Biology subjects

Liu, F.

Publications and source records attributed to Liu, F..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Sociality shapes mitochondrial adaptations supporting hypoxia tolerance

Oxygen deprivation or hypoxia is poorly dealt with by most terrestrial species and often leads to permanent tissue damage and death. One prominent exception is the naked mole-rat (Heterocephalus glaber) which is remarkably adapted to withstand prolonged periods ([~]18 mins) of severe hypoxia, a trait likely driven by its crowded underground lifestyle. Other African mole-rat species are less social or entirely solitary like the Cape mole-rat (Georychus capensis). Here, we asked whether cellular and molecular adaptations to hypoxia map to social traits. We discovered that at the cellular level naked mole-rat fibroblasts survive >30 hours in 1% oxygen, while fibroblasts from terrestrial or non-social mole-rat species (human, mouse and Cape mole-rat) die rapidly under hypoxic conditions. We further show that naked mole-rat mitochondria have evolved morphological, functional and proteomic adaptations crucial for hypoxia resistance, remaining unaffected after long periods of severe hypoxia. We identify the mitochondrial protein Optic Atrophy 1 (OPA1) as a key player in naked mole-rat hypoxia resilience. Naked mole-rat mitochondria not only express more protective forms of OPA1, but also harbor a structurally unique isoform that likely protects cells from hypoxic damage. We show that evolutionary changes including the functionalization of a unique Opa1 exon support mitochondrial mediated cellular protection. Indeed, knockdown of OPA1 in naked mole-rat cells is sufficient to render them equally susceptible to hypoxia as human cells or cells from non-social African species. Our study demonstrates how molecular evolution drives unique adaptations that enable cells to achieve unprecedented resistance to hypoxic damage. We also show that molecular changes at the level of mitochondria are crucial in conferring hypoxia resistance. Our results thus chart a novel molecular path to understand how robust cellular hypoxia resistance can be achieved. Such knowledge may eventually inspire novel strategies to circumvent the consequences of hypoxic-damage in humans.

physiology↗

bioRxiv2024

Evaluation of scalp-based targeting methods of DLPFC for TMS therapy: EEG cap F3, Beam F3, CPC F3, and adjusted Beam F3

BackgroundRepetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex (DLPFC) offers a promising approach for treating depression. Scalp-based targeting methods, including EEG Cap, Beam F3, CPC F3, and adjusted Beam F3, have evolved to improve clinical application. ObejectivesTo evaluate and compare the accuracy, reliability, speed, and training efficacy of these four methods. MethodsThree trained technicians conducted repeated DLPFC targeting measurements on 10 3D-printed head models. Accuracy was assessed by calculating targeting error and electric field strength at the subgenual anterior cingulate cortex anti-correlated peak. Reliability was evaluated through inter- and intra-rater variability, and training efficacy was examined by comparing targeting errors between trained technicians and novices. ResultsCPC F3, Beam F3, and adjusted Beam F3 demonstrated comparable accuracy in terms of electric field strength, but CPC F3 had the lowest targeting error (4.2 mm). CPC F3 also exhibited the highest reliability (inter-rater variability at 3.3 mm, intra-rater variability at 2.3 mm). The EEG cap was the fastest method (80 seconds), while CPC F3 was faster than Beam F3 but slower than EEG Cap. No significant differences in targeting error between trained technicians and novices were noted with CPC F3 and adjusted Beam F3. ConclusionThe comparative analysis of four scalp-based targeting methods provides insights that can enhance clinical decision-making and the practical application. While accuracy among CPC F3, Beam F3, and adjusted Beam F3 was comparable, CPC F3 emerges as highly practical due to its significantly better reliability, training efficacy, moderate speed, and straightforward implementation.

neuroscience↗

bioRxiv2024

Integrative Molecular Dynamics Simulations Untangle Cross-Linking Data to Unveil Mitochondrial Protein Distributions

Cross-linking mass spectrometry (XL-MS) enables the mapping of protein-protein interactions on the cellular level. When applied to all compartments of mitochondria, the sheer number of cross-links and connections can be over-whelming, rendering simple cluster analyses convoluted and uninformative. To address this limitation, we integrate the XL-MS data, 3D electron microscopy data, and localization annotations with a supra coarse-grained molecular dynamics simulation to sort all data, making clusters more accessible and interpretable. In the context of mitochondria, this method, through a total of 6.9 milliseconds of simulations, successfully identifies known, suggests unknown protein clusters, and reveals the distribution of inner mitochondrial membrane proteins allowing a more precise localization within compartments. Our integrative approach suggests, that two so-far ambigiously placed proteins FAM162A and TMEM126A are localized in the cristae, which is validated through super resolution microscopy. Together, this demonstrates the strong potential of the presented approach. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/612425v2_ufig1.gif" ALT="Figure 1"> View larger version (74K): org.highwire.dtl.DTLVardef@1a3236dorg.highwire.dtl.DTLVardef@16ad120org.highwire.dtl.DTLVardef@1c79bfdorg.highwire.dtl.DTLVardef@1d20e51_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOEntry for the Table of ContentsC_FLOATNO The approach combines cross-linking mass spectrometry, electron microscopy, and coarse-grained molecular dynamics simulations to map protein-protein interactions in mitochondria. This integration makes complex data clusters accessible, revealing protein distributions and localizations. Notably, it allows the localization of FAM162A and TMEM126A through super-resolution microscopy, showcasing the synergy of experimental and computational methods. C_FIG

biophysics↗

bioRxiv2024

Telomere-to-telomere African wild rice (Oryza longistaminata) reference genome reveals segmental and structural variation

Rice (Oryza sativa) is one of the most important staple food crops worldwide, and its wild relatives serve as an important gene pool in its breeding. Compared with cultivated rice species, African wild rice (Oryza longistaminata) has several advantageous traits, such as resistance to increased biomass production, clonal propagation via rhizomes, and biotic stresses. However, previous O. longistaminata genome assemblies have been hampered by gaps and incompleteness, restricting detailed investigations into their genomes. To streamline breeding endeavors and facilitate functional genomics studies, we generated a 343-Mb telomere-to-telomere (T2T) genome assembly for this species, covering all telomeres and centromeres across the 12 chromosomes. This newly assembled genome has markedly improved over previous versions. Comparative analysis revealed a high degree of synteny with previously published genomes. A large number of structural variations were identified between the O. longistaminata and O. sativa. A total of 2,466 segmentally duplicated genes were identified and enriched in cellular amino acid metabolic processes. We detected a slight expansion of some subfamilies of resistance genes and transcription factors. This newly assembled T2T genome of O. longistaminata provides a valuable resource for the exploration and exploitation of beneficial alleles present in wild relative species of cultivated rice.

genomics↗

bioRxiv2024

Sec18 side-loading is essential for universal SNARE recycling across cellular contexts

SNARE proteins drive membrane fusion at different cell compartments as their core domains zipper into a parallel four-helix bundle. After fusion, these bundles are disassembled by the AAA+ protein Sec18/NSF and its adaptor Sec17/-SNAP to make them available for subsequent rounds of membrane fusion. SNARE domains are often flanked by C-terminal transmembrane or N-terminal domains. Previous structures of the NSF--SNAP-SNARE complex revealed binding to the D1 ATPase pore, posing a topological constraint as SNARE transmembrane domains would prevent complete substrate threading as suggested for other AAA+ systems. Using mass-spectrometry in yeast cells, we show N-terminal SNARE domain interactions with Sec18, exacerbating this topological issue. We present cryo-EM structures of a yeast SNARE complex, Sec18, and Sec17 in a non-hydrolyzing condition, which show SNARE Sso1 threaded through the D1 and D2 ATPase rings of Sec18, with its folded, N-terminal Habc domain interacting with the D2 ring. This domain does not unfold during Sec18/NSF activity. Cryo-EM structures under hydrolyzing conditions revealed substrate-released and substrate-free states of Sec18 with a coordinated opening in the side of the ATPase rings. Thus, Sec18/NSF operates by substrate side-loading and unloading topologically constrained SNARE substrates.

biophysics↗

bioRxiv2024

Structural basis of phosphate export by human XPR1

Phosphorus is an essential element for all living organisms. While inorganic phosphate (Pi) cellular import is well documented, export is poorly characterized despite the recent discovery of the inositol pyrophosphate (PP-IP)-dependent Pi exporter XPR1. In this study, we determined the cryo-EM structures of XPR1. XPR1 forms a loose dimer, with each protomer containing 10 transmembrane helices (TMs) that can be divided into a peripheral domain (TM1, 3 and 4) and a core domain (TM2 and TM5-10) structurally related to ion-translocating rhodopsins. Bound Pi is observed in a tunnel formed by the helical bundle inside the core domain at a narrowest point that separates the tunnel into an intracellular vestibule (IV) and an extracellular vestibule (EV). This narrowest point contains a cluster of Pi-coordinating basic residues, and their substitution by mutagenesis strongly impaired phosphate export. PP-Ips stimulate XPR1 activity by binding to its SPX domain. Loss of this interaction induces a conformational change of the wide open EV (conducting state) into a collapsed EV (closed state), mainly caused by structural movements of TM9 and the bulky sidechain of Trp573 right above the Pi binding site, which are essential for the Pi export activity of XPR1. Our structural and functional characterization paves the way for further in-depth studies of XPR1.

biochemistry↗

bioRxiv2024

Bioinspired Bimetallic Ions Functionalized MOF SAzyme Nanocomposites for Synergistic Ferroptosis/Cuproptosis-Enhanced Immune Checkpoint Therapy

Immune checkpoint blockade (ICB) generates sustained responses in immunogenic cancers, but its effectiveness is limited in tumors lacking immune activity. Here, we construct a bioinspired bimetallic ions functionalized nanoscale metal-organic framework (NMOF) single-atom nanozyme (SAzyme) loaded with doxorubicin (Dox) (NMOF-Fe/Cu-Dox nanocomposite) to effectively trigger anti-tumor immune responses while addressing the immunosuppressive tumor microenvironment (TME). The NMOF-Fe/Cu-Dox nanocomposite has been demonstrated to efficiently reverse the TME by generating reactive oxygen species and oxidizing glutathione. Camouflaging NMOF-Fe/Cu-Dox nanocomposites with bioinspired cancer cell membrane (NMOF-Fe/Cu-Dox@M) enables its navigation to the tumor region through homologous targeting. The highly efficient uptaken by cancer cells selectively induced synergistic ferroptosis and cuproptosis in these cells. Furthermore, in vitro and in vivo experiments demonstrate that the ferroptosis in cancer cells can polarize tumor-associated macrophages (TAMs) towards anti-tumoral M1 phenotype and significantly diminish pro-tumoral M2 phenotype. We find that NMOF-Fe/Cu-Dox@M could induce the ferroptosis of M2 macrophages, while no effect to M1 macrophages. In addition, a significant increase of anti-tumor infiltrating CD8+ T cells, while a remarkable decrease of CD4+ regulatory T cells were observed. These findings suggested that NMOF-Fe/Cu-Dox@M could efficiently modulate TME, enhance tumoricidal immunity and elevate the therapeutic efficiency of ICB. Moreover, the combination of NMOF-Fe/Cu-Dox@M with PD-1 effectively eradicated hepatocellular carcinoma cells in vivo, outperforming the use of either NMOF-Fe/Cu-Dox@M or PD-1 alone. In summary, our study presents a therapeutic strategy that leverages coordinated ferroptosis and cuproptosis with therapeutic efficiency of ICB, underscoring the promise of combined chemoimmunotherapy.

bioengineering↗

bioRxiv2024

PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery. PTEN is a crucial negative regulator of the PI3K/Akt signaling pathway. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight that an elevated level of PTEN neddylation is markedly associated with resistance to palbociclib, a CDK4/6 inhibitor used in luminal subtype breast cancer patients. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more notably, upregulates the activity of the AP-1 transcription factor. Our data showed that PTEN neddylation stabilizes JUND, a transcription factor involved in the AP-1 complex, by disrupting its interaction with the E3 ubiquitin ligase ITCH. Consequently, activated JUND leads to the release of cytokines and chemokines, which in turn may drive an inflammatory tumor microenvironment, potentially contributing to drug resistance. Then, we identified Echinacoside as a potent inhibitor of PTEN neddylation both in vivo and in vitro by disrupting its interaction with XIAP, the E3 ligase responsible for PTEN neddylation. Combination of Echinacoside effectively overcome resistance to palbociclib in breast cancer treatment. These findings highlight targeting PTEN neddylation as a promising strategy for restoring tumor suppressor activity and overcoming resistance.

cell biology↗

bioRxiv2024

Extensive mutual influences of SMC complexes shape 3D genome folding

Mammalian genomes are folded by the distinct actions of SMC complexes which include the chromatin loop-extruding cohesin, the sister-chromatid cohesive cohesin, and the mitotic chromosome-associated condensins. While these complexes function at different stages of the cell cycle, they co-exist on chromatin during the G2/M-phase transition, when genome structure undergoes a dramatic reorganization. Yet, how distinct SMC complexes affect each other and how their mutual interplay orchestrates the dynamic folding of 3D genome remains elusive. Here, we engineered all possible cohesin/condensin configurations on mitotic chromosomes to delineate the concerted, mutual influential action of SMC complexes. We find that: (i) The mitotic SMC complex condensin disrupts the focal accumulation of extrusive-cohesin at CTCF binding sites, thereby promoting the disassembly of interphase TADs and chromatin loops during mitotic progression. Conversely, extrusive-cohesin can impair condensin activity and alter mitotic chromosome helicity. (ii) Condensin diminishes cohesive-cohesin focal enrichment and, conversely, cohesive-cohesin can counteract condensin function and impede mitotic chromosome longitudinal shortening. (iii) The co-presence of extrusive- and cohesive-cohesin synergistically antagonizes condensin function and dramatically delays mitotic chromosome condensation. (iv) Extrusive-cohesin positions cohesive-cohesin at CTCF binding sites. However, cohesive-cohesin by itself is insufficient to mediate the formation of TADs or chromatin loop, implying non-overlapping function with extrusive-cohesin. Instead, cohesive-cohesin restricts chromatin loop expansion, potentially by limiting extrusive-cohesin movement. Collectively, our data describe a comprehensive three-way interplay among major SMC complexes that dynamically sculpts chromatin architecture during cell cycle progression.

cell biology↗

bioRxiv2024

Proteome-wide quantification of inositol pyrophosphate-protein interactions

Inositol polyphosphates (InsPs) and inositol pyrophosphates (PP-InsPs) constitute a group of highly phosphorylated molecules that are involved in many cellular signaling processes. To characterize discrete signaling events of these structurally closely related molecules, a mass spectrometry approach was developed to derive apparent binding constants for these ligands on a proteome-wide scale. The method employed a series of chemically synthesized, biotinylated affinity reagents for inositol hexakisphosphate (InsP6), and the inositol pyrophosphates 1PP-InsP5, 5PP-InsP5 and 1,5(PP)2-InsP4 (also termed InsP8). Application of these affinity reagents at different concentrations, in combination with tandem mass tag (TMT) labeling, provided binding data for thousands of proteins from a mammalian cell lysate. Investigation of different enrichment conditions, where Mg2+ ions were either available or not, showcased a strong influence of Mg2+ on the protein binding capacities of PP-InsPs. Gene ontology analysis closely linked PP-InsP-interacting proteins to RNA processing in the nucleus and nucleolus. Subsequent data analysis enabled a targeted search for protein pyrophosphorylation among PP-InsP interactors, and identified four new pyrophosphorylated proteins. The data presented here constitute a valuable resource for the community, and application of the method reported here to other biological contexts will enable the exploration of PP-InsP dependent signaling pathways across species.

biochemistry↗

bioRxiv2024

Nucleoside diphosphate kinase A (NME1) catalyze its own oligophosphorylation

Protein phosphorylation is a central regulatory mechanism in eukaryotic cell signaling, and was recently expanded to include protein pyrophosphorylation and protein polyphosphorylation. Here, we report the discovery of yet another mode of phosphorylation - protein oligophosphorylation. Using site-specifically phosphorylated and pyrophosphorylated nucleoside diphosphate kinase A (NME1), the effects of these modifications on enzyme activity were investigated. Phosphorylation, and more so pyrophosphorylation, on threonine 94 notably reduced the nucleoside diphosphate kinase activity. Nevertheless, both phosphoprotein and pyrophosphoprotein were able to catalyze their own oligophosphorylation - up to the formation of a hexaphosphate chain - using ATP as a co-factor. This reaction was critically dependent on the catalytic histidine residue H118, and cryo-EM analysis of the differently modified proteins suggests an intramolecular phosphoryl transfer, likely via a phosphohistidine intermediate. Oligophosphorylation of NME1 in biochemical samples, as well as cell lysates, was further confirmed using mass spectrometry, and oligophophorylation promoted a new set of protein interactions. Our results highlight the complex nature of phosphoregulation, and the methods described here provide the opportunity to investigate the impact of this novel modification in the future.

biochemistry↗

bioRxiv2024

Identifying Artifacts from Large Library Docking

While large library docking has discovered potent ligands for multiple targets, as the libraries have grown, the very top of the hit-lists can become populated with artifacts that cheat our scoring functions. Though these cheating molecules are rare, they become ever-more dominant with library growth. Here, we investigate rescoring top-ranked molecules from docking screens with orthogonal methods to identify these artifacts, exploring implicit solvent models and absolute binding free energy perturbation (AB-FEP) as cross-filters. In retrospective studies, this approach deprioritized high-ranking non-binders for nine targets while leaving true ligands relatively unaffected. We tested the method prospectively against results from large library docking AmpC {beta}-lactamase. From the very top of the docking hit lists, we prioritized 128 molecules for synthesis and experimental testing, a mixture of 39 molecules that rescoring flagged as likely cheaters and another 89 that were plausible true actives. None of the 39 predicted cheating compounds inhibited AmpC up to 200{micro}M in enzyme assays, while 57% of the 89 plausible true actives did do so, with 19 of them inhibiting the enzyme with apparent Ki values better than 50{micro}M. As our libraries continue to grow, a strategy of catching docking artifacts by rescoring with orthogonal methods may find wide use in the field. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/603966v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@c2f1a5org.highwire.dtl.DTLVardef@86bc58org.highwire.dtl.DTLVardef@1b739c7org.highwire.dtl.DTLVardef@325b93_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

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

Identifying foraging spatial cues in beehive sound activity using machine learning methods

The beehive sound, a continuous signal produced by bees within the hive, has been found to correlate with different behavioral states of the colony, like being queenless and swarming. We investigated the possibility of identifying foraging spatial cues in this signal. We recorded a colonys sound while foraging from food sources located at three different distances from the hive, one at a time. The recordings were split into frames to obtain six statistics of their Mel Frequency Cepstral Coefficients. Then, we evaluated different autoencoding networks to obtain a latent space that allowed frames from different foraging distances to be easily differentiable. The high accuracy, silhouette score, and F1 score shown in the obtained latent spaces strongly support our approach for identifying foraging spatial cues in beehive sound activity.

animal behavior and cognition↗

bioRxiv2024

Stat3 mediates Fyn kinase driven dopaminergic neurodegeneration and microglia activation

The Alzheimers Disease and Parkinsons Disease risk locus Fyn kinase is implicated in neurodegeneration and inflammatory signaling. To investigate in vivo mechanisms of Fyn driven neurodegeneration, we built a zebrafish neural specific Gal4:UAS model of constitutively active FynY531F signaling. Using in vivo live imaging we demonstrate neural FynY531F expression lead to dopaminergic neuron loss and mitochondrial aggregation in 5 day larval brain. Dopaminergic loss coincided with microglia activation and induction of tnfa, il1b, and il12a inflammatory cytokine expression. Transcriptome analysis revealed Stat3 signaling as a potential Fyn target. Chemical inhibition experiments confirmed Fyn driven dopaminergic neuron loss and the inflammatory response were dependent upon activation of Stat3 and NF-{kappa}B pathways. Dual chemical inhibition demonstrated Stat3 acts synergistically with NF-{kappa}B in dopaminergic neuron degeneration. These results identify Stat3 as a novel downstream effector of Fyn signaling in neurodegeneration and inflammation. Summary StatementThis study describes a novel in vivo model of neural Fyn Kinase activation and identifies Stat3 signaling as a downstream Fyn effector in dopaminergic neuron degeneration and neuroinflammation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/602238v1_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1d783a4org.highwire.dtl.DTLVardef@3b838org.highwire.dtl.DTLVardef@33790eorg.highwire.dtl.DTLVardef@1508c64_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO - Neural Fyn signaling drives dopaminergic neurodegeneration, mitochondria accumulation, and microglia activation - Fyn driven neurodegeneration and cytokine expression are dependent on Stat3 - Stat3 and NF-kB pathways synergize in dopaminergic neuron degeneration C_FIG

developmental biology↗

bioRxiv2024

Innate immune system signaling and CD11b+CD11c+CD103+ cell migration to the brain underlie changes in mouse behavior after microbial colonization.

Background and AimsAccumulating evidence suggests the microbiota is a key factor in disorders of gut-brain interaction (DGBI), by affecting host immune and neural systems. However, the underlying mechanisms remain elusive due to their complexity and clinical heterogeneity of patients with DGBIs. We aimed to identify neuroimmune pathways that are critical in microbiota-gut-brain communication during de novo gut colonization. MethodsWe employed a combination of gnotobiotic and state-of-the-art microbial tools, behavioral analysis, immune and pharmacological approaches. Germ-free wild type, MyD88-/- Ticam1-/- and SCID mice were studied before and after colonization with specific pathogen-free microbiota, Altered Schaedler Flora, E. coli or S. typhimurium (permanent or transient colonizers). TLR agonists and antagonists, CCR7 antagonist or immunomodulators were used to study immune pathways. We assessed brain c-Fos, brain-derived neurotrophic factor, and dendritic and glial cells by immunofluorescence, expression of neuroimmune genes by NanoString and performed brain proteomics. ResultsBacterial monocolonization, conventionalization or administration of microbial products to germ-free mice altered mouse behavior similarly, acting through Toll-like receptor or nucleotide-binding oligomerization domain signaling. The process required CD11b+CD11c+CD103+ cell activation and migration into the brain. The change in behavior did not require the continued presence of bacteria and was associated with activation of multiple neuro-immune networks in the gut and the brain. ConclusionsChanges in neural plasticity occur rapidly upon initial gut microbial colonization and involve innate immune signaling to the brain, mediated by CD11b+CD11c+CD103+ cell migration. The results identify a new target with therapeutic potential for DGBIs developing in context of increased gut and blood-brain barrier permeability. HighlightsO_LIMicrobiota impairment is a key factor in disorders of gut-brain interaction (DGBI) C_LIO_LIMicrobial colonization induces changes in brain and behavior via innate immunity C_LIO_LIMicrobial colonization activates multiple neuro-immune networks in gut and brain C_LIO_LIBehavioral change is mediated by CD11b+CD11c+CD103+ cells migration to the brain C_LI

animal behavior and cognition↗

bioRxiv2024

Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer

Colon cancer, as a highly prevalent malignant tumor globally, poses a significant threat to human health. In recent years, ferroptosis and cuproptosis, as two novel forms of cell death, have attracted widespread attention for their potential roles in the development and treatment of colon cancer. However, the investigation into the subtypes and their impact on the survival of colon cancer patients remains understudied. In this study, utilizing data from TCGA and GEO databases, we examined the expression differences of ferroptosis and cuproptosis-related genes in colon cancer and identified two subtypes. Through functional analysis and bioinformatics methods, we elucidated pathway differences and biological characteristics between these two subtypes. By leveraging differential genes between the two subtypes, we constructed a prognostic model using univariate Cox regression and multivariate Cox regression analysis as well as LASSO regression analysis. Further survival analysis and receiver operating characteristic curve analysis demonstrated the models high accuracy. To enhance its clinical utility, we evaluated the clinical significance of the model and constructed a nomogram, significantly improving the predictive ability of the model and providing a new tool for prognostic assessment of colon cancer patients. Subsequently, through immune-related analysis, we revealed differences in immune cell infiltration and immune function between high- and low-risk groups. Further analysis of the relationship between the model and immune cells and functions revealed potential therapeutic targets. Drug sensitivity analysis revealed associations between the expression of model-related genes and drug sensitivity, suggesting their involvement in tumor resistance through certain mechanisms. AZD8055_1059, Bortezomib_1191, Dihydrorotenone_1827, and MG-132_1862 were more sensitive in the high-risk group. Finally, we analyzed differential expression of model-related genes between tumor tissues and normal tissues, validated through real-time quantitative PCR. In summary, our study provides a relatively accurate prognostic tool for colon cancer patients, offering guidance for treatment selection and indicating the potential of immunotherapy in colon cancer.

bioinformatics↗

bioRxiv2024

Early Developmental Origins of Cortical Disorders Modeled in Human Neural Stem Cells

The implications of the early phases of human telencephalic development, involving neural stem cells (NSCs), in the etiology of cortical disorders remain elusive. Here, we explored the expression dynamics of cortical and neuropsychiatric disorder-associated genes in datasets generated from human NSCs across telencephalic fate transitions in vitro and in vivo. We identified risk genes expressed in brain organizers and sequential gene regulatory networks across corticogenesis revealing disease-specific critical phases, when NSCs are more vulnerable to gene dysfunctions, and converging signaling across multiple diseases. Moreover, we simulated the impact of risk transcription factor (TF) depletions on different neural cell types spanning the developing human neocortex and observed a spatiotemporal-dependent effect for each perturbation. Finally, single-cell transcriptomics of newly generated autism-affected patient-derived NSCs in vitro revealed recurrent alterations of TFs orchestrating brain patterning and NSC lineage commitment. This work opens new perspectives to explore human brain dysfunctions at the early phases of development. One-sentence summaryThe temporal analysis of gene regulatory networks in human neural stem cells reveals multiple early critical phases associated with cortical disorders and neuropsychiatric traits.

neuroscience↗