of Large-scale Spatiotemporal Patterns of Activity Across Brain States

A few large-scale spatiotemporal patterns of brain activity (quasiperiodic patterns or QPPs) account for most of the spatial structure observed in resting state functional magnetic resonance imaging (rs-fMRI). The QPPs capture well-known features such as the evolution of the global signal and the alternating dominance of the default mode and task positive networks. These widespread patterns of activity have plausible ties to neuromodulatory input that mediates changes in nonlocalized processes, including arousal and attention. To determine whether QPPs exhibit variations across brain conditions, the relative magnitude and distribution of the three strongest QPPs were examined in two scenarios. First, in data from the Human Connectome Project, the relative incidence and magnitude of the QPPs was examined over the course of the scan, under the hypothesis that increasing drowsiness would shift the expression of the QPPs over time. Second, using rs-fMRI in rats obtained with a novel approach that minimizes noise, the relative incidence and magnitude of the QPPs was examined under three different anesthetic conditions expected to create distinct types of brain activity. The results indicate that both the distribution of QPPs and their magnitude changes with brain state, evidence of the sensitivity of these large-scale patterns to widespread changes linked to alterations in brain conditions.

neuroscience↗

bioRxiv2024

Fish CDK2 recruits Dtx4 to degrade TBK1 through ubiquitination in the antiviral response

Although the classical biological protein cell cycle protein kinase CDK2 has been extensively studied in higher vertebrates, its function in lower vertebrates beyond the regulation of mitosis remains unknown. In this study, we report a distinct mechanism whereby IFN expression is negatively regulated in fish by CDK2. After infection with the spring viremia of carp virus (SVCV), fish CDK2 expression significantly increased in tissues and cells. Moreover, antiviral resistance was improved in cdk2-/- homozygotes, and the antiviral cytokine interferon (IFN) expression was significantly higher. At the cellular level, CDK2 overexpression reduced IFN expression, while cdk2 knockdown increased the ability of cells to produce IFN. Subsequently, it was discovered that fish CDK2 binds and degrades TBK1, resulting in reduced IFN. CDK2 increases the K48-linked ubiquitination of TBK1, causing its degradation, while E3 ubiquitin ligase Dtx4 was found to be involved in this process following the significant enhancement of TBK1 K48-linked ubiquitination. Protein mass spectrometry and immunoblot analysis confirmed that the K567 site on TBK1 is essential for CDK2 to engage with Dtx4 and degrade TBK1; thus, after mutating the K567 site, K48-linked ubiquitination of TBK1 was not enhanced by Dtx4, and TBK1 was not degraded by CDK2. Our data demonstrate that fish CDK2 recruits the E3 ubiquitin ligase Dtx4 to target the K567 site of TBK1 and promote its degradation. These results suggest that CDK2 in lower vertebrates is implicated in a specialized role for antiviral innate immunity.

immunology↗

bioRxiv2024

PLM_Sol: predicting protein solubility by benchmarking multiple protein language models with the updated Escherichia coli protein solubility dataset

Protein solubility plays a crucial role in various biotechnological, industrial and biomedical applications. With the reduction in sequencing and gene synthesis costs, the adoption of high-throughput experimental screening coupled with tailored bioinformatic prediction has witnessed a rapidly growing trend for the development of novel functional enzymes of interest (EOI). High protein solubility rates are essential in this process and accurate prediction of solubility is a challenging task. As deep learning technology continues to evolve, attention-based protein language models (PLMs) can extract intrinsic information from protein sequences to a greater extent. Leveraging these models along with the increasing availability of protein solubility data inferred from structural database like the Protein Data Bank (PDB), holds great potential to enhance the prediction of protein solubility. In this study, we curated an Updated Escherichia coli (E.coli) protein Solubility DataSet (UESolDS) and employed a combination of multiple PLMs and classification layers to predict protein solubility. The resulting best-performing model, named Protein Language Model-based protein Solubility prediction model (PLM_Sol), demonstrated significant improvements over previous reported models, achieving a notable 5.7% increase in accuracy, 9% increase in F1_score, and 10.4% increase in MCC score on the independent test set. Moreover, additional evaluation utilizing our in-house synthesized protein resource as test data, encompassing diverse types of enzymes, also showcased the superior performance of PLM_Sol. Overall, PLM_Sol exhibited consistent and promising performance across both independent test set and experimental set, thereby making it well-suited for facilitating large-scale EOI studies. PLM_Sol is available as a standalone program and as an easy-to-use model at https://zenodo.org/doi/10.5281/zenodo.10675340.

bioinformatics↗

bioRxiv2024

Comparative genomics of macaques and integrated insights into genetic variation and population history

The crab-eating macaques (Macaca fascicularis) and rhesus macaques (M. mulatta) are widely studied nonhuman primates in biomedical and evolutionary research. Despite their significance, the current understanding of the complex genomic structure in macaques and the differences between species requires substantial improvement. Here, we present a complete genome assembly of a crab-eating macaque and 20 haplotype-resolved macaque assemblies to investigate the complex regions and major genomic differences between species. Segmental duplication in macaques is [~]42% lower, while centromeres are [~]3.7 times longer than those in humans. The characterization of [~]2 Mbp fixed genetic variants and [~]240 Mbp complex loci highlights potential associations with metabolic differences between the two macaque species (e.g., CYP2C76 and EHBP1L1). Additionally, hundreds of alternative splicing differences show post-transcriptional regulation divergence between these two species (e.g., PNPO). We also characterize 91 large-scale genomic differences between macaques and humans at a single-base-pair resolution and highlight their impact on gene regulation in primate evolution (e.g., FOLH1 and PIEZO2). Finally, population genetics recapitulates macaque speciation and selective sweeps, highlighting potential genetic basis of reproduction and tail phenotype differences (e.g., STAB1, SEMA3F, and HOXD13). In summary, the integrated analysis of genetic variation and population genetics in macaques greatly enhances our comprehension of lineage-specific phenotypes, adaptation, and primate evolution, thereby improving their biomedical applications in human diseases.

genomics↗

bioRxiv2023

Dysregulated Repeat Element Viral-like Immune Response in Hepatocellular Carcinoma

PurposeHepatocellular carcinoma (HCC) is a lethal malignancy driven by complex interactions between cancer cells, immune cells, and additional stromal cells in the tumor microenvironment (TME). The LINE1 retrotransposon is a ubiquitous repeat RNA whose de-repression leads to significant cancer cell-intrinsic and TME changes that promote aggressive tumor characteristics. We leveraged single cell spatial transcriptomic profiling to characterize the relationship between LINE1 and differences in the heterogeneous HCC TME. Experimental DesignWe applied our profiling methodology to a cohort of 23 tissue specimens collected from patients who had undergone liver resection or transplantation and validated it in a partially-overlapping similar cohort of 39 specimens using RNA in-situ hybridization (RNA-ISH). ResultsWe found that LINE1-high tumors and LINE1-high single HCC cells exhibited a de-differentiated, stem-like, and inflammatory phenotype. Furthermore, within individual tumors, LINE1 high cancer cells associated spatially with one another and excluded the larger, organized immune cell conglomerates seen in LINE1 low tumors. Finally, we found that LINE1 RNA expression correlated with worse overall survival in the larger expanded retrospective cohort. ConclusionsOur study is the first to show a clearly disorganized immune TME in HCC driven by LINE1 expression, and this observation correlated with poor survival for patients whose tumors expressed large amounts of the LINE1 repeat RNA. These results provide further evidence of how effective anti-tumor immune responses contribute to cures after definitive surgery and may lead to novel biomarkers or drug targets in HCC. TRANSLATIONAL RELEVANCEThe viral-like LINE1 retrotransposon is known to influence tumor cell state and the immune response in a variety of cancer. Here, we have used single cell spatial transcriptomic profiling to resolve repeat and coding gene RNA expression in a cohort of hepatocellular carcinoma (HCC) patients. LINE1 RNA expression in HCC tumor cells was correlated with an undifferentiated stem-like cancer state and a disorganized, sparse immune infiltrate. Using in situ hybridization on an expanded validation cohort, we noted significantly worsened survival in the LINE1 high group. Altogether, LINE1 repeat RNA is a tumor intrinsic biomarker of more aggressive features that can be used for risk stratification and a potential biomarker for response to immunotherapies that merits further investigation.

cancer biology↗

bioRxiv2023

QPPLab: A generally applicable software package for detecting, analyzing, and visualizing large-scale quasiperiodic spatiotemporal patterns (QPPs) of brain activity

Quasi-periodic patterns (QPPs) are prominent spatiotemporal brain dynamics observed in functional neuroimaging data, reflecting the alternation of high and low activity across brain regions and their propagation along cortical gradients. QPPs have been linked to neural processes such as attention, arousal fluctuations, and cognitive function. Despite their significance, existing QPP analysis tools are limited by study-specific parameters and complex workflows. To address these challenges, we present QPPLab, an open-source MATLAB-based toolbox for detecting, analyzing, and visualizing QPPs from fMRI time series. QPPLab integrates correlation-based iterative algorithms, supports customizable parameter settings, and features automated workflows to simplify analysis. Processing times vary depending on dataset size and the selected mode, with the fast detection mode completing analyses that can be 4-6 times faster than the robust detection mode. Results include spatiotemporal templates of QPPs, sliding correlation time courses, and functional connectivity maps. By reducing manual parameter adjustments and providing user-friendly tools, QPPLab enables researchers to efficiently study QPPs across diverse datasets and species, advancing our understanding of intrinsic brain dynamics. Metadata O_TBL View this table: org.highwire.dtl.DTLVardef@1f4f44dorg.highwire.dtl.DTLVardef@d31544org.highwire.dtl.DTLVardef@19384corg.highwire.dtl.DTLVardef@1bf2360org.highwire.dtl.DTLVardef@1ab9b80_HPS_FORMAT_FIGEXP M_TBL C_TBL

bioinformatics↗

bioRxiv2023

Comparative transcriptome in rhesus macaques and crab-eating macaques

Understanding the variations in gene expression between species is pivotal for deciphering the evolutionary diversity in phenotypes. Rhesus macaques and crab-eating macaques serve as crucial nonhuman primate biomedical models with different phenotypes, but the large-scale of comparative transcriptome research between these two species has yet to be fully elucidated. Here, we conduct systematic comparisons utilizing newly sequenced RNA-seq data from 84 samples encompassing 14 common tissues. Our findings reveal that a small fraction of genes ([~]3.7%) show differential expression between the two macaque species, while [~]36.5% of genes show tissue-specific expression in both macaques. We also compare gene expression between macaques and humans and [~]22.6 % of the orthologous genes show differential expression in at least 2 tissues. Moreover, [~]19.41% of genes overlapped with macaque-specific structural variants are more likely to show differential expression between humans and macaques. Of these, FAM220A shows elevated gene expression in humans compared to macaques because of lineage-specific duplication. In summary, our study presents a large-scale analysis of the transcriptomes within macaque species and between macaques and humans. These insights into gene expression variations will enhance the biomedical utility of macaque models and contributing to the broader realm of primate genomic studies.

bioinformatics↗

bioRxiv2023

Cell type-specific consequences of mosaic structural variants in hematopoietic stem and progenitor cells

The functional impact and cellular context of mosaic structural variants (mSVs) in normal tissues is understudied. Utilizing Strand-seq, we sequenced 1,133 single cell genomes from 19 human donors of increasing age, revealing a heterogeneous mSV landscape in hematopoietic stem and progenitor cells (HSPCs). While mSV clonal expansions are confined to individuals over 60, de novo mSV formation occurs consistently across age, frequently leading to megabase-scale segmental aneuploidies. Cells harboring subclonal mosaicism show evidence for increased mSV formation. To enable high-resolution cell-typing of each Strand-seq library, we generated single-cell MNase-seq reference datasets for eight distinct HSPCs. Subclonal mSVs frequently exhibit enrichment in myeloid progenitors, and single-cell multiomic analysis suggests that these mSVs result in recurrent dysregulation of pathways related to proliferation and metabolism, including Ras signaling and lipid metabolism. The comprehensive mSV landscape identified in this study implicates mSVs in cell type-specific molecular phenotypes, establishing a foundation for deciphering links between mSVs, aging, and disease risk.

genomics↗

bioRxiv2023

Time-varying Functional Connectivity Predicts Fluctuations in Sustained Attention in a Serial Tapping Task

The mechanisms for how large-scale brain networks contribute to sustained attention is unknown. Attention fluctuates from moment to moment and this continuous change is consistent with dynamic changes in functional connectivity between brain networks involved in the internal and external allocation of attention. In this study, we investigated how brain network activity varied across different levels of attentional focus (i.e., "zones"). Participants performed a finger-tapping task, and guided by previous research, in-the-zone performance or state was identified by low reaction time variability and out-of-the-zone as the inverse. Employing a novel method of time-varying functional connectivity, called the quasi-periodic pattern analysis (i.e., reliable network-level low-frequency fluctuations), we found that the activity between the default mode network (DMN) and task positive network is significantly more anti-correlated during in-the-zone states versus out-of-the-zone states. Furthermore, it is the fronto-parietal control network (FPCN) that drives this difference. Activity in the dorsal attention network (DAN) and DMN were desynchronized across both zone states. During in-the-zone periods, FPCN synchronized with DAN, while during out-of-the-zone periods, FPCN synchronized with DMN. In contrast, the ventral attention network synchronized more closely with DMN during in-the-zone periods compared to out-of-the-zone periods. These findings demonstrate that time-varying functional connectivity across different brain networks varies with fluctuations in sustained attention.

neuroscience↗