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Biology subjects

Lei, B.

Publications and source records attributed to Lei, B..

13 recordsLinked to original sources

A Kernel-Spectral Index for Single-Neuron Input-Output Complexity

The computational capacity of individual neurons in the brain is a central problem in computational neuroscience and an increasingly relevant link between neuroscience and AI. Recent work fitting artificial neural networks to detailed cortical pyramidal neurons showed that reproducing their millisecond-precision input-output behavior can require temporal convolutional networks with five to eight layers, suggesting that cortical neurons may function as deep computational units inside brain circuits. Yet current quantitative studies of single-neuron complexity are largely surrogate-based; consequently, the obtained results are difficult to interpret, and the process often demands massive computational resources. We introduce the Spectral Complexity Index (SCI), a white-box measure that represents presynaptic histories with an explicit kernel geometry and quantifies how many ordered spectral modes are needed to explain somatic response energy. Across 35 biophysically detailed human and mouse cortical neuron models, SCI yields a statistically significant separation of the two species, strongly agrees with the DNN-based Functional Complexity Index on these cells (Spearman correlation: {rho}=0.797), and remains stable under sampling and kernel perturbations. Additionally, compared to existing methods such as FCI, the computational cost of SCI is reduced to approximately 1/10 or less. SCI turns single-neuron complexity from a black-box surrogate property into an interpretable spectral object, enabling reproducible, fast, and efficient comparisons of neuronal computation across cells and species.

neuroscience↗

Spacing effect improves generalization in biological and artificial systems

Generalization is a fundamental criterion for evaluating learning effectiveness, a domain where biological intelligence excels yet artificial intelligence continues to face challenges. In biological learning and memory, the well-documented spacing effect shows that appropriately spaced intervals between learning trials can significantly improve behavioral performance. While multiple theories have been proposed to explain its underlying mechanisms, one compelling hypothesis is that spaced training promotes integration of input and innate variations, thereby enhancing generalization to novel but related scenarios. Here we examine this hypothesis by introducing a bio-inspired spacing effect into artificial neural networks, integrating input and innate variations across spaced intervals at the neuronal, synaptic, and network levels. These spaced ensemble strategies yield significant performance gains across various benchmark datasets and network architectures. Biological experiments on Drosophila further validate the complementary effect of appropriate variations and spaced intervals in improving generalization, which together reveal a convergent computational principle shared by biological learning and machine learning.

neuroscience↗

Multi-omics analysis reveals genetic regulatory mechanismsof muscle traits in wild and domesticated Bactrian camels

Bactrian camels, large domesticated animals adapted to extreme environments, have evolved under natural and artificial selection to suit their living conditions and meet human needs. In arid and semi-arid regions, they provide valuable resources through economically important traits such as meat, milk, and wool production, contributing significantly to both economy and ecology. However, research on gene function, adaptive evolution, and molecular mechanisms underlying complex traits in Bactrian camels remains limited, constraining the full utilization of their breeding potential and conservation efforts.To address this gap, we performed whole-genome resequencing (WGS) on 35 domesticated Bactrian camels from the Chinese Sunite local population and integrated this data with publicly available WGS data from 112 Asian Bactrian camels. Our comprehensive analysis revealed significant genetic differences and genomic features between wild and domesticated Bactrian camels. We further integrated 27 epigenomic (ATAC-seq) and transcriptomic (RNA-seq) datasets from eight biologically important tissues of four Bactrian camels, along with skeletal muscle scRNA-seq and scATAC data. This allowed us to identify tissue-specific genes, regulatory elements, and genes under positive selection.Our integrated analysis identified target genes and their upstream regulatory elements, including potential regulatory transcription factors, with a focus on positively selected regions in Bactrian camel muscle tissue. We constructed regulatory pathways from key SNPs to regulatory elements to genes, and for the first time, identified regulatory elements in major tissues of the Bactrian camel genome. Our results also summarized the single-cell transcriptional landscape of Bactrian camel skeletal muscle, revealing cellular heterogeneity and genetic expression patterns across two developmental stages.This comprehensive regulatory element map provides a valuable resource for genetic and genomic studies in Bactrian camels. It reveals key regulatory networks, important genes, and regulatory elements influencing muscle development, as well as potentially significant functional variants affecting meat production traits. These findings will provide crucial data support for future genetic improvement and breeding efforts in Bactrian camels.

genetics↗

The m6A Reader ECT1 Mediates Seed Germination via the DAG2-ECT1-PHYB Regulatory Cascade in Arabidopsis

The N6-methyladenosine (m6A) RNA modification, a significant epitranscriptomic mark, is integral to plant growth and development. m6A reader proteins are capable of recognizing m6A modifications to impact RNA metabolic and biological processes. Here, we discovered ECT1 as an m6A reader protein that directly binds to the m6A site and plays a role in positively regulating seed germination in the context of gibberellins (GAs). ECT1 undergoes m6A modification to ensure its own stability and engages in self-interaction to enhance its protein stability. Moreover, ECT1 establishes a regulatory circuit with DAG2, which has been reported to play a positive regulatory role in GA-mediated seed germination. We found that DAG2 directly binds to the ECT1 promoter to control its transcription. ECT1 modulates the mRNA stability of DAG2. Furthermore, we identified PHYB, which encodes a key photoreceptor controlling GA-regulated seed germination, as a common downstream target of DAG2 and ECT1. DAG2 and ECT1 regulate the expression of PHYB at the transcriptional and post-transcriptional levels, respectively. ECT1 binds directly to PHYB, thereby influencing its stability. While DAG2 binds to the PHYB promoter to regulate its transcription. Together, these results unveil that ECT1 participates in the m6A signaling pathway through complex and multifaceted molecular mechanisms, broadening the spectrum of m6A reader functions and deepening our insight into the m6A signaling network in Arabidopsis.

plant biology↗

Multi-omics analysis reveals critical cis-regulatory roles of transposable elements in livestock genomes

As a major source of genetic and regulatory variation in their host genome, transposable elements (TEs) have gained a growing interest in research on humans and model organisms. In this species, integrative analysis of multi-omics data has shed light on the regulatory functions of TEs. However, there remains a notable gap in our understanding of TEs in domesticated animals. we annotated TEs in the genomes of pigs, cattle, and chickens, respectively, and systematically compared the genome distributions and amplification patterns of TEs across these three species. Furthermore, by integrating multi-tissue RNA-seq, ATAC-seq, and histone modification ChIP-seq data, we explored the expression atlas of TEs and their contribution to cis-regulatory elements (CREs) in different tissues of the three species. Most importantly, we developed a novel computational framework that revealed TE-mediated gene regulatory networks (TE-GRNs) underlying tissue-related biological processes. To demonstrate the power of this approach, we applied our framework to analyze liver tissues across the three different species. Overall, our research provides novel insights into the regulatory functions of TEs in livestock animals and highlights a computational framework to uncover TE-GRNs in various biological contexts.

genomics↗

Interrogation of inter-layer neuronal connectivity via cross-region all-optical physiology with high temporal resolution

The interrogation of functional neural circuits is crucial for uncovering how the brain works during diverse behaviors. Multi-plane neurophysiological measurement systems with high temporal resolution are indispensable, especially for dissecting inter-layer functional connectivity. Here, we develop a cross-layer all-optical physiology system (CLAOP) that enables the simultaneous recording and manipulation of single-neuron activities in multiple neuronal layers, with axial intervals as large as 530 m, at high temporal resolutions. Based on spatiotemporal multiplexing, our system enables all-optical analysis with a high frame rate up to 396 Hz and minimal time delay in inter-layer imaging and photostimulation, in both the mouse cortex and hippocampus in vivo. Combined with behavioral experiments, CLAOP provides all-optical evidence linking behavioral responses to neuronal connectivity in the primary visual cortex (V1) of live mice. Furthermore, we demonstrate that CLAOP can perturb the activity response of inter-layer cortical neurons to sensory stimuli according to their functional signatures. Overall, CLAOP provides an all-optical approach for mapping inter-layer connectivity at the single-neuron level and for modifying neuronal responses in behaving animals.

neuroscience↗

Integrating gene mutation spectra from tumors and the general population with gene expression topological networks to identify novel cancer driver genes

BackgroundUnderstanding the genetics underlying cancer development and progression is the most important goal of biomedical research to improve patient survival rates. Recently, researchers have proposed computationally combining the mutational burden with biological networks as a novel means to identify cancer driver genes. However, these approaches treated all mutations as having the same functional impact on genes and incorporated gene-gene interaction networks without considering tissue specificity, which may have hampered our ability to identify novel cancer drivers. MethodsWe have developed a framework, DGAT-cancer that integrates the predicted pathogenicity of somatic mutation in cancers and germline variants in the healthy population, with topological networks of gene expression in tumor tissues, and the gene expression levels in tumor and paracancerous tissues in predicting cancer drivers. These features were filtered by an unsupervised approach, Laplacian selection, and those selected were combined by Hotelling and Box-Cox transformations to score genes. Finally, the scored genes were subjected to Gibbs sampling to determine the probability that a given gene is a cancer driver. ResultsThis method was applied to nine types of cancer, and achieved the best area under the precision-recall curve compared to three commonly used methods, leading to the identification of 571 novel cancer drivers. One of the top genes, EEF1A1 was experimentally confirmed as a cancer driver of glioma. Knockdown of EEF1A1 led to a ~ 41-50% decrease in glioma size and improved the temozolomide sensitivity of glioma cells. ConclusionBy combining the pathogenic status of mutational spectra in tumors alongside the spectrum of variation in the healthy population, with gene expression in both tumors and paracancerous tissues, DGAT-cancer has significantly improved our ability to detect novel cancer driver genes.

bioinformatics↗

Dihydroartemisinin inhibits EMT of glioma via gene BASP1 in extrachromosomal DNA

The mechanism of dihydroartemisinin (DHA) inhibiting the migration and invasion of glioma in an ROS-DSB-dependent manner has been revealed. Extrachromosomal DNAs (ecDNAs) which are generated by DNA damage have great potential in glioma treatment. However, the role of ecDNAs in DHAs pharmacological mechanisms in glioma is still unknown. In this study, DHA was found to inhibit proliferative activity, increase ROS levels and promote apoptosis in U87 and U251 cells. Migration and invasion have also been suppressed. ecDNA expression profiles were found in gliomas. EcDNA-BASP1 was found, by means of bioinformatics analysis, to be present in GBM tissues and positively correlated with patient prognosis. Proliferation, migration and invasion were upregulated after knockdown of ecDNA-BASP1. The expression of vimentin and N-cadherin also had the same tendency. Finally, we found that the ecDNA-BASP1 content in nude mouse transplant tumors was significantly increased after DHA treatment, which might exert a better suppressive effect on glioma. The upregulation of tumor suppressor ecDNA-BASP1 played an important role in the suppression of glioma progression induced by DHA. EcDNA-BASP1 may inhibit glioma migration and invasion through repressing epithelial-mesenchymal transition (EMT).

cancer biology↗

Investigating racial disparities in carcinomas through TCGA transcriptomic and proteomic database

Simple Summary: Racial disparities in cancer incidence and outcome rates are prevalent in the US, with a variety of contributing factors such as socioeconomic status, differences in lifestyle and environmental exposures, and gene polymorphisms. The goal of this research was to broadly analyze public data to identify critical differences in molecular signatures and pathways between races. Additionally, to ensure the clinical translatability of our work, we analyzed the impact of these differences on patient survival. Our findings will help inform the use of novel biomarkers in clinical settings and the future development of precision therapies. Abstract:Epidemiological studies highlight a disparity in cancer incidence and outcome rates between racial groups in the United States. In our study, we investigated molecular differences among racial groups in 10 carcinoma types. We used publicly available data from The Cancer Genome Atlas to identify patterns of differential gene expression in tumors obtained from 4,112 White, Black/African American, and Asian patients. We identified race-dependent expression of numerous genes whose mRNA transcript levels were significantly correlated with patient survival. A small subset of these genes was differentially expressed in multiple carcinomas, including genes involved in cell cycle progression such as CCNB1, CCNE1, CCNE2, and FOXM1. In contrast, genes such as transcriptional factor ETS1 and apoptotic gene BAK1 were differ-entially expressed and clinically significant only in specific cancer types. Our analyses also revealed race-dependent regulation of relevant pathways. Importantly, homology directed repair and ERBB4-mediated nuclear signaling were both upregulated in Black patients compared to Whites in four carcinoma types. This large-scale pan-cancer study refines our understanding of the cancer health disparity and can help inform the use of novel biomarkers in clinical settings as well as the future development of precision therapies.

bioinformatics↗

VLA-4 suppression by senescence signals regulates meningeal immunity and leptomeningeal metastasis

Leptomeningeal metastasis is associated with dismal prognosis and has few treatment options. However, very little is known about the immune response to leptomeningeal metastasis. Here, by establishing an immunocompetent mouse model of breast cancer leptomeningeal metastasis, we found that tumor-specific CD8+ T cells were generated in deep cervical lymph nodes (dCLNs) and played an important role in controlling leptomeningeal metastasis. Mechanistically, T cells in dCLNs displayed a senescence phenotype and their recruitment was impaired in mice bearing cancer cells that preferentially colonized in leptomeningeal space. Upregulation of p53 suppressed the transcription of VLA-4 in senescent dCLN T cells and consequently inhibited their migration to the leptomeningeal compartment. Clinically, CD8+ T cells from cerebrospinal fluid of patients with leptomeningeal metastasis exhibited senescence and VLA-4 downregulation. Collectively, our findings demonstrated that CD8+ T cell immunosenescence drives leptomeningeal metastasis.

immunology↗

Crosstalk between H2A variant-specific modifications impacts vital cell functions

Histone variants are distinguished by specific substitutions and motifs that might be subject to post-translational modifications (PTMs). Compared with the high conservation of H3 variants, the N- and C-terminal tails of H2A variants are more divergent and are potential substrates for a more complex array of PTMs, which have remained largely unexplored. We used mass spectrometry to inventory the PTMs of the two heterochromatin-enriched variants H2A.W.6 and H2A.W.7 of Arabidopsis, which harbor the C-terminal motif KSPK. This motif is also found in macroH2A variants in animals and confers specific properties to the nucleosome. We showed that H2A.W.6 is phosphorylated by the cell cycle-dependent kinase CDKA specifically at KSPK. In contrast, this modification is absent on H2A.W.7, which also harbors the SQ motif associated with the variant H2A.X. Phosphorylation of the SQ motif is critical for the DNA damage response but is suppressed in H2A.W.7 by phosphorylation of KSPK. To identify factors involved in this suppression mechanism, we performed a synthetic screen in fission yeast expressing a mimic of the Arabidopsis H2A.W.7. Among those factors was the BRCT-domain protein Mdb1. We showed that phosphorylation of KSPK prevents binding of the BRCT-domain protein Mdb1 to phosphorylated SQ and as a result hampers response to DNA damage. Hence, cross-talks between motif-specific PTMs interfere with the vital functions of H2A variants. Such interference could be responsible for the mutual exclusion of specific motifs between distinct H2A variants. We conclude that sequence innovations in H2A variants have potentiated the acquisition of many specific PTMs with still unknown functions. These add a layer of complexity to the nucleosome properties and their impact in chromatin regulation.

synthetic biology↗

Adult newborn granule cells confer emotional-state-dependent plasticity in memory retrieval

Achieving optimal behavior requires animals to flexibly retrieve prior knowledge. Here we show that adult newborn granule cells (anbGCs) mediate emotional-state-dependent plasticity of memory retrieval. We find that acute social reward (aSR) enhances memory retrieval by increasing the reactivation of engram cells, while acute social stress (aSS) weakens retrieval and reduces the reactivation. Such bidirectional regulation relies on the activation of distinct populations of anbGCs by aSR and aSS, triggering opposing modifications of dDG activity, which is sufficient to regulate and predict the performance of memory retrieval. Concordantly, in emotional disorder models, aSR-dependent memory plasticity is impaired, while the effect of aSS remains intact. Together, our data revealed that anbGCs mediate plasticity of memory retrieval, allowing animals to flexibly retrieve memory according to the current emotional state, and suggested the essential roles of anbGCs in translating emotional information to the regulation of memory expression.

neuroscience↗

Hybrid origin of Populus tomentosa Carr. identified through genome sequencing and phylogenomic analysis

Populus tomentosa is widely distributed and cultivated in the Northern and Central China, where it is of great economic and ecological importance. However, the origin of P. tomentosa remains controversial. Here, we used a PacBio+Hi-C+Illumina strategy to sequence and assemble its 740.2 Mb (2n) genome. The assembly accounts for greater than 92.1% of the 800-megabase genome, comprises 38 chromosomes, and contains 59,124 annotated protein-coding genes. Phylogenomic analyses elucidated dynamic genome evolution events among its closely related white poplars, and revealed that tomentosa is comprised of two subgenomes, which we deomonstrate is likely to have resulted from hybridization between Populus adenopoda as the female, and Populus alba var. pyramidalis as the male, around 3.93 Mya. We also detected structural variations and allele-indels across genome. Our study presents a high quality and well assembled genome, unveils the origin of the widely distributed and planted P. tomentosa, and provides a powerful resource for comparative plant biology, breeding, and biotechnology.

genomics↗