Biology subjects

Lv, J.

Publications and source records attributed to Lv, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Neural representational precision of distance predicts arithmetic performance

Focusing on the distance between magnitudes as the start point to investigate the mechanism of relationship detecting and its contribution to mathematical thinking, this study explores the precision of neural representations of numerical distance and their impact on arithmetic performance. By employing neural decoding techniques and representational similarity analysis, the present study investigates how accurately the brain represents numerical distances and how this precision relates to arithmetic skills. Thirty-two children participated, completing a dot number comparison task during fMRI scanning and an arithmetic fluency test. Results indicated that neural activation patterns in the intra-parietal sulcus decoded the distance between the presented pair of dots, and higher precision in neural distance representation correlates with better arithmetic performance. These findings suggest that the accuracy of neural decoding can serve as an index of the neural representation precision and that the ability to precisely encode numerical distances in the brain is a key factor in mathematical abilities. This provides new insights into the neural basis of mathematical cognition and learning. HighlightsO_LIUtilizing representational similarity analysis and neural decoding techniques, the research proposes that the accuracy of neural decoding serve as an index of neural representation precision. C_LIO_LIThe precision of neural representation of numerical distances in the brain predicts task performance and math arithmetic proficiency in children. C_LIO_LIThese findings imply the potential significance of relational information in general cognition and learning beyond mathematical learning. C_LI

neuroscience↗

bioRxiv2024

Multi-omics Reveals Immune Response and Metabolic Profiles during High-Altitude Mountaineering

The physiological perturbations induced by high-altitude exposure in mountain climbers, manifesting as metabolic and immunologic deviations, have been previously reported but are not fully understood. In this study, we obtained longitudinal multi-omic profiles of blood samples for healthy mountain climbers during two mountaineering stages (acclimatization and extreme altitude mountaineering). Our integrative assay included metabolomics and lipidomics profiling of plasma coupled with single-cell transcriptomic analysis of 375,722 immune cells. Longitudinal analysis revealed dynamic immune response profiles, during the acclimatization period, characterized by the downregulation of inflammatory responses in monocytes and classical dendritic cells (cDCs) and an increase in the proportion of cytotoxic CD8+ T cells with enhanced immune effector processes. In contrast, during extreme altitude mountaineering, the activation of inflammatory responses and impairment of T cell effector function were observed, concomitant with an increased cellular response to hypoxia and oxidative stress pathways. Furthermore, we found upregulated glycolysis and antioxidant gene expression during extreme altitude mountaineering, which was primarily orchestrated by HIF1A and NFE2L2, while decreased expression of these genes was observed in dysregulated plasmacytoid dendritic cells (pDCs). Finally, high-resolution plasma metabolic analysis revealed significant alterations in the metabolism of climbers, involving enhanced glutamine and fatty acid metabolism.

bioinformatics↗

bioRxiv2024

FLASH Irradiation Regulates IFN-β induction by mtDNA via Cytochrome c Leakage

Ultrahigh dose rate radiotherapy (FLASH-RT) is under intensive investigation for its biological benefits. The mechanisms underlying its ability to spare normal tissues while suppress tumor growth still remain controversial. Here we reveal that compared to the low dose rate electron irradiation (0.36 Gy/s), FLASH electron irradiation at 61 or 610 Gy/s enhances the cytochrome c leakage from mitochondria in human breast cells MCF-10A, which elicits substantial caspase activation, suppresses both the cytosolic mitochondrial DNA (mtDNA) accumulation and IFN-{beta} secretion. Besides, the deletion of mtDNA severely decreases the radiation-induced cGAS-STING activation. Conversely, the cytochrome c leakage in carcinoma cells MDA-MB-231 post electron irradiation is limited, especially for the case of FLASH irradiation, resulting in less cytosolic cytochrome c but stronger cGAS-STING activation than those in MCF-10A cells. The enhanced difference of cytochrome c leakage between cancer cells and normal cells post FLASH irradiation indicates a potential mechanism of FLASH effect by regulating the apoptotic and inflammatory pathway.

biophysics↗

bioRxiv2024

Large-scale statistical mapping of T-cell receptor β sequences to Human Leukocyte Antigens

T-cell receptors (TCRs) interacting with peptides presented by human leukocyte antigens (HLAs) are the foundation of the adaptive immune system but population-level analysis of TCR-HLA interactions is lacking. Here we statistically associate[~] 106 public TCRs to specific HLAs using the TCR{beta} repertoires sampled from 4,144 HLA-genotyped subjects. The TCRs we associate are specific to unique HLA allotypes, not allelic groups, and to the paired -{beta} heterodimer of class II HLAs though exceptions are observed. This specificity permits highly accurate imputation of 248 class I and II HLAs from the TCR{beta} repertoire. Notably, 45 HLA-DP and -DQ heterodimers lack associated TCRs because they likely arise from non-functional trans-complementation. The public class I and II HLA-associated TCRs we identify are primarily expressed on CD8+ and CD4+ memory T cells, respectively, which are responding to various common antigens. Our results recapitulate fundamental biology, provide insights into the functionality of HLAs and demonstrate the power and potential of population-level TCR repertoire sequencing.

immunology↗

bioRxiv2024

Natural selection exerted by historical coronavirus epidemic(s): comparative genetic analysis in China Kadoorie Biobank and UK Biobank

BackgroundPathogens have been one of the primary sources of natural selection affecting modern humans. The footprints of historical selection events - "selective sweeps" - can be detected in the genomes of present-day individuals. Previous analyses of 629 samples from the 1000 Genomes Project suggested that an ancient coronavirus epidemic [~]20,000 years ago drove multiple selective sweeps in the ancestors of present-day East Asians, but not in other worldwide populations. ResultsUsing a much larger genetic dataset of 76,719 unrelated individuals from each of the China Kadoorie Biobank (CKB) and UK Biobank (UKB) to identify regions of long-range linkage disequilibrium, we further investigated signatures of past selective sweeps and how they reflect previous viral epidemics. Using independently-curated lists of human host proteins which interact physically or functionally with viruses (virus-interacting proteins; VIPs), we found enrichment in CKB for regions of long-range linkage disequilibrium at genes encoding VIPs for coronaviruses, but not DNA viruses. By contrast, we found no clear evidence for any VIP enrichment in UKB. These findings were supported by additional analyses using saltiLASSi, a selection-scan method robust to false positives caused by demographic events. By contrast, for GWAS signals for SARS-Cov2 susceptibility (critical illness, hospitalisation, and reported infection), there was no difference between UKB and CKB in the number located at or near signals of selection, as expected for a novel virus which has had no opportunity to impact the CKB/UKB study populations. ConclusionsTogether, these results provide evidence of selection events consistent with historical coronavirus epidemic(s) originating in East Asia. These results show how biobank-scale datasets and evolutionary genomics theory can provide insight into the study of past epidemics. The results also highlights how historic infectious diseases epidemics can shape the genetic architecture of present-day human populations.

genomics↗

bioRxiv2024

Topology-informed regulatory element collections coordinate cell identity gene expression programs

Transcription proteins are concentrated at nuclear transcriptional condensates. These condensates contain cis-regulatory elements (CREs), including enhancers and promoters, that are thought to regulate genes in the same condensate. The roles of condensates are of great current interest, but research into their function is limited by an inability to comprehensively identify their associated CREs. Here, we present a conceptual framework and algorithm, BOUQUET, for integrating genome topology, chromatin occupancy, and graph theory to associate CREs and transcription protein machinery with target genes and identify exceptionally protein-rich communities that interact with condensates. BOUQUET uncovers surprising quantitative correlations between community protein accumulation and gene expression phenotypes by combining accurate CRE-gene assignment with co-activator binding profiles. A small subset of communities, which we call "3D-super-enhancers," is exceptionally protein-rich. BOUQUET-predicted 3D-SEs are comparable in number to co-activator nuclear puncta, and all genes known to interact with co-activator condensates in embryonic stem cells are within 3D-SEs. 3D-SEs are enriched for association with cell identity genes across mammalian tissues. Microscopy analyses show frequent co-localization and co-expression of genes from the same 3D-SE within a single co-activator punctum, suggesting 3D-SE components interact with co-activator condensates. Thus 3D-SEs correspond to co-activator puncta, which nominates additional condensate-associated genes and CREs.

molecular biology↗

bioRxiv2023

Expanding RNA editing toolkit using an IDR-based strategy

RNA base editors should ideally be free of immunogenicity, compact, efficient and specific, which has not been achieved for C>U editing. Here we first describe a compact C>U editor entirely of human origin, created by fusing the human C>U editing enzyme RESCUE-S to CIRTS, a tiny, human-originated programmable RNA binding domain. This editor, CIRTS-RESCUEv1 (V1), was inefficient. Remarkably, a short Histidine-Rich Domain (HRD), which is derived from the Internal Disordered Region (IDR) in the human CYCT1, a protein capable of liquid-liquid phase separation (LLPS), enhanced V1 editing at on-targets as well as off-targets, the latter effect being minor. The V1-HRD fusion protein formed puncta characteristic of LLPS, and various other IDRs (but not an LLPS-impaired mutant) could replace HRD to effectively induce puncta and potentiate V1, suggesting that the diverse domains acted via a common, LLPS-based mechanism. Importantly, the HRD fusion strategy was applicable to various other types of C>U RNA editors. Our study expands the RNA editing toolbox and showcases a general method for stimulating C>U RNA base editors.

molecular biology↗

bioRxiv2023

M1 Macrophage-Related Genes Model for NSCLC Immunotherapy Response Prediction

2.Patients diagnosed with non-small cell lung cancer have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for anti-tumor immunity. This study aimed to develop an immunotherapy response evaluation model for NSCLC patients based on transcriptional expression. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy were downloaded from POPLAR and OAK projects. Immune cell infiltration in NSCLC patients has been examined, and thereafter different co-expressed genes were identified. Following that, the impact of M1 macrophage related genes on the prognosis of NSCLC patients was investigated. Six M1 macrophage co-expression genes, namely NKX2-1, CD8A, SFTA3, IL2RB, IDO1, and CXCL9, exhibited a strong association with the prognosis of NSCLC and served as effective predictors for immunotherapy response. A response model was constructed using Cox regression model and Lasso Cox regression analysis. The M1 genes were validated on our previous TD- FOREKNOW NSCLC clinical trial by RT-qPCR. The response model showed excellent immunotherapy response predicting and prognosis evaluating value in advanced stage of NSCLC. The model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs.

immunology↗

bioRxiv2023

Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and non-human primates

Pathogenic mutations in the OTOF gene cause autosomal recessive hearing loss 9 (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed an OTOF gene therapy agent by dual AAV1 carrying human OTOF coding sequences with the expression driven by the hair cell-specific promoter Myo15, AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models by pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing in Otof -/- mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea although it was detected in other organs such as the central nervous system and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety of Myo15 promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear of Macaca fascicularis via the round window membrane. AAV1-GFP transduced 60-94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation.

genetics↗

bioRxiv2023

Reduced brain glutathione levels during normal aging are associated with visuospatial memory

During aging, the brain is subject to greater oxidative stress (OS), which is thought to play a critical role in cognitive impairment. Glutathione (GSH), as a major antioxidant in the brain, can be used to combatting OS. However, how brain GSH levels vary with age and their associations with cognitive function remain unclear. In this study, we combined point-resolved spectroscopy and edited spectroscopy sequences to investigate GSH levels in the anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), and occipital cortex (OC) of 276 healthy participants (166 females, age range 20-70 years) and examined their relationships with age and cognitive function. The results revealed decreased GSH levels with age in the PCC among all participants. Notably, the timecourse of GSH level changes in the PCC and ACC differed between males and females. Additionally, positive correlations were observed between GSH levels in the PCC and OC and visuospatial memory. Taken together, these findings enhance our understanding of the brain GSH timecourse during normal aging and associations with sex and memory, which is an essential first step for understanding the neurochemical underpinnings of OS-related diseases.

neuroscience↗

bioRxiv2023

High red/far-red ratio promotes root colonization of Serratia plymuthica A21-4 in tomato by root exudates-stimulated chemotaxis and biofilm formation

Effective colonization on plant roots is a prerequisite for plant growth promoting rhizobacterias (PGPR) to exert beneficial activities. Light is essential for plant growth, development and stress response. However, how light modulates root colonization of PGPR remains unclear. Here, we found that high red/far red(R/FR) light promoted and low R/FR light inhibited the colonization and growth enhancement of Serratia plymuthica A21-4 on tomato. Non-targeted metabolomic analysis of root exudates collected from different R/FR ratio treated tomato seedlings with A21-4 inoculation by ultra performance liquid chromatography-tandem mass spectrometry showed that 64 primary metabolites including amino acids, sugars and organic acids in high R/FR light-grown plants significantly increased compared with those determined for low R/FR light-grown plants. Among them, 7 amino acids, 1 organic acid and 1 sugar obviously induced the chemotaxis and biofilm formation of A21-4 compared to the control. Furthermore, exogenous addition of five artificial root exudate compontents (leucine, methionine, glutamine, 6-aminocaproic acid and melezitose) regained and further increased the colonization and growth promoting ability of A21-4 in tomato under low R/FR light and high R/FR light, respectively, indicating their involvement in high R/FR light-regulated the interaction of tomato root and A21-4. Taken together, our results, for the first time, clearly demonstrate that high R/FR light-induced root exudates play a key role in chemotaxis, biofilm formation and root colonization of A21-4. This study provides new insights into the interactions of plant-PGPR under different light conditions and can help promote the combined application of light supplementation and PGPR to facilitate crop growth and health in green agricultural production.

microbiology↗

bioRxiv2022

Alteration of pro-carcinogenic gut microbiota is associated with clear cell renal cell carcinoma tumorigenesis

Increasing evidence suggests that gut microbiota is involved in the occurrence and progression of urinary system diseases such as clear cell renal cell carcinoma (ccRCC). However, the mechanism of how alteration of gut metagenome promotes ccRCC remains unclear. Here we aim to elucidate the association of specific gut bacteria and their metabolites with ccRCC. In a pilot case-control study among 30 ccRCC patients and 30 healthy controls, 16S ribosomal RNA (rRNA) gene sequencing were analyzed from fecal samples collected prior to surgery or hospitalization. Alpha diversity and beta diversity analysis of the gut microbiota were performed, and differential taxa were identified by multivariate statistics. Meanwhile, serum metabolism was measured by UHPLC-MS, and differential genes were identified based on the TCGA database. Random Forests revealed the relative abundances of 20 species differed significantly between the RCC group and the Control group, among which 9 species, such as Desulfovibrionaceae, were enriched in the RCC group, and 11 species, such as four kinds of Lactobacillus, were less abundant. Concomitantly, serum level of taurine, which was considered to be consumed by Desulfovibrionaceae and released by Lactobacillus, has decreased in the RCC group. In addition, macrophage-related genes such as Gabbr1 was upregulated in ccRCC patients from our results. IMPORTANCETo our knowledge, few studies investigate the correlation of gut microbiota and ccRCC tumorigenesis. Overall, our sequencing data suggest that changes in the composition of specific gut microbiota, especially Lactobacillus and Desulfovibrionaceae, may be involved in ccRCC. Numerous serum metabolites, for example, taurine, which were modified in concert with dysregulation of gut microbiota, were associated with metabolic status during ccRCC development. Furthermore, through comparative analysis of clinical indicators, we found that gut dysbiosis could potentially reshape systemic inflammation, which participated in ccRCC tumorigenesis and we performed bioinformatics analysis to draw this conclusion. In Summary, it could be concluded from our study that the reduction of protective bacteria Lactobacillus, proliferation of sulfide-degrading bacteria Desulfovibrionaceae, reduction of taurine, and enrichment of macrophage related genes might be the risk predictors of ccRCC.

microbiology↗

bioRxiv2022

A host E3 ubiquitin ligase regulates Salmonella virulence by targeting an SPI-2 effector involved in SIF biogenesis

Salmonella Typhimurium creates an intracellular niche for its replication by utilizing a large cohort of effectors, including several that function to interfere with host ubiquitin signaling. Although the mechanism of action of many such effectors has been elucidated, how the interplay between the host ubiquitin network and bacterial virulence factors dictates the outcome of infection largely remains undefined. Here we found that the SPI-2 effector SseK3 inhibits SNARE pairing to promote the formation of Salmonella-induced filament by Arg-GlcNAcylation of SNARE proteins, including SNAP25, VAMP8, and Syntaxin. Further study reveals that host cells counteract the activity of SseK3 by inducing the expression of the ubiquitin E3 ligase TRIM32, which catalyzes K48-linked ubiquitination on SseK3 and targets its membrane-associated portion for degradation. Hence, TRIM32 antagonizes SNAP25 Arg-GlcNAcylation induced by SseK3 to restrict SIF biogenesis and Salmonella replication. Our study reveals a mechanism by which host cells inhibit bacterial replication by eliminating specific virulence factor.

cell biology↗

bioRxiv2022

Regulation of pDC Fate Determination by Histone Deacetylase 3

Dendritic cells (DCs), the key antigen-presenting cells, are primary regulators of immune responses. Transcriptional regulation of DC development had been one of the major research interests in DC biology, however, the epigenetic regulatory mechanisms during DC development remains unclear. Here, we report that Histone deacetylase 3 (Hdac3), an important epigenetic regulator, is highly expressed in pDCs, and its deficiency profoundly impaired the development of pDCs. Significant disturbance of homeostasis of hematopoietic progenitors was also observed in HDAC3-deficient mice, manifested by altered cell numbers of these progenitors and defective differentiation potentials for pDCs. Using the in vitro Flt3L supplemented DC culture system, we further demonstrated that HDAC3 was required for the differentiation of pDCs from progenitors at all developmental stages. Mechanistically, HDAC3 deficiency resulted in enhanced expression of cDC1-associated genes, owing to markedly elevated H3K27 acetylation (H3K27ac) at these gene sites in BM pDCs. In contrast, the expression of pDC-associated genes was significantly downregulated, leading to defective pDC differentiation. SummaryThis work reveals for the first time that HDAC3 is required for the development of pDCs and maintenance of homeostasis of hematopoietic progenitors with DC differentiation potential. Mechanistically, HDAC3 promotes pDC development by repressing the expression of cDC1 associated genes in a deacetylase dependent manner.

immunology↗

bioRxiv2022

Building a Tissue-unbiased Brain Template of Fibre Orientation Distribution and Tractography with Multimodal Registration

A brain template provides a standard space for statistical analysis of brain structure and function. For decades, the T1- and T2-weighted brain templates have been widely used for brain grey matter anatomical and functional analysis. However, T1- and T2-weighted templates provide very limited information about the axonal organization within the white matter. Recent advances in Diffusion MRI have enabled the detailed modelling of the axonal fibre orientation distribution (FOD) in white matter. Therefore, building a FOD template is essential for more robust white matter anatomy related analysis; however, it is important that this template aligns well with the cortical and subcortical structures. From such a FOD template, a tractography template can be also generated by fibre tracking algorithms, which can be used for subsequent applications, such as to perform the joint structural and functional analysis while ensuring rigorous fibre-to-fibre correspondence. In this paper, we explore the potential of generating the FOD template based on multimodal registration, in order to constrain the tempalte unbiased to both white and grey matter. We combine the information from T1-weighted, T2-weighted and Diffusion MRI to generate a coherent transformation for FOD registration and template generation. Our FOD template preserves the structural details at the white-grey matter boundary. To illustrate the benefit of this new approach, the resulting tractography template was used for joint structural-functional connectivity analysis.

neuroscience↗

bioRxiv2022

Highly efficient multiplex genome editing in dicot plants using improved CRISPR/Cas systems

CRISPR/Cas9-mediated gene editing provides a powerful tool for dissecting gene function and improving important traits in crops. However, there are still persisting challenges to obtain high homozygous/bi-allelic (ho/bi) mutations in dicot plants. Here, we develop an improved CRISPR/Cas9 system harboring a calreticulin-like gene promoter, which can boost targeted mutations in dicots. Additionally, the pDC45_dsg construct, combining a 35Spro-tRNA_sgRNA-EU unit and PCE8pro-controlled Cas9, can achieve more than 80.0% ho/bi mutations at target sites in allotetraploid tobacco. We construct pDC45_Fast system that can simultaneously fulfill gene editing and shorten the life span of T0 generation tobacco and tomato. This study provides new tools for improving targeted gene mutagenesis in dicots, and makes manipulations of genes in Solanum more feasible.

plant biology↗

bioRxiv2021

Anatomical connectivity along the anterior-posterior axis of the human hippocampus: new insights using quantitative fibre-tracking.

The hippocampus supports multiple cognitive functions including episodic memory. Recent work has highlighted functional differences along the anterior-posterior axis of the human hippocampus but the neuroanatomical underpinnings of these differences remain unclear. We leveraged track-density imaging to systematically examine anatomical connectivity between the cortical mantle and the anterior-posterior axis of the in-vivo human hippocampus. We first identified the most highly connected cortical areas and detailed the degree to which they preferentially connect along the anterior-posterior axis of the hippocampus. Then, using a tractography pipeline specifically tailored to measure the location and density of streamline endpoints within the hippocampus, we characterised where, within the hippocampus, these cortical areas preferentially connect. Our results were striking in showing that different parts of the hippocampus preferentially connect with distinct cortical areas. Furthermore, we provide evidence that both gradients and circumscribed areas of dense extrinsic anatomical connectivity exist within the human hippocampus. These findings inform conceptual debates in the field by unveiling how specific regions along the anterior-posterior axis of the hippocampus are associated with different cortical inputs/outputs. Overall, our results represent a major advance in our ability to map the anatomical connectivity of the human hippocampus in-vivo and inform our understanding of the neural architecture of hippocampal dependent memory systems in the human brain. This detailed characterization of how specific portions of the hippocampus anatomically connect with cortical brain regions may promote a better understanding of its role in cognition and we emphasize the importance of considering the hippocampus as a heterogeneous structure.

neuroscience↗

bioRxiv2021

Oxalic acid binds to gustatory receptor Gr23a and inhibits feeding in the brown planthopper

Plants produce diverse secondary compounds as natural protection against microbial and insect attack. Most of these compounds, including bitters and acids, are sensed by insect gustatory receptors (Grs). Acids are potentially toxic to insects, but there are few reports on sour compounds as ligands of insect Grs. Here, using two different heterologous expression systems, the insect Sf9 cell line and the mammalian HEK293T cell line, we started from crude extracts of rice (Oryza sativa) and successfully identified oxalic acid (OA) as a ligand of NlGr23a, a Gr in the brown planthopper Nilaparvata lugens. The antifeedant effect of OA on the brown planthopper was dose dependent, and NlGr23a is essential for OAs antifeedant activity in both artificial diets and rice plants. NlGr23a is also indispensable for tarsal OA sensing. To our knowledge, OA is the first identified ligand starting from plant crude extracts and the first known strong acid for insect Grs. These findings on rice-planthopper interactions will be of broad interest for pest control in agriculture and also for better understanding of how insects select host plants. Research organismNilaparvata lugens

ecology↗