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Deng, T.

Publications and source records attributed to Deng, T..

At least 19 recordsLinked to original sources

Canalized gene regulatory networks stabilize floral polymorphism and enable modular transgressive expression

O_LIFloral polymorphisms frequently persist across heterogeneous environments despite ongoing gene flow, yet the regulatory mechanisms maintaining discrete phenotypes remain unclear. We tested whether alternative flower-colour morphs in Stellera chamaejasme L. are maintained by canalized gene regulatory architectures that stabilize expression around morph-specific optima. C_LIO_LIWe used a pan-transcriptomic and eco-evolutionary framework integrating genome-wide gene expression profiling, co-expression network analysis, functional enrichment, ortholog-based phylogenomics, and variance-based modeling of regulatory canalization and transgressive expression to quantify regulatory variation across morphs. C_LIO_LITranscriptomic variation was structured primarily by morph identity rather than geography, indicating consistent morph-associated regulatory programs. Parental morphs showed reduced within-morph variance in gene co-expression modules, consistent with strong regulatory constraint at the network level. In contrast, a naturally occurring mosaic morph exhibited extensive non-additive and predominantly transgressive expression, with most genes falling outside the parental range. This transgressive signal was modular, with most networks remaining stable while a subset showed elevated variance and disrupted inheritance. Functional analyses further reveal that floral pigmentation is embedded within broader metabolic and stress-response pathways, linking color polymorphism to coordinated physiological states and ecological differentiation. C_LI

plant biology↗

Global Insights into Evolution and Adaptation in KPC and NDM Coproducing Carbapenem-Resistant Klebsiella pneumoniae.

ObjectivesThe worldwide dissemination of carbapenem-resistant Klebsiella pneumoniae co-producing KPC and NDM (KPC-NDM-CRKP) poses a substantial clinical challenge. MethodsThis study characterized 5 KPC-NDM-CRKP isolates from a tertiary hospital in southern China and integrated 460 global isolates genomes to demonstrate the population framework of this epidemic pathogen. Results5 clinical isolates were multidrug resistance, exhibiting high level resistance to first-line drugs including carbapenems and ceftazidime/avibactam. Globally, KPC-2-NDM-1 (50.3%) were the most common and an increasing trend of ST11-KL64 (20%) isolates carrying iucA and rmpA/A2. Resistance and virulence genes were positively associated with specific mobile elements including blaKPC-3 with Tn4401, iucABC with IncHI1B, iroBCDN with IncQ1. The phylogenetic analysis revealed distinct lineage-specific mutations and pan-genome enrichments synergistically promoted adaptive evolution: cluster 1 had membrane transport and secretion but enhanced immune evasion and horizontal gene transfer, cluster 3 adapted metabolically for nutrient-limited niches; cluster 4 reprogrammed metabolism for host adaptation, cluster 6 displayed membrane repair and reduced virulence (e.g., KC187). High-risk iucA/rmpA-positive isolates in cluster 2 acquired enhanced virulence and metabolic adaptive capacity through recombination hotspots (ABC transporters DdpABCD, efflux systems MdtABCD, metabolic enzymes XylB and MtlD, regulators BaeR and OmpR) and pan-genome enrichment (siderophore biosynthesis, toxin-antitoxin VapC and restriction-modification systems). Functionally, these traits correlated with high mucoviscosity, serum resistance, siderophore production and lower survival rates in G. mellonella that contribute to epidemiological success. ConclusionsThese findings demonstrated the discrete mutation, horizontal transfer, and accessory genome plasticity collectively drove the epidemiological success of KPC-NDM-CRKP.

microbiology↗

A CRISPR/Cas9-based system using dual-sgRNAs for efficient gene deletion in Mycobacterium abscessus

The increasing global prevalence of Mycobacterium abscessus infections presents a significant clinical challenge due to the pathogens intrinsic resistance to multiple antibiotics and poor treatment outcomes. Despite the necessity of genetic tools for studying its physiology, pathogenesis, and drug resistance, efficient methods for large-fragment deletions remain underdeveloped. Here, we report a CRISPR/Cas9-based dual-sgRNA system employing Streptococcus thermophilus CRISPR1-Cas9 (Sth1Cas9), enabling efficient large-fragment knockout in M. abscessus with deletion efficiencies exceeding 90% at certain loci and spanning up to 16.7 kb. Furthermore, we systematically optimized the modular arrangement of genetic components in Cas9/dual-sgRNA expression plasmids and refined their construction workflow, achieving a significant reduction in cassette loss rates while enabling single-step plasmid assembly. Notably, deletion efficiency was position-dependent rather than correlated with target size, suggesting an influence of chromatin structure on editing outcomes. As the first CRISPR/Cas9-based platform capable of kilobase-scale deletions in M. abscessus, this system advances functional genomics studies and facilitates targeted investigations into virulence and antibiotic resistance mechanisms.

microbiology↗

Cocktail Chemical Labeling for In-Depth Surfaceome Profiling of Bone-Marrow Derived Dendritic Cells

Cell surface proteins (CSPs) are crucial identifiers for cell types and states, especially in dendritic cells (DCs). Current proteomic methods for profiling CSPs are limited by their hydrophobic nature and low abundance, which often require genetic or cell surface engineering and exhibit biased and insufficient labeling efficiency. Herein, we report [Ru(bpy)3]Cl2 (Ru) for effective biotinylation on the cell surfaceome via a simple "mix and lighten" method. The versatile photoredox pathways of Ru are leveraged using a probe cocktail of biotin-phenol and biotin-hydrazide for improved substrate coverage. The "cocktail" labeling strategy results in reproducible identification of up to 733 plasma membrane proteins on HeLa cells, and is further applied to map dynamic changes in the surfaceome during the differentiation of primary bone marrow-derived dendritic cells, which demonstrates a user-friendly and deep-surfaceome-coverage tool for profiling dynamic changes in primary cells, with potential implications for cell identities, functional states, and novel drug targets.

cell biology↗

LEGEND: Identifying Co-expressed Genes in Multimodal Transcriptomic Sequencing Data

Identifying co-expressed genes across tissue domains and cell types is essential for revealing co-functional genes involved in biological or pathological processes. While both single-cell RNA-sequencing (scRNA-seq) and spatially-resolved transcriptomic (SRT) data offer insights into gene co-expression patterns, current methods typically utilize either data type alone, potentially diluting the co-functionality signals within co-expressed gene groups. To bridge this gap, we introduce LEGEND, a novel computational method that integrates scRNA-seq and SRT data for identifying groups of co-expressed genes at both cell type and tissue domain levels. LEGEND employs an innovative hierarchical clustering algorithm designed to maximize intra-cluster redundancy and inter-cluster complementarity, effectively capturing more nuanced patterns of gene co-expression and spatial coherence. Enrichment and cofunction analyses further showcase the biological relevance of these gene clusters, and their utilities in exploring context-specific novel gene functions. Notably, LEGEND can reveal shifts in gene-gene interactions under different conditions, furnishing insights for disease-associated gene crosstalk. Moreover, LEGEND can be utilized to enhance the annotation accuracy of both spatial spots in SRT and single-cells in scRNA-seq, and pioneers in identifying genes with designated spatial expression patterns. LEGEND is available at https://github.com/ToryDeng/LEGEND.

genomics↗

The theory of massively repeated evolution and full identifications of Cancer Driving Nucleotides (CDNs)

Tumorigenesis, like most complex genetic traits, is driven by the joint actions of many mutations. At the nucleotide level, such mutations are Cancer Driving Nucleotides (CDNs). The full sets of CDNs are necessary, and perhaps even sufficient, for the understanding and treatment of each cancer patient. Currently, only a small fraction of CDNs is known as most mutations accrued in tumors are not drivers. We now develop the theory of CDNs on the basis that cancer evolution is massively repeated in millions of individuals. Hence, any advantageous mutation should recur frequently and, conversely, any mutation that does not is either a passenger or deleterious mutation. In the TCGA cancer database (sample size n = 300 - 1000), point mutations may recur in i out of n patients. This study explores a wide range of mutation characteristics to determine the limit of recurrences (i*) driven solely by neutral evolution. Since no neutral mutation can reach i* = 3, all mutations recurring at i [&ge;] 3 are CDNs. The theory shows the feasibility of identifying almost all CDNs if n increases to 100,000 for each cancer type. At present, only < 10% of CDNs have been identified. When the full sets of CDNs are identified, the evolutionary mechanism of tumorigenesis in each case can be known and, importantly, gene targeted therapy will be far more effective in treatment and robust against drug resistance.

evolutionary biology↗

On the discovered Cancer Driving Nucleotides (CDNs)-Distributions across genes, cancer types and patients

A central goal of cancer genomics is to identify, in each patient, all the cancer driving mutations. Among them, point mutations are referred to as Cancer Driving Nucleotides (CDNs), which recur in cancers. The companion study shows that the probability of i recurrent hits in n patients would decrease exponentially with i; hence, any mutation with i [&ge;] 3 hits in the TCGA database is a high-probability CDN. This study characterizes the 50[~]150 CDNs identifiable for each cancer type of TCGA (while anticipating 10 times more undiscovered ones) as follows: i) CDNs tend to code for amino acids of divergent chemical properties. ii) At the genic level, far more CDNs (>5-fold) fall on non-canonical than canonical cancer driving genes (CDGs). Most undiscovered CDNs are expected to be on unknown CDGs. iii) CDNs tend to be more widely shared among cancer types than canonical CDGs, mainly because of the higher resolution at the nucleotide than the whole-gene level. iv) Most important, among the 50[~]100 coding region mutations carried by a cancer patient, 5[~]8 CDNs are expected but only 0[~]2 CDNs have been identified at present. This low level of identification has hampered functional test and gene targeted therapy. We show that, by expanding the sample size to 105, most CDNs can be identified. Full CDN identification will then facilitate the design of patient-specific targeting against multiple CDN-harboring genes.

evolutionary biology↗

African Swine Fever Virus Protein B263R Inhibits Autophagy by Promoting Proteasomal Degradation of Beclin1

African swine fever (ASF) is a highly contagious viral disease that affects both domestic and wild pigs, leading to substantial economic losses in the swine industry. However,the precise role of ASFV-encoded viral protein in viral replication and disease has remained elusive. In our study, we elucidated that B263R inhibited autophagy by interacting with Beclin1. Mechanistically, the binding of B263R to Beclin1 promotes its degradation through the mediation of K48-linked ubiquitination at site K31. Notably, the knockdown of Beclin1 mitigated the effect of B263R on reducing the levels of LC3-II, thus further affirming the pivotal role of Beclin1 in B263R-mediated autophagy inhibition. The proliferation of recombinant adenovirus inherently expressing B263R significantly decreased, underscoring the inherent role of B263R-mediated autophagy in virus replication. These findings shed light on the molecular mechanisms employed by ASFV to evade host cell autophagic defenses and offered potential targets for therapeutic interventions against ASFV infection. IMPORTANCEUnderstanding the mechanisms underlying the evasion of host cellular defenses by the African swine fever virus (ASFV) is of pivotal significance owing to its profound impact on the global swine industry. The precise functional roles of ASFV proteins in virus replication and disease remain incompletely characterized. In this study, it is demonstrated that a specific ASFV protein, B263R, acts to inhibit autophagy by interacting with Beclin1, thereby facilitating its degradation. The elucidation of this molecular pathway not only advances our comprehension of ASFV pathogenesis but also furnishes potential targets for therapeutic interventions against ASFV infection. By unraveling the intricate interplay between ASFV and host cell autophagy, this scholarly endeavor contributes invaluable insights to the development of strategies aimed at mitigating the spread of ASFV and minimizing its adverse repercussions on the swine industry.

microbiology↗

Longer mandible or nose? Co-evolution of feeding organs in early elephantiforms

The long-trunked elephantids underwent a significant evolutionary stage characterized by an exceptionally elongated mandible. The initial elongation and subsequent regression of the long mandible, along with its co-evolution with the trunk, present an intriguing issue that remains incompletely understood. Through comparative functional and eco-morphological investigations, as well as feeding preference analysis, we reconstructed the feeding behavior of major groups of longirostrine elephantiforms. In the Platybelodon clade, the rapid evolutionary changes observed in the narial region, strongly correlated with mandible and tusk characteristics, suggest a crucial evolutionary transition where feeding function shifted from the mandible to the trunk, allowing proboscideans to expand their niches to more open regions. This functional shift further resulted in elephantids relying solely on their trunks for feeding. Our research provides insights into how unique environmental pressures shape the extreme evolution of organs, particularly in large mammals that developed various peculiar adaptations during the late Cenozoic global cooling trends.

paleontology↗

Genomic underpinnings of convergent adaptation to high altitudes for alpine plants

Evolutionary convergence is one of the most striking examples of adaptation driven by natural selection. However, genomic evidence for convergent adaptation to extreme environments remains scarce. The Himalaya-Hengduan Mountains represent the worlds most species-rich temperate alpine biota, providing an ideal "natural laboratory" for studying convergent adaptation to high altitudes. Here, we generate reference genomes for two alpine plants, Saussurea obvallata (Asteraceae) and Rheum alexandrae (Polygonaceae), with 37,938 and 61,463 annotated protein-coding genes. By integrating an additional five alpine genomes, we investigate genomic signatures of convergent adaptation to the hostile environments of high altitudes. We show that alpine genomes tend to mitigate their genetic load by contracting genes functioning in the immune system to survive such harsh environments with few pathogens present. We detect signatures of convergent positive selection on a set of genes involved in reproduction and development and reveal that molecular convergence has acted on genes involved in self-incompatibility, cell wall modification, DNA repair and stress resistance, which underlie adaptation to extremely cold, high UV radiation and hypoxia environments. Using gene expression profiles, we further demonstrate that genes associated with cuticular wax and flavonoid biosynthetic pathways exhibit higher expression levels in leafy bracts, shedding lights on the genetic mechanisms of the adaptive greenhouse morphology. Our integrative data provide genomic insights into the convergent evolution at higher-taxonomic levels, aiding in deep understanding of genetic adaptation to complex environments.

evolutionary biology↗

Survival of mineral-bound peptides into the Miocene

The oldest authenticated peptide sequences to date were reported in 2016 from 3.8 Ma old ostrich eggshell (OES) from the site of Laetoli, Tanzania (Demarchi et al., 2016). Here we demonstrate survival of the same sequences in 6.5-9 Ma OES recovered from a palaeosteppe setting in northwestern China. The eggshell is thicker than those observed in extant species and consistent with the Liushu Struthio sp. ootaxon. These findings push the preservation of ancient proteins back to the Miocene and highlight their potential for paleontology, paleoecology and evolutionary biology.

paleontology↗

A Comprehensive Roadmap of Human Placental Development in vitro

Human pluripotent stem cells (hPSCs) represent a powerful model system to study early developmental processes. However, lineage specification into trophectoderm (TE) remains poorly understood and access to well-characterized placental cells for biomedical research is limited, largely depending on fetal tissues or cancer cell lines. Here, we developed novel strategies enabling highly efficient TE specification that generates cytotrophoblast (CTB) and multinucleated primary syncytiotrophoblast (STB) followed by establishment of trophoblast stem cells (TSCs) capable of differentiating into extravillous trophoblast (EVT) and STB after long-term expansion. We confirmed stepwise induction of lineage- and cell-type-specific genes and substantiated typical features of placental cells using morphological, biochemical, integrated multi-omics, and single-cell analyses. Our data provide conclusive evidence that conventional hPSCs can be directly and exclusively converted into TE, thereby providing an unlimited source of diverse placental cell types suitable for a broad range of biomedical applications.

developmental biology↗

Scalable Generation of Pseudo-Unipolar Sensory Neurons from Human Pluripotent Stem Cells

Development of new non-addictive analgesics requires advanced strategies to differentiate human pluripotent stem cells (hPSCs) into relevant cell types amenable for translational research. Here, we developed a highly efficient and reproducible method that differentiates hPSCs into peptidergic and non-peptidergic nociceptors. By modulating specific cell signaling pathways, hPSCs were first converted into SOX10+ neural crest cells, followed by differentiation into sensory neurons with an in vivo-like pseudo-unipolar morphology. Detailed characterization confirmed that the hPSC-derived nociceptors displayed molecular and cellular features comparable to native dorsal root ganglion (DRG) neurons, and expressed high-threshold primary sensory neuron markers, transcription factors, neuropeptides, and over 150 ion channels and receptors, including critical pain-relevant drug targets (e.g., TRPV1, TAC1, CALCA, NAV1.7, NAV1.8). Moreover, after confirming robust functional activities and differential response to noxious stimuli and specific drugs, a robotic cell culture system was employed to produce large quantities of human sensory neurons, which can be used to develop nociceptor-selective analgesics.

developmental biology↗

Enhancing the Fitness of Embryoid Bodies and Organoids by Chemical Cytoprotection

Embryoid bodies (EBs) and self-organizing organoids derived from human pluripotent stem cells (hPSCs) recapitulate tissue development in a dish and hold great promise for disease modeling and drug development. However, current protocols are hampered by cellular stress and apoptosis during cell aggregation, resulting in variability and impaired cell differentiation. Here, we demonstrate that EBs and various organoid models (e.g., brain, gut, and kidney) can be optimized by using the CEPT small molecule cocktail, a polypharmacology approach that ensures cytoprotection and cell survival. Application of CEPT (chroman 1, emricasan, polyamines, trans-ISRIB) for just 24 hours during cell aggregation has long-lasting consequences affecting morphogenesis, gene expression, and cellular differentiation. Various qualification methods confirmed that CEPT treatment consistently improved EB and organoid fitness as compared to the widely used ROCK inhibitor Y-27632. Collectively, we discovered that stress-free cell aggregation and superior cell survival in the presence of CEPT are critical quality control determinants that establish a robust foundation for bioengineering complex tissue and organ models.

developmental biology↗

Reconstructing phylogeny of the hornless rhinoceros Aceratheriinae

This study presents the first phylogenetic analysis focused on the Subfamily Aceratheriinae to date, with 391 characters coded from 43 taxa at the species level. We added 77 newly defined and 33 revised characteristics, including features of the skull, teeth, and postcranial bones. In the present analysis, the tribe Teleoceratini, as well as the tribe Aceratheriini, was reclassified within Aceratheriinae, however, the traditionally established monophyly of each tribe was decomposed. Combined with detailed morphological comparisons, we reconstructed the phylogeny of Aceratheriinae and revised the diagnosis of Aceratheriinae. The reported skull and teeth specimens of Turkanatherium from the late Early Miocene indicate that it is not an acerathere and has been placed as a basal rhinocerotid. The Aceratheriinae has undergone evolutionary adaptation several times during the early stage of evolution, and several genera from the Oligocene to the Early Miocene have been reconstructed as early diverging taxa, such as Molassitherium, Protaceratherium, Plesiaceratherium and Chilotheridium; Aprotodon and Mesaceratherium from the Late Oligocene to the Early Miocene were united as the earliest divergent clade of Aceratheriinae; meanwhile, due to the limited materials, the phylogenies of Floridaceras and Dromoceratherium are unstable in this analysis, and both have been tentatively considered as the early diverging clades of Aceratheriinae. Alicornops was reclassified a member of Teleoceratini. Aceratheriini and Teleoceratini have been redefined as two highly specialized groups. Furthermore, Aceratheriini has been divided into two/three clades based on the difference in the skull outlines and the occlusal patterns of the cheek teeth.

paleontology↗

Molecular Mechanisms for Frequency Specificity in a Drosophila Hearing Organ

Discrimination for sound frequency is essential for auditory communications in animals. Here, by combining in vivo calcium imaging and behavioral assay, we found that Drosophila larvae can sense a wide range of sound frequency and the behavioral specificity is mediated with the selectivity of the lch5 chordotonal organ neurons to sounds that forms a combinatorial coding of frequency. We also disclosed that Brivido1 (Brv1) and Piezo-like (Pzl), each expresses in a subset of lch5 neurons and mediate hearing sensation to certain frequency ranges. Intriguingly, mouse Piezo2 can rescue pzl-mutants phenotypes, suggesting a conserved role of the Piezo family proteins in high-frequency hearing.

neuroscience↗

A DNA Replication-Independent Function of the pre-Replication Complex during Cell Invasion in C. elegans

Cell invasion is an initiating event during tumor cell metastasis and an essential process during development. A screen of C. elegans orthologs of genes over-expressed in invasive human melanoma cells has identified several components of the conserved DNA pre-replication complex (pre-RC) as positive regulators of anchor cell (AC) invasion. The pre-RC functions cell-autonomously in the G1-arrested AC to promote invasion, independently of its role in licensing DNA replication origins in proliferating cells. While the helicase activity of the pre-RC is necessary for AC invasion, the downstream acting DNA replication initiation factors are not required. The pre-RC promotes the invasive fate by regulating the expression of extracellular matrix genes and components of the PI3K signaling pathway. Increasing PI3K pathway activity partially suppressed the AC invasion defects caused by pre-RC depletion, suggesting that the PI3K pathway is one critical pre-RC target. We propose that the pre-RC acts in the non-proliferating AC as a transcriptional regulator that facilitates the switch to an invasive phenotype.

cell biology↗

gcaPDA: A Haplotype-resolved Diploid Assembler

Generating chromosome-scale haplotype resolved assembly is important for functional studies. However, current de novo assemblers are either haploid assemblers that discard allelic information, or diploid assemblers that can only tackle genomes of low complexity. Here, we report a diploid assembler, gcaPDA (gamete cells assisted Phased Diploid Assembler), which exploits haploid gamete cells to assist in resolving haplotypes. We generate chromosome-scale phased diploid assemblies for the highly heterozygous and repetitive genome of a maize F1 hybrid using gcaPDA and evaluate the assembly result thoroughly. With applicability of coping with complex genomes and fewer restrictions on application than other diploid assemblers, gcaPDA is likely to find broad applications in studies of eukaryotic genomes.

genomics↗