Biology subjects

Xu, X.

Publications and source records attributed to Xu, X..

At least 289 records · Page 16Linked to original sources

bioRxiv2024

Stiffness-tunable neurotentacles for minimally invasive implantation and long-term neural activity recordings

Flexible implantable microelectrodes have been demonstrated to exhibit excellent biocompatibility for chronic neural activity recordings. However, the low bending strength of the commonly employed flexible materials presents a significant challenge for probe insertion into the brain. Traditional implantation methods for flexible electrodes generally require additional auxiliary materials or tools, which tend to have a much larger footprint than the probes themselves, greatly increasing the damage to neurons during insertion. Here we have proposed a stiffness-tunable polyimide probe for deep brain implantation, referred to as Neurotentacle, enabled by embedded microchannels in which the liquid pressure is controllable (from 0.1MPa to more than 2.0MPa). During the insertion phase into the brain, the neurotentacle can pose a high stiffness under elevated internal pressure to penetrate the brain tissues without the use of any additional materials or tools. Once the device has been successfully inserted, it can regain its flexibility by reducing the internal pressure. Importantly, the novel multilayer microfabrication process keeps the structural dimensions of the neurotentacle similar to those of a regular flexible probe. Therefore, the neurotentacle can produce an extremely low level of damage to brain tissue during its insertion phase, while extending its long-term biocompatibility and stability, which has been experimentally verified in histological evaluations conducted on both acute and chronic animal specimens. In addition, the chronically implanted neurotentacles enabled stable neural activity recordings in mice with an average spike yield of 96% and an average signal-to-noise ratio of 15.2. The proposed neurotentacle does not necessitate the use of complex devices and its insertion process is straightforward and highly controllable, thus rendering it an appealing technique for minimally invasive implantation and long-term neural recording of flexible electrodes.

neuroscience↗

bioRxiv2024

Spatial Transcriptomics and Single-Nucleus Multi-omics Analysis Revealing the Impact of High Maternal Folic Acid Supplementation on Offspring Brain Development

Folate, an essential vitamin B9, is crucial for diverse biological processes including neurogenesis. Folic acid (FA) supplementation during pregnancy is a standard practice for preventing neural tube defects (NTDs). However, concerns are growing over the potential risks of excessive maternal FA intake. Here, we employed mouse model and spatial transcriptomics and single-nucleus multi-omics approaches to investigate the impact of high maternal FA supplementation during the periconceptional period on offspring brain development. Maternal high FA supplementation affected gene pathways linked to neurogenesis and neuronal axon myelination across multiple brain regions, as well as gene expression alterations related to learning and memory in thalamic and ventricular regions. Single-nucleus multi-omics analysis revealed that maturing excitatory neurons in the dentate gyrus (DG) are particularly vulnerable to high maternal FA intake, leading to aberrant gene expressions and chromatin accessibility in pathways governing ribosomal biogenesis critical for synaptic formation. Our findings provide new insights into specific brain regions, cell types, gene expressions and pathways that can be affected by maternal high FA supplementation.

neuroscience↗

bioRxiv2024

The impact of Library Size and Scale of Testing on Virtual Screening

Virtual libraries for ligand discovery have recently increased 10,000-fold, and this is thought to have improved hit rates and potencies from library docking. This idea has not, however, been experimentally tested in direct comparisons of larger-vs-smaller libraries. Meanwhile, though libraries have exploded, the scale of experimental testing has little changed, with often only dozens of high-ranked molecules investigated, making interpretation of hit rates and affinities uncertain. Accordingly, we docked a 1.7 billion molecule virtual library against the model enzyme AmpC {beta}-lactamase, testing 1,521 new molecules and comparing the results to the same screen with a library of 99 million molecules, where only 44 molecules were tested. Encouragingly, the larger screen outperformed the smaller one: hit rates improved by two-fold, more new scaffolds were discovered, and potency improved. Overall, 50-fold more inhibitors were found, supporting the idea that there are many more compounds to be discovered than are being tested. With so many compounds evaluated, we could ask how the results vary with number tested, sampling smaller sets at random from the 1521. Hit rates and affinities were highly variable when we only sampled dozens of molecules, and it was only when we included several hundred molecules that results converged. As docking scores improved, so too did the likelihood of a molecule binding; hit rates improved steadily with docking score, as did affinities. This also appeared true on re-analysis of large-scale results against the {sigma}2 and dopamine D4 receptors. It may be that as the scale of both the virtual libraries and their testing grows, not only are better ligands found but so too does our ability to rank them.

biophysics↗

bioRxiv2024

Unveiling the Structural Proteome of an Alzheimer's Disease Rat Brain Model

Studying native protein structures at near-atomic resolution in crowded environment presents a challenge. Consequently, understanding the structural intricacies of proteins within pathologically affected tissues often relies on mass spectrometry and proteomic analysis. In this study, we utilized electron cryomicroscopy (cryo-EM) and a specific method of analysis called Build and Retrieve (BaR) to investigate structural characteristics of protein complexes such as post-translational modification, active site occupancy, and arrested conformational state in Alzheimers Disease (AD) using brain lysate from a rat model (TgF344-AD) of the disease. Our findings reveal novel insights into the architecture of these complexes, which we corroborate through mass spectrometry analysis. Interestingly, it has been shown that the dysfunction of these protein complexes extends beyond AD, implicating them in cancer, as well as other neurodegenerative disorders such as Parkinsons disease, Huntingtons disease, and Schizophrenia. By elucidating the structural details of these complexes, our work not only enhances our understanding of disease pathology but also suggests new avenues for future approaches in therapeutic intervention.

biochemistry↗

bioRxiv2024

Extracellular vesicle-derived miRNA-mediated cell-cell communication inference for single-cell transcriptomic data with miRTalk

MicroRNAs are released from cells in extracellular vesicles (EVs), representing an essential mode of cell-cell communication (CCC) via an inhibitory effect on gene expression. The advent of single-cell RNA-sequencing (scRNA-seq) technologies has ushered in an era of elucidating EV-derived miRNA-mediated CCC. However, the lack of computational methods to infer such CCC poses an outstanding challenge. Herein, we present miRTalk (https://github.com/multitalk/miRTalk), a pioneering framework for inferring EV-derived miRNA-mediated CCC with a probabilistic model and a curated database, miRTalkDB, which includes EV-derived miRNA-target associations. The benchmarking against simulated and real-world datasets demonstrated the remarkable accuracy and robustness of miRTalk. Subsequently, we employed miRTalk to uncover the in-depth CCC mechanisms underlying three disease scenarios. In summary, miRTalk represents the first approach for inferring EV-derived miRNA-mediated CCC with scRNA-seq data, providing invaluable insights into the CCC dynamics underpinning biological processes.

bioinformatics↗

bioRxiv2024

UCS: a unified approach to cell segmentation for subcellular spatial transcriptomics

Subcellular Spatial Transcriptomics (SST) represents an innovative technology enabling researchers to investigate gene expression at the subcellular level within tissues. To comprehend the spatial architecture of a given tissue, cell segmentation plays a crucial role in attributing the measured transcripts to individual cells. However, existing cell segmentation methods for SST datasets still face challenges in accurately distinguishing cell boundaries due to the varying characteristics of SST technologies. In this study, we propose a unified approach to cell segmentation (UCS) specifically designed for SST data obtained from diverse platforms, including 10X Xenium, NanoString CosMx, MERSCOPE, and Stereo-seq. UCS leverages deep learning techniques to achieve high accuracy in cell segmentation by integrating nuclei segmentation from nuclei staining and transcript data. Compared to current methods, UCS not only provides more precise transcript assignment to individual cells but also offers computational advantages for large-scale SST data analysis. The analysis output of UCS further supports versatile downstream analyses, such as subcellular gene classification and missing cell detection. By employing UCS, researchers gain the ability to characterize gene expression patterns at both the cellular and subcellular levels, leading to a deeper understanding of tissue architecture and function.

bioinformatics↗

bioRxiv2024

Hornworts reveal a spatial model for pyrenoid-based CO2-concentrating mechanisms in land plants

Pyrenoid-based CO2-concentrating mechanisms (pCCMs) turbocharge photosynthesis by saturating CO2 around Rubisco. Hornworts are the only land plants with a pCCM. Owing to their closer relationship to crops, hornworts could offer greater translational potential compared to the green alga Chlamydomonas, the traditional model for studying pCCM. Here we report the first thorough investigation of a hornwort pCCM using the emerging model Anthoceros agrestis. The pyrenoids in A. agrestis exhibit liquid-like properties similar to Chlamydomonas, but differ by lacking starch sheaths and being enclosed by multiple thylakoids. We found that the core pCCM components in Chlamydomonas, including BST, LCIB, and CAH3, are conserved in A. agrestis and likely have similar functions based on their subcellular localizations. Therefore, the underlying chassis for concentrating CO2 might be shared between hornworts and Chlamydomonas, and ancestral to land plants. Our study presents the first spatial model for pCCM in a land plant, paving the way for future biochemical and genetic investigations.

plant biology↗

bioRxiv2024

Genomic evolution reshapes cell type diversification in the amniote brain

Over 320 million years of evolution, amniotes have developed complex brains and cognition through largely unexplored genetic and gene expression mechanisms. We created a comprehensive single-cell atlas of over 1.3 million cells from the telencephalon and cerebellum of turtles, zebra finches, pigeons, mice, and macaques, employing single-cell resolution spatial transcriptomics to validate gene expression patterns across species. Our study revealed significant species-specific variations in cell types, highlighting their conservation and diversification in evolution. We found pronounced differences in telencephalon excitatory neurons (EX) and cerebellar cell types between birds and mammals. Birds predominantly express SLC17A6 in EX, whereas mammals expressed SLC17A7 in neocortex and SLC17A6 elsewhere, possibly due to loss of SLC17A7 function loss in birds. Additionally, we identified a novel bird-specific Purkinje cell subtype (SVIL+), implicating the LSD11/KDM1A pathway in learning and circadian rhythms, and related numerous positively selected genes in birds, suggesting an evolutionary optimization of cerebellar functions for ecological and behavioral adaptation. Our findings elucidate the complex interplay between genetic evolution and environmental adaptation, underscoring the role of genetic diversification in the development of specialized cell types across amniotes.

evolutionary biology↗

bioRxiv2024

Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits

Unraveling the regulatory mechanisms that govern complex traits is pivotal for advancing crop improvement. Here we present a comprehensive regulome atlas for rice (Oryza sativa), charting the chromatin accessibility across 23 distinct tissues from three representative varieties. Our study uncovers 117,176 unique open chromatin regions (OCRs), accounting for [~]15% of the rice genome, a notably higher proportion compared to previous reports in plants. Integrating RNA-seq data from matched tissues, we confidently predict 59,075 OCR-to-gene links, with enhancers constituting 69.54% of these associations, including many known enhancer-to-gene links. Leveraging this resource, we re-evaluate genome-wide association study results and discover a previously unknown function of OsbZIP06 in seed germination, which we subsequently confirm through experimental validation. We optimize deep learning models to decode regulatory grammar, achieving robust modeling of tissue-specific chromatin accessibility. This approach allows to predict cross-variety regulatory dynamics from genomic sequences, shedding light on the genetic underpinnings of cis-regulatory divergence and morphological disparities between varieties. Overall, our study establishes a foundational resource for rice functional genomics and precision molecular breeding, providing valuable insights into regulatory mechanisms governing complex traits.

genomics↗

bioRxiv2024

Central nucleus of the amygdala to medial prefrontal cortex 5-HTergic neural circuit modulates the recovery of consciousness during sevoflurane anesthesia

Preoperative anxiety and depression are significant risk factors for prolonged general anesthesia emergence, raising postoperative complications and mortality. However, the neural mechanisms underlying this association remain unclear, limiting effective interventions and development of effective preventive and therapeutic strategies. Previous studies have shown that sleep-wakefulness neural circuit is closely related to neural circuitry of anesthesia recovery, with 5-Hydroxytryptamine (5-HT) playing a pivotal role of anesthesia arousal. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry and retrograde tracing to demonstrate that activation of the 5-HTergic neural circuit between the central amygdala (CeA) and medial prefrontal cortex (mPFC) accelerates recovery from sevoflurane anesthesia. Particularly for individuals with anxiety- and depression-like symptoms, who exhibit more severe delayed emergence, it is necessary to enhance 5-HT neuronal activity by further optimizing parameters. To further validate the reliability of our findings and the specificity of viral tools, we successfully bred TPH2-Cre transgenic mice and repeated key experiments, which robustly confirmed all original conclusions. Pharmacological experiments further demonstrated that both 5-HTA and 5-HT2A receptors mediate the pro-arousal function of this circuit. Collectively, our study identifies a key CeA-mPFC serotonergic pathway linking emotional disorders to abnormal anesthetic emergence, providing potential targets for optimizing anesthesia management in vulnerable patients. HighlightsO_LIBoosting the 5-HTergic neural circuit between the CeA and mPFC promotes emergence from sevoflurane anesthesia, with 5-HT1A and 5-HT2A receptors playing a critical role in modulating consciousness transitions. C_LIO_LIPreoperative anxiety and depression exacerbate delayed emergence from anesthesia, highlighting the need for targeted interventions. C_LIO_LIDeciphering the aberrant neurocircuitry mechanisms underlying delayed emergence to inversely deduce the neurocircuitry principles of normal physiology represents a pathological-to-physiological research paradigm. C_LIO_LIStepwise enhancement of intervention parameters reverses delayed emergence in pathological states. C_LIO_LITailored activation of the 5-HTergic circuit offers a novel approach to mitigate complications from delayed emergence in vulnerable patient populations. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/599720v3_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@589b26org.highwire.dtl.DTLVardef@13204fforg.highwire.dtl.DTLVardef@e6374dorg.highwire.dtl.DTLVardef@38cac0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

PPTC7 acts as an essential co-factor of the SCFFBXL4 ubiquitin ligase complex to restrict BNIP3/BNIP3L-dependent mitophagy

Mitophagy is a selective process that targets damaged, dysfunctional, or superfluous mitochondria for degradation through autophagy. The SCFFBXL4 ubiquitin ligase complex suppresses basal mitophagy by targeting BNIP3 and BNIP3L, two key mitophagy cargo receptors, for ubiquitin-proteasomal degradation. FBXL4 loss-of-function mutations lead to excessive BNIP3/3L-dependent mitophagy, thereby causing a devasting multi-system disorder called mitochondrial DNA depletion syndrome, type 13 (MTDPS13). PPTC7, a mitochondrial matrix phosphatase, is essential for proper mitochondrial function and biogenesis. Here, we show that a proportion of PPTC7 is located on the outer mitochondrial membrane, where it interacts with FBXL4 and BNIP3/3L. PPTC7 decreases BNIP3/3L protein stability in a protein phosphatase activity-independent manner. Using in vitro cell culture and Pptc7 knockout mice models, we demonstrate that PPTC7 deficiency activates high levels of basal mitophagy in a BNIP3/3L-dependent manner. Mechanistically, PPTC7 facilitates SCFFBXL4-mediated ubiquitin-proteasomal degradation of BNIP3/3L. Overall, these findings establish PPTC7 as an essential co-factor of the SCFFBXL4 complex and a suppressor of BNIP3/3L-dependent mitophagy.

cell biology↗

bioRxiv2024

Mealtime alters daily rhythm in nuclear O-GlcNAcome to regulate hepatic gene expression

The liver circadian clock and hepatic transcriptome are highly responsive to metabolic signals generated from feeding-fasting rhythm. Previous studies have identified a number of nutrient-sensitive signaling pathways that could interpret metabolic input to regulate rhythmic hepatic biology. Here, we investigated the role of O-GlcNAcylation, a nutrient-sensitive post-translational modification (PTM) in mediating metabolic regulation of rhythmic biology in the liver. We observe daily oscillation of global nuclear protein O-GlcNAcylation in the liver of mice subjected to night-restricted feeding (NRF) using label-free global O-GlcNAc proteomics. Additional site-specific O-GlcNAc analysis by tandem mass tag mass spectrometry further supports temporal differences in O-GlcNAcylation by revealing day-night differences. Proteins involved in gene expression are enriched among rhythmically O-GlcNAcylated proteins, suggesting rhythmic O-GlcNAcylation may directly regulate the daily rhythmicity of the hepatic transcriptome. We show that rhythmic O-GlcNAcylation can also indirectly modulate the hepatic transcriptome by interacting with phosphorylation. Several proteins harboring O-GlcNAcylation-phosphorylation interplay motif exhibit rhythmic O-GlcNAcylation and phosphorylation. Specifically, we show that O-GlcNAcylation occurs at a phospho-degron of a key circadian transcriptional activator, circadian locomotor output cycles kaput (CLOCK), thus regulating its stability and transcriptional output. Finally, we report that day-restricted feeding (DRF) in the nocturnal mouse significantly alters O-GlcNAcylation rhythm. Whereas global O-GlcNAcylation analysis indicates dampening of global O-GlcNAcylation rhythm in mice fed under DRF, site-specific analysis reveals differential responses of O-GlcNAc sites when timing of food intake is altered. Notably, a substantial number of O-GlcNAcylation sites exhibit inverted day-night profiles when mice are subjected to DRF. This suggests the dysregulation of daily nuclear protein O-GlcNAcylation rhythm may contribute to the disruption in liver transcriptomic rhythm previously observed in DRF condition. In summary, our results provide new mechanistic insights into metabolic regulation of daily hepatic transcriptomic rhythm via interplay between O-GlcNAcylation and phosphorylation and shed light on the deleterious effects of improper mealtimes.

physiology↗

bioRxiv2024

Structural connectivity matures along a sensorimotor-association connectional axis in youth

Childhood and adolescence are marked by protracted developmental remodeling of cortico-cortical structural connectivity. However, the spatiotemporal variability of white matter connectivity development across the human connectome and its relevance to cognition and psychopathology remains unclear. Using diffusion MRI data from three independent developmental cohorts spanning youth, we identified a robust divergence in structural connectivity maturation along a predefined sensorimotor-association (S-A) connectional axis during youth (http://connectcharts.cibr.ac.cn). This developmental continuum ranged from early childhood increases in sensorimotor-sensorimotor connectivity strength to late adolescent increases in association-association connectivity strength, with the transition occurring around age 15. The S-A connectional axis also captured spatial variations in the associations between structural connectivity and both higher-order cognition and general psychopathology. Moreover, group-level developmental trajectories of structural connectivity differed by cognitive and psychopathological levels, with psychopathological effects predominantly observed in association connections. These findings delineate a spatiotemporal continuum of structural connectivity development during youth, providing a normative reference for quantifying developmental variability in psychiatric disorders.

neuroscience↗

bioRxiv2024

The effects of 17α-estradiol treatment on endocrine system revealed by single-nucleus transcriptomic sequencing of hypothalamus

In this study, we investigated 17-estradiols role in lifespan extension from long-term administration. Pooled hypothalami from aged male Norway brown rats treated with 17-estradiol (O.T), aged male controls (O), and young male controls (Y) underwent single-nucleus transcriptomic sequencing (snRNA-seq). To evaluate the effects of 17-estradiol on aging neurons, supervised clustering of neurons based on neuropeptides and their receptors were used to evaluate the responses of each neuron subtype during aging and after 17-estradiol treatment. The elevated cellular metabolism, stress and decreased expression levels of pathways involved in synapse formation in neurons initiated by aging were significantly attenuated by 17-estradiol. Assessment of changes in neuron populations showed that neurons related to food intake, reproduction, blood pressure, stress response, and electrolyte balance were sensitive to 17-estradiol treatment. 17-estradiol treatment not only increased serum Oxytocin (Oxt), but also heightened the activity of hypothalamic-pituitary-gonadal (HPG) axis, as evidenced by significantly elevated levels of plasma Gnrh, total testosterone, and decreased estradiol. Elevated Gnrh1 was confirmed to be one of the causal effects mediating the role of 17-estradiol in energy homeostasis, neural synapse, and stress response. Notably, Crh neurons exhibited prominent stressed phenotype in O.T, distinct to appetite-stimulating neurons Agrp and Ghrl. Therefore, the HPG axis and energy metabolism may be key targets of 17-estradiol in male hypothalamus. Additionally, supervised clustering of neurons was shown to be a useful method for assessing treatment responses and cellular perturbation among different neuron subtypes in the hypothalamus.

neuroscience↗

bioRxiv2024

Distribution, Prevalence, and Antibiotic Resistance of Non-Tuberculous Mycobacteria on Hainan Island

Non-tuberculous mycobacteria (NTM) infections are increasingly recognized as a public health concern, yet their distribution and antibiotic resistance patterns on Hainan Island, Chinas tropical hotspot, remain understudied. This study analyzes 158 clinical respiratory samples from 2015-2018 across 14 cities, identifying 118 NTM isolates from 24 species. Predominant species include Mycobacterium abscessus (23.73%), M. intracellulare (22.03%), and M. simiae (14.41%). Spatial mapping reveals elevated prevalence in coastal areas, with no significant north-south divergence on the island (Bray-Curtis dissimilarity: 0.5954, P = 0.694), but substantial differences from mainland China (North: 0.9604, P = 0.0011; South: 0.9340, P = 0.0013). Antimicrobial testing of M. abscessus isolates indicates complete resistance to doxycycline (100%), moderate sensitivity to amikacin (71.4%) and linezolid (50.0%), and variable responses to other agents. Novel detections of M. algericus and M. sinensis expand Hainans NTM diversity. These findings establish a baseline for region-specific surveillance, antibiotic stewardship, and intervention strategies to combat NTM misdiagnosis and mortality in tropical settings. IMPORTANCEPrevious studies have not covered the distribution of NTM in various regions of Hainan province. This study provides the first comprehensive geographic map of NTM in Hainan, Chinas tropical island hotspot. By monitoring NTM across 14 cities over four years, we reveal key patterns in their habitat preferences and dominant species in infections. These findings establish a foundational framework for region-specific surveillance and treatment protocols in Hainan and offer a replicable model for global tropical regions combating NTM infections. Ultimately, this work empowers public health initiatives to reduce misdiagnosis, enhance antibiotic stewardship, and lower mortality rates among at-risk populations.

microbiology↗

bioRxiv2024

CLCC1 Governs Bilayer Equilibration at the Endoplasmic Reticulum to Maintain Cellular and Systemic Lipid Homeostasis

The intricate orchestration of lipid production, storage, and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardio-metabolic diseases, the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospho-lipids onto the lumenal apolipoprotein B (APOB), in a poorly-defined process7-10. Here we show that trans-bilayer equilibration of phospholipids, regulated by the ER protein CLCC1, determines lipid partition across the ER membrane and consequently systemic lipid homeostasis. CLCC1 partners with the phospholipid scramblase TMEM41B11,12 to recognize imbalanced bilayers and promote lipid scrambling, thereby licensing lipoprotein biogenesis and the subsequent bulk lipid transport. Strikingly, loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by extensively imbalanced ER bilayers, and consequently drastically accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis (MASH). The above results establish phospholipid scrambling at the ER as the lynchpin to maintain a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13-16, our study may enable further elucidation of a previously under-appreciated homeostatic control mechanism intrinsic to the ER function in lipid biogenesis and distribution.

cell biology↗

bioRxiv2024

c-di-GMP modulates ribosome assembly by inhibiting rRNA methylation

Cyclic diguanosine monophosphate (c-di-GMP) is a ubiquitous bacterial secondary messenger, with diverse functions, many of which are yet to be uncovered. Stemming from an Escherichia coli proteome microarray, we found that c-di-GMP bound to 23S rRNA methyltransferases (RlmI and RlmE). rRNA methylation assays showed that c-di-GMP inhibits RlmI activity, thereby modulating ribosome assembly. Based on molecular dynamic simulation and mutagenesis studies, we found that c-di-GMP binds to RlmI at residues R64, R103, G114, and K201. Structural simulation revealed that c-di-GMP quenches RlmI activity by inducing the closure of the catalytic pocket. Furthermore, we revealed that c-di-GMP promotes antibiotic tolerance by regulating RlmI activity, which played a role in antibiotic-resistant strains. Finally, the binding and methylation assays showed that the effect of c-di-GMP on RlmI is conserved, at least in various pathogenic bacteria. This study discovered an unexpected functional role of c-di-GMP in regulating ribosome assembly by inhibiting rRNA methylases. This study identified an unexpected but crucial member among the c-di-GMP effectors. HighlightsO_LIc-di-GMP regulates ribosome assembly in Escherichia coli. C_LIO_LIc-di-GMP inhibits rRNA methylation activity of RlmI by inducing catalytic pocket closure. C_LIO_LIc-di-GMP promotes antibiotic resistance by regulating ribosome assembly. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/597503v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@52baforg.highwire.dtl.DTLVardef@176f86dorg.highwire.dtl.DTLVardef@1afed11org.highwire.dtl.DTLVardef@f53687_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2024

Adaptive loss of shortwave cone opsins during genomic evolution in cartilaginous fish

There is ample evidence of the loss of the shortwave visual protein gene in cartilaginous fish. However, the underlying logic and mechanisms by which organisms need to adapt to the environment behind the opsin loss are still unclear. Here, we report the assembly structure of the whole genome of Okamejei kenojei and Prionace glauca, identify TcMar difference between skates/rays and sharks/chimaeras, and analyze the distribution characteristics and intra group differentiation of opsin-related genes in cartilaginous fish. By establishing a zebrafish model with short wave opsin gene deletion, we find blue or violet light via short-wave sensitive opsins SWS1 or SWS2 can cause the photoreceptor layer thinning (the biomarker for age-related macular degeneration in human eye) through enactive the cell aging. The loss of sws is helpful for alleviating the short-wave light damage on the eye. Since the tapetum lucidum in the eye is found broad existence in various cartilaginous fish, a logical hypothesis was creatively proposed that the existence of tapetum lucidum on the retina of cartilaginous fish is interdependent with the loss of shortwave visual protein gene, providing a new perspective and explanatory path for further understanding of the evolution of visual genes in cartilaginous fish.

bioinformatics↗