Biology subjects

Dong, X.

Publications and source records attributed to Dong, X..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Stratifying variant deleteriousness and trait-modulating effect under human recent adaptation

Despite advances in annotating and interpreting human genetic variants, existing methods to distinguish deleterious/pathogenic from neutral variants still inadequately capture the nuanced impact of genetic variants on fitness and disease susceptibility. In this study, we introduced a new deep learning framework, the FIND model, by stratifying genetic variants into refined categories based on selection pressures and derived allele frequency. FIND demonstrated superior performance over existing genome-wide methods, delivering enhanced resolution in differentiating trait-modulating alleles from those that are pathogenic or neutral. Access to base-wise informative annotations has unveiled novel features that significantly enhance the model interpretability, and FIND has adeptly delineated evolutionary trends in human accelerated regions. Furthermore, applying FIND to the interpretation of clinical variants demonstrates its substantial potential in reclassifying variants of unknown significance. This work advances our understanding of the genetic underpinnings of human adaptation and disease, providing a new tool to explore the complexities of genetic contributions to health.

genetics↗

bioRxiv2024

Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis

The pathology of diabetic small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the skin during the stages of obesity and pre-diabetes. However, the initiation and progression of morphological and functional abnormalities in skin sensory nerves remains elusive. To address this, we utilized ear skin from mice with diet-induced obesity (DIO), the mouse models for obesity and pre-type 2 diabetes. We evaluated pain-associated wiping behavior and conducted ex vivo live Ca2+ imaging of the DIO ear skin to detect sensory hypersensitivity. Our findings reveal sensory hypersensitivity in skin nociceptive axons followed by axon degeneration. Further mechanistic analysis identified keratinocytes as a major source of nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptors through NGF-mediated signaling. Indeed, the local inactivation of NGF and its receptor TrkA-mediated downstream signaling, including the phosphoinositide 3-kinases (PI3K) pathway, suppresses sensory hypersensitivity in DIO skin. Thus, targeting these local interactions between keratinocytes and nociceptors offers a therapeutic strategy for managing neuropathic pain, avoiding the adverse effects associated with systemic interventions.

neuroscience↗

bioRxiv2024

Illuminating microbial phosphorus cycling in deep-sea cold seep sediments using protein language models

Phosphorus is essential for life and critically influences marine productivity. Despite geochemical evidence of active phosphorus cycling in deep-sea cold seep ecosystems, the microbial processes involved remain poorly understood. Traditional sequence-based searches often fail to detect proteins with remote homology. To address this, we developed a protein language model (PLM) named LucaPCycle that integrates sequence and structural information. This PLM-based approach identified 4,606 new phosphorus-cycling protein families based on the non-redundant gene and genome catalogs from global cold seeps, substantially enhancing our understanding of their diversity, ecology, and function. Among previously unannotated sequences, we discovered three novel alkaline phosphatase families (ALP1, ALP2 and ALP3) that feature unique domain organizations and preserved enzymatic capabilities. These results highlight previously overlooked ecological importance of phosphorus cycling within cold seeps, corroborated by data from porewater geochemistry, metatranscriptomics, and metabolomics. We identified a previously unrecognized diversity of archaea contributing to organic phosphorus mineralization and inorganic phosphorus solubilization through various mechanisms. This includes ecologically significant groups such as Asgardarchaeota, anaerobic methanotrophic archaea (ANME), and Thermoproteota. Additionally, viruses can enhance their hosts (e.g., ANME) phosphorus utilization through the PhoR-PhoB regulatory system and PhnCDE transporter, indirectly influencing methane dynamics. Overall, our PLM-based functional predictions are capable of accessing previously hidden sequence spaces for microbial phosphorus cycling, and can be applied to other various ecosystems.

microbiology↗

bioRxiv2024

Alpine lakes harbor diverse, endemic and structurally unique RNA viruses

Alpine lakes, characterized by isolation, low temperatures, oligotrophic conditions, and intense ultraviolet radiation, remain a poorly explored ecosystem for RNA viruses. Here, we present the first comprehensive metatranscriptomic study of RNA viruses in Lake Nam Co, a high-altitude alkaline saline lake on the Tibetan Plateau. Using a combination of sequence- and structure-based homology searches, we identified 742 RNA virus species, including 383 novel genus-level groups and 84 novel family-level groups exclusively found in Lake Nam Co. These findings significantly expand the known diversity of the Orthornavirae, uncovering evolutionary adaptations such as permutated RNA-dependent RNA polymerase (RdRP) motifs and distinct RNA secondary structures. Notably, 14 previously unknown RNA virus families potentially infecting prokaryotes were predicted, broadening the known host range of RNA viruses and questioning the traditional assumption that RNA viruses predominantly target eukaryotes. The presence of auxiliary metabolic genes (AMGs) in viral genomes suggested that RNA viruses (families f.0102 and Nam-Co_family_51) exploit host energy production mechanisms in energy-limited alpine lakes. Low nucleotide diversity, SNP frequencies, and pN/pS ratios indicate strong purifying selection in Nam Co viral populations. Our findings offer insights into RNA virus evolution and ecology, highlighting the importance of extreme environments in uncovering hidden viral diversity, and further shed light into their potential ecological implications, particularly in the context of climate change. Significance StatementThis study unveils the hidden diversity and complexity of RNA viruses in the high-altitude ecosystem of Lake Nam Co, significantly expanding the known RNA virome. The discovery of novel viral clades, expanded potential host ranges, and unique evolutionary adaptations emphasizes the importance of exploring extreme environments to uncover viral diversity and evolutionary pathways. Our findings offer critical insights into viral evolution, host-virus interactions, and the ecological roles of RNA viruses, particularly in the context of climate change and environmental resilience.

microbiology↗

bioRxiv2024

Wetland tree barks are dynamic hotspots for microbial trace gas cycling

Wetland tree stems have recently been shown to be a major source of methane emissions. However, the microbial communities associated within these stems (the caulosphere) and their contribution to biogeochemical cycling of methane and other compounds remain poorly understood. Here, we reveal that specialised microbial communities inhabit the bark of multiple Australian tree species and actively mediate the cycling of methane, hydrogen, and other climate-active trace gases. Based on genome-resolved metagenomics, most bark-associated bacteria are hydrogen metabolisers and facultative fermenters, adapted to dynamic redox and substrate conditions. Over three quarters of assembled genomes encoded genes for hydrogen metabolism, including novel lineages of Acidobacteriota, Verrucomicrobiota, and the candidate phylum JAJYCY01. Methanotrophs such as Methylomonas were abundant in certain trees and coexisted with hydrogenotrophic methanogenic Methanobacterium. Bark-associated microorganisms mediated aerobic oxidation of hydrogen, carbon monoxide, and methane at concentrations seen in planta, but under anoxic conditions barks could become a significant source of these gases. Field-based experiments and upscaling analysis suggested that bark communities are quantitatively significant mediators of global biogeochemical cycling, mitigating climatically-active gas emissions from stems and contributing to the net terrestrial sink of atmospheric hydrogen. These findings highlight the caulosphere as an important new research frontier for understanding microbial gas cycling and biogeochemistry.

microbiology↗

bioRxiv2024

Transcriptional pathobiology and multi-omics predictors for Parkinson's disease

Early diagnosis and biomarker discovery to bolster the therapeutic pipeline for Parkinsons disease (PD) are urgently needed. In this study, we leverage the large-scale whole-blood total RNA-seq dataset from the Accelerating Medicine Partnership in Parkinsons Disease (AMP PD) program to identify PD-associated RNAs, including both known genes and novel circular RNAs (circRNA) and enhancer RNAs (eRNAs). There were 1,111 significant marker RNAs, including 491 genes, 599 eRNAs, and 21 circRNAs, that were first discovered in the PPMI cohort (FDR < 0.05) and confirmed in the PDBP/BioFIND cohorts (nominal p < 0.05). Functional enrichment analysis showed that the PD-associated genes are involved in neutrophil activation and degranulation, as well as the TNF-alpha signaling pathway. We further compare the PD-associated genes in blood with those in post-mortem brain dopamine neurons in our BRAINcode cohort. 44 genes show significant changes with the same direction in both PD brain neurons and PD blood, including neuroinflammation-associated genes IKBIP, CXCR2, and NFKBIB. Finally, we built a novel multi-omics machine learning model to predict PD diagnosis with high performance (AUC = 0.89), which was superior to previous studies and might aid the decision-making for PD diagnosis in clinical practice. In summary, this study delineates a wide spectrum of the known and novel RNAs linked to PD and are detectable in circulating blood cells in a harmonized, large-scale dataset. It provides a generally useful computational framework for further biomarker development and early disease prediction. Significance statementEarly and accurate diagnosis of Parkinsons disease (PD) is urgently needed. However, biomarkers for early detection of PD are still lacking. Also, the limit of sample size remains one of the main pitfalls of current PD biomarker studies. We employed an analysis of large-scale whole-blood RNA-seq data. By identifying 1,111 significant marker RNAs, we establish a robust foundation for early PD detection, which implicated in neutrophil activation, degranulation, and TNF-alpha signaling, offer unprecedented insights into PD pathogenesis. Our multi-omics machine learning model, boasting an AUC of 0.89, outperforms previous studies, promising a transformative tool for precise PD diagnosis in clinical settings. This study marks a pivotal step toward enhanced biomarker development and early disease prediction.

neuroscience↗

bioRxiv2024

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

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

neuroscience↗

bioRxiv2024

Viral diversiy within marine biofilms and their potential roles in microbially influenced corrosion

In marine environments, a wide variety of microbes exert an important influence on the corrosion of materials. Viruses are widely distributed in biofilms formed on materials and may influence the corrosion process through interactions with key corrosive microbes. However, our understanding of the viral communities within biofilms and their implications for corrosion remains notably limited. To fill this knowledge gap, we utilized 53 publicly metagenomes to investigate the ecological dynamics of viruses within biofilms on 8 different materials and their potential roles in the corrosion of materials. In biofilms, the type of materials may be the primary factor driving differences in the diversity of viral communities. Viruses within biofilms predominantly belong to Caudoviricetes, and phylogenetic analysis of Caudoviricetes and protein-sharing networks with other environments revealed the presence of numerous novel viral clades in biofilms. The presence of virus-host linkages revealed a close association between viruses and corrosive microbes in biofilms. Viruses play a key role in corrosion by modulating host corrosion-related metabolism. It was observed that viruses could enhance host resistance to metals and antibiotics via horizontal gene transfer. Furthermore, viruses can protect themselves from host antiviral systems through anti-defense systems. Overall, this work illustrates the diversity of viruses within biofilms formed on materials and the intricate interactions between viruses and corrosive microbes, revealing the potential roles of viruses in microbially influenced corrosion.

microbiology↗

bioRxiv2024

Cold seeps are hotspots of deep-sea nitrogen-loss driven by microorganisms across 21 phyla

Nitrogen bioavailability, governed by the balance of fixation and loss processes, is a key factor regulating oceanic productivity, ecosystem functions, and global biogeochemical cycles. The key nitrogen-loss organisms--denitrifiers and anaerobic ammonium-oxidizing (anammox) bacteria--are not well understood in marine seafloor environments, especially in deep-sea cold seeps. In this study, we combined geochemical measurements, 15N stable isotope tracer analysis, metagenomics, metatranscriptomics, and three-dimensional protein structural simulations to investigate the diversity of denitrifying and anammox microbial communities and their biogeochemical roles in these habitats. Geochemical evidence from 301 sediment samples shows significantly higher nitrogen-loss rates in cold seeps compared to typical deep-sea sediments, with an estimated annual nitrogen loss of 6.16 Tg from seafloor surface sediments. Examination of a total of 147 million non-redundant genes reveals a high prevalence and active expression of nitrogen-loss genes, including nitrous-oxide reductase (NosZ; 6.88 genes per million or GPM on average), nitric oxide dismutase (Nod; 1.29 GPM), and hydrazine synthase (HzsA; 3.35 GPM) in surface sediments. Analysis of 3,164 metagenome-assembled genomes from this habitat has expanded the known diversity of nitrous-oxide reducers to six phyla and nitric oxide-dismutating organisms to one phylum and two new orders, while ten phyla host anammox bacteria going beyond Planctomycetota. These microbes show diverse structural adaptations and complex gene cluster arrangements that potentially enable survival in the harsh conditions of cold seeps. These findings suggest that cold seeps, despite their low temperatures, are significant, previously underestimated hotspots of nitrogen loss, potentially contribute substantially to the global nitrogen cycle.

microbiology↗

bioRxiv2024

Mitochondrial DNA is a sensitive surrogate and oxidative stress target in oral cancer cells

Cellular oxidative stress mediated by intrinsic and/or extrinsic reactive oxygen species (ROS) is associated with disease pathogenesis. Oxidative DNA damage can naturally be substituted by mitochondrial DNA (mtDNA), leading to base lesion/strand break formation, copy number changes, and mutations. In this study, we devised a single test for the sensitive quantification of acute mtDNA damage, repair, and copy number changes using supercoiling-sensitive quantitative PCR (ss-qPCR) and examined how oxidative stress-related mtDNA damage responses occur in oral cancer cells. We observed that exogenous hydrogen peroxide (H2O2) induced dynamic mtDNA damage responses, as reflected by early structural DNA damage, followed by DNA repair if damage did not exceed a particular threshold. However, high oxidative stress levels induced persistent mtDNA damage and caused a 5-30-fold depletion in mtDNA copy numbers over late responses. This dramatic depletion was associated with significant growth arrest and apoptosis, suggesting persistent functional consequences. Moreover, oral cancer cells responded differentially to oxidative injury when compared with normal cells, and different ROS species triggered different biological consequences under stress conditions. In conclusion, we developed a new method for the sensitive detection of mtDNA damage and copy number changes, with exogenous H2O2 inducing dynamic mtDNA damage responses associated with functional changes in stressed cancer cells. Finally, our method can help characterize oxidative DNA damage in cancer and other human diseases.

cancer biology↗

bioRxiv2024

Molecular Display of the Animal Meta-Venome for Discovery of Novel Therapeutic Peptides

Animal venoms, distinguished by their unique structural features and potent bioactivities, represent a vast and relatively untapped reservoir of therapeutic molecules. However, limitations associated with extracting or expressing large numbers of individual venoms and venom-like molecules have precluded their therapeutic evaluation via high throughput screening. Here, we developed an innovative computational approach to design a highly diverse library of animal venoms and "metavenoms". We employed programmable M13 hyperphage display to preserve critical disulfide-bonded structures for highly parallelized single-round biopanning with quantitation via high-throughput DNA sequencing. Our approach led to the discovery of Kunitz type domain containing proteins that target the human itch receptor Mas-related G protein-coupled receptor X4 (MRGPRX4), which plays a crucial role in itch perception. Deep learning-based structural homology mining identified two endogenous human homologs, tissue factor pathway inhibitor (TFPI) and serine peptidase inhibitor, Kunitz type 2 (SPINT2), which exhibit agonist-dependent potentiation of MRGPRX4. Highly multiplexed screening of animal venoms and metavenoms is therefore a promising approach to uncover new drug candidates.

molecular biology↗

bioRxiv2024

Human birth tissue products as a regenerative medicine to inhibit post-surgical pain through multi-modal action

Pain after surgery causes significant suffering. Opioid analgesics cause severe side effects and accidental death. Therefore, there is an urgent need to develop non-opioid therapies for managing post-surgical pain. Local application of Clarix Flo (FLO), a human amniotic membrane (AM) product, attenuated established post-surgical pain hypersensitivity without exhibiting known side effects of opioid use in mice. This effect was achieved through direct inhibition of nociceptive dorsal root ganglion (DRG) neurons via CD44-dependent pathways. We further purified the major matrix component, the heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3) from human AM that has greater purity and water solubility than FLO. HC-HA/PTX3 replicated FLO-induced neuronal and pain inhibition. Mechanistically, HC-HA/PTX3 induced cytoskeleton rearrangements to inhibit sodium current and high-voltage activated calcium current on nociceptive neurons, suggesting it is a key bioactive component mediating pain relief. Collectively, our findings highlight the potential of naturally derived biologics from human birth tissues as an effective non-opioid treatment for post-surgical pain. Moreover, we unravel the underlying mechanisms of pain inhibition induced by FLO and HC-HA/PTX3.

neuroscience↗

bioRxiv2024

Fast adaptive super-resolution lattice light-sheet microscopy for rapid, long-term, near-isotropic subcellular imaging

Lattice light-sheet microscopy (LLSM) provides a crucial observation window into intra- and inter-cellular physiology of living specimens with high speed and low phototoxicity, however, at the diffraction-limited resolution or anisotropic super-resolution with structured illumination. Here we present the meta-learning-empowered reflective lattice light-sheet virtual structured illumination microscopy (Meta-rLLS-VSIM), which instantly upgrades LLSM to a near-isotropic super resolution of [~]120-nm laterally and [~]160-nm axially, more than twofold improvement in each dimension, without any modification of the optical system or sacrifice of other imaging metrics. Moreover, to alleviate the tremendous demands on training data and time necessitated by existing deep-learning (DL) methods, we devised an adaptive online training approach by synergizing the front-end imaging system and back-end meta-learning framework, which reduced the total time for data acquisition and model training down to tens of seconds. With this method, a new model can be well-trained with tenfold less data and three orders of magnitude less time than current standard supervised learning. We demonstrate the versatile functionalities of Meta-rLLS-VSIM by imaging a variety of bioprocesses with ultrahigh spatiotemporal resolution for long duration of hundreds of multi-color volumes, characterizing the dynamic regulation of contractile ring filaments during mitosis and the growth of pollen tubes, and delineating the nanoscale distributions, dispersion, and interaction pattern of multiple organelles in embryos and eukaryotic cells.

biophysics↗

bioRxiv2024

Complete list of canonical post-transcriptional modifications in the Bacillus subtilis ribosome and their link to RbgA driven large subunit assembly

Ribosomal RNA modifications in prokaryotes have been sporadically studied, but there is a lack of a comprehensive picture of modification sites across bacterial phylogeny. B. subtilis is a preeminent model organism for gram-positive bacteria, with a well-annotated and editable genome, convenient for fundamental studies and industrial use. Yet remarkably, there has been no complete characterization of its rRNA modification inventory. By expanding modern MS tools for the discovery of RNA modifications, we found a total of 25 modification sites in 16S and 23S rRNA of B. subtilis, including the chemical identity of the modified nucleosides and their precise sequence location. Furthermore, by perturbing large subunit biogenesis using depletion of an essential factor RbgA and measuring the completion of 23S modifications in the accumulated intermediate, we provide a first look at the order of modification steps during the late stages of assembly in B. subtilis. While our work expands the knowledge of bacterial rRNA modification patterns, adding B. subtilis to the list of fully annotated species after E. coli and T. thermophilus, in a broader context, it provides the experimental framework for discovery and functional profiling of rRNA modifications to ultimately elucidate their role in ribosome biogenesis and translation.

microbiology↗

bioRxiv2024

Domain consolidation in Bacterial 50S assembly revealed by Anti-Sense Oligonucleotide Probing

Investigating the intricate and rapid folding kinetics of large RNA-protein complexes (RNPs), like the bacterial ribosome, remains a formidable challenge in structural biology. Previous genetic approaches to probe assembly have focused on modulating the expression of either r-proteins or assembly factors. Here, anti-sense oligonucleotides (ASOs) were used to disrupt native RNA/RNA and RNA/protein interactions, in order to generate novel folding intermediates. In an in vitro co-transcriptional assembly assay, 8 assembly inhibitor ASOs were identified. Using cryo-electron microscopy, 38 new intermediate structures were determined resulting from the specific inhibitions. In particular a novel intermediate class provided compelling evidence of independent rRNA domain folding before proper interdomain docking. Three PNAs targeting domain-I of 23S- rRNA further subdivided the previously identified assembly core into smaller blocks representing the earliest steps in assembly. The resulting assembly graph reveals template-directed RNA foldon docking and domain consolidation, which provides a hierarchical view of the RNP assembly process.

biochemistry↗

bioRxiv2024

Negative Selection Allows DNA Mismatch Repair-Deficient Mouse Fibroblasts In Vitro to Tolerate High Levels of Somatic Mutations

Substantial numbers of somatic mutations have been found to accumulate with age in different human tissues. Clonal cellular amplification of some of these mutations can cause cancer and other diseases. However, it is as yet unclear if and to what extent an increased burden of random mutations can affect cellular function without clonal amplification. We tested this in cell culture, which avoids the limitation that an increased mutation burden in vivo typically leads to cancer. We performed single-cell whole-genome sequencing of primary fibroblasts from DNA mismatch repair (MMR) deficient Msh2-/- mice and littermate control animals after long-term passaging. Apart from analyzing somatic mutation burden we analyzed clonality, mutational signatures, and hotspots in the genome, characterizing the complete landscape of somatic mutagenesis in normal and MMR-deficient mouse primary fibroblasts during passaging. While growth rate of Msh2-/-fibroblasts was not significantly different from the controls, the number of de novo single-nucleotide variants (SNVs) increased linearly up until at least 30,000 SNVs per cell, with the frequency of small insertions and deletions (INDELs) plateauing in the Msh2-/- fibroblasts to about 10,000 INDELS per cell. We provide evidence for negative selection and large-scale mutation-driven population changes, including significant clonal expansion of preexisting mutations and widespread cell-strain-specific hotspots. Overall, our results provide evidence that increased somatic mutation burden drives significant cell evolutionary changes in a dynamic cell culture system without significant effects on growth. Since similar selection processes against mutations preventing organ and tissue dysfunction during aging are difficult to envision, these results suggest that increased somatic mutation burden can play a causal role in aging and diseases other than cancer.

genomics↗

bioRxiv2024

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation

Background and ObjectiveProstate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. MethodsA novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Resultsunveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. ConclusionThe lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

cancer biology↗

bioRxiv2024

Assembly of the Bacterial Ribosome with Circularly Permuted rRNA

Co-transcriptional assembly is an integral feature of the formation of RNA-protein complexes that mediate translation. For ribosome synthesis, prior studies have indicated that the strict order of transcription of rRNA domains may not be obligatory during bacterial ribosome biogenesis, since a series of circularly permuted rRNAs are viable. In this work, we report the insights into assembly of the bacterial ribosome large subunit (LSU) based on cryo-EM density maps of intermediates that accumulate during in vitro ribosome synthesis using a set of circularly permuted (CiPer) rRNAs. The observed ensemble of twenty-three resolved ribosome large subunit intermediates reveals conserved assembly routes with an underlying hierarchy among cooperative assembly blocks. There are intricate interdependencies for the formation of key structural rRNA helices revealed from the circular permutation of rRNA. While the order of domain synthesis is not obligatory, the order of domain association does appear to proceed with a particular order, likely due to the strong evolutionary pressure on efficient ribosome synthesis. This work reinforces the robustness of the known assembly hierarchy of the bacterial large ribosomal subunit, and offers a coherent view of how efficient assembly of CiPer rRNAs can be understood in that context.

biophysics↗