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Biology subjects

Zhang, Z.

Publications and source records attributed to Zhang, Z..

At least 577 records · Page 32Linked to original sources

Brain Feature Maps Reveal Progressive Animal-Feature Representations in the Ventral Stream.

What are the fundamental units of representation in the primate visual brain? While objects have become an intuitive framework for studying neurons in many parts of cortex, it is possible that neurons follow a more expressive organizational principle, such as encoding generic features present across textures, places, and objects. In this study, we used multi-electrode arrays to record from neurons in early (V1/V2), middle (V4), and late (posterior inferotemporal cortex (PIT)) areas across the visual hierarchy, estimating the local operation of each neuron over the entire visual scene. These estimates, called "heatmaps," approximate the weight sharing operation of convolutional neural networks. We found that while populations of neurons across V1, V4, and PIT responded over the full scene, they focused on salient sub-regions within object outlines. The best captured object feature class belonged to animals, not general objects, as a trend that increased over the visual hierarchy. These results show that the monkey ventral stream is partially organized to encode local animal features over objects, even as early as primary visual cortex.

neuroscience↗

Cardiolipin-mimic lipid nanoparticles without antibody modification delivered senolytic in-vivo CAR-T therapy for inflamm-aging

mRNA-based in vivo CAR T cell engineering offers advantages over ex vivo therapies, including streamlined manufacturing and transient expression. However, current delivery requires antibody-modified vehicles with manufacturing challenges. In this study, inspired by cardiolipin, we identified a cardiolipin-like di-phosphoramide lipid that improved T cell transfection without targeting ligands, both in vivo and in vitro. The T cell-favored tropism is likely due to the lipids packing, shape, and rigidity. Encapsulating circular RNA further prolonged mRNA expression in the spleen and T cells. Using PL40 lipid nanoparticles, we delivered mRNA encoding a CAR targeting the senolytic and inflammatory antigen urokinase-type plasminogen activator receptor (uPAR), alleviating uPAR-related liver fibrosis and rheumatoid arthritis (RA). Single cell sequencing in humans confirmed uPARs relevance to senescence and inflammation in RA. To further enhance clinical translation, we screened and humanized scFvs against uPAR, establishing PL40 mRNA encoding a circular human uPAR CAR, with potential for treating aging-inflamed disorders. One Sentence SummaryWeve developed a unique class of Cardiolipin-mimic lipids that facilitate mRNA delivery to T cells in vivo without the need for antibody modification, enhancing the treatment of liver fibrosis and rheumatoid arthritis through circular CAR uPAR RNA and propelling the clinical application of humanized CAR against human uPAR.

bioengineering↗

Clonal analysis of murine HSC self-renewal and differentiation in native hematopoiesis

Hematopoietic stem cells (HSC) maintain lifelong hematopoiesis. However, in current clonal analyses with unbiased "barcoding" approaches, steady-state hematopoietic clones in young and middle-aged adults rarely have detectable HSCs, which precludes comprehensive interrogation of HSC clonal behaviors. In the current study, we used the previously described Sleeping Beauty transposon model to investigate HSC self-renewal and differentiation at a clonal level following a lifelong chase that significantly enriched HSC-derived clones. From seventeen mice, we detected over seventy thousand clones in native hematopoiesis that reflected the known HSC differentiation biases observed in transplantation. Our data indicated an intimate connection between megakaryocytic-restricted differentiation and HSC self-renewal expansion. By comparing the differentiation patterns of clones derived from transplanted HSCs, we further demonstrated the abilities of HSCs to preserve their cell fates towards self-renewal or multilineage differentiation. Unlike HSCs, clonal expansion in multipotent progenitors was associated with either a differentiation-active or differentiation-indolent state. Moreover, the clonal expansion events in the more differentiated stem and progenitor cells, but not the most primitive HSCs, drove clonal expansion in the megakaryocyte and myeloid cell lineages. Our study provided a comprehensive portrait of native hematopoiesis at a clonal level and revealed the general patterns in which HSCs maintained self-renewal and multi-lineage differentiation.

developmental biology↗

Multimodal CRISPR screens uncover DDX39B as a global repressor of A-to-I RNA editing

Adenosine-to-Inosine (A-to-I) RNA editing is a critical post-transcriptional modification that diversifies the transcriptome and influences various cellular processes. Despite its significance, the regulatory mechanisms controlling A-to-I editing remain largely unknown. In this study, we present two complementary CRISPR-based genetic screening platforms: CREDITS (CRISPR-based RNA EDITing regulator Screening), which enables genome-scale identification of editing regulators using an RNA recorder-based reporter system, and scCREDIT-seq (single-cell CRISPR-based RNA EDITing sequencing), which provides multiplexed single-cell characterization of transcriptome and editome changes for pooled perturbations on dozens of selected genes. Through screening 1,350 RNA-binding proteins, we identified a series of known and novel A-to-I editing regulators. Detailed mechanistic investigation revealed DDX39B as a global repressor of A-to-I editing, which functions by preventing double-stranded RNA accumulation through its helicase and ATPase activities. We demonstrate that targeting DDX39B significantly enhances the efficiency of RNA editing-based tools like CellREADR and LEAPER, and represents a promising strategy for anti-HDV therapy by modulating viral genome editing. These technological advances not only expand our understanding of RNA editing regulation but also provide powerful tools for exploring tissue-specific and context-dependent RNA modification mechanisms, with broad implications for therapeutic development.

molecular biology↗

De novo identification of protein domains in cryo-electron tomography maps from AlphaFold2 models

In situ cryo-electron tomography (cryo-ET) enables visualization of protein complexes within their native cellular environments. However, sub-tomogram averaging (STA) often fails to achieve resolutions sufficient for atomic model building based on side-chain information, hindering accurate protein identification and assignment. To address this challenge, we developed DomainSeeker, a computational workflow that integrates AlphaFold2-predicted structures with experimental data to identify protein domains in cryo-ET density maps. DomainSeeker partitions AlphaFold2-predicted structures into domains using clique analysis based on predicted aligned errors and then fits these domains into target densities segmented from input cryo-ET maps. Each domain-density fit is evaluated globally and locally to derive prior probabilities, which are subsequently integrated with complementary data, such as cross-linking mass spectrometry (XL-MS), through Bayesian inference to compute posterior probabilities. Applying DomainSeekers prior probability analysis to densities from mouse sperm microtubule doublets revealed substantially higher recognition accuracy and resolution robustness compared with existing approaches. Incorporating XL-MS data for yeast nuclear pore complex densities further enhanced both recognition performance and confidence. Finally, we implemented an interactive ChimeraX plugin to facilitate user access. Together, DomainSeeker overcomes a key bottleneck in in situ structural biology, providing a robust and accessible tool for visual proteomics to uncover the structural and functional organization of native cellular assemblies.

biophysics↗

Neuromorphic Imaging Cytometry on Human Blood Cells

AO_SCPLOWBSTRACTC_SCPLOWImage-enhanced cytometry and sorting are powerful technologies that provide single-cell resolution and, where possible, cell actuation based on spatial and fluorescence characterisation. With the emergence of deep learning (DL), numerous cytometry-related works incorporate DL to assist their research in handling data-intensive and repetitive workloads. The rich spatial information provided by single-cell images has exceptional use with DL models to classify cells, detect rare cell events, disclose irregularity and achieve higher sample purity than a conventional feature-gating strategy. One of the significant challenges in these image-enable technologies is the constrained throughput owing to the data-expensive image acquisition and balancing between speed and resolution. This work introduces a novel paradigm by adopting a bio-inspired neuromorphic photosensor to capture fast-moving cell events. It facilitates a data-efficient, fluorescence-sensitive, fast inference approach to establish a foundation for neuromorphic-enabled cytometry/sorting applications. We have also curated the first neuromorphic-encoded cell dataset, including human blood cells (red blood cells, neutrophils, lymphocytes, thrombocytes), endothelial cells and polystyrene-based microparticles. To evaluate the data quality and potential of DL-based gating, we have directly trained a hybrid classification model based on this dataset, accomplishing a promising performance of 97% accuracy and F1 score with a significant reduction in memory usage and power consumption. Combining neuromorphic imaging and DL holds substantial potential to develop into a next-generation AI-assisted cytometry and sorting application.

cell biology↗

Morphological brain alterations and morphological brain network disorganizations in heroin and methamphetamine abstinent patients

Heroin and methamphetamine are the two common types of drugs abused, which poses significant health risks. However, the neural mechanisms underlying the effects of drug addiction on human brain are unclear. In this study, we collected T1-weighted magnetic resonance imaging data from 26 heroin abstinent (HA) patients, 24 methamphetamine abstinent (MA) patients and 32 healthy controls. Four surface-based morphological features including cortical thickness (CT), fractal dimension (FD), gyrification index (GI), and sulcal depth (SD) were calculated, and further used to construct the morphological brain networks. We observed the common CT reductions of the right TE 1.0 and TE 1.2 and SD reductions of the right intermediate lateral area 20 for HA and MA patients, HA-specific CT reductions in the left area 2, and the MA-specific GI reductions in the left medial area 6 and right dorsomedial parietooccipital sulcus. For the morphological brain networks, HA patients exhibited the global disorganizations (higher shortest path length) in CT-based networks, whereas MA patients showed the disrupted nodal efficiency of the left medial area 38 in CT-based networks, the right caudal area 7 in GI-based networks, and the right inferior occipital gyrus in SD-based networks. Furthermore, the altered SD of HA patients and disrupted nodal efficiency of MA patients were associated with drug abuse-related clinical variables. Our findings suggest the morphological index-dependent effects of drug addiction on human brain morphology, and indicate the differential neural mechanism underlying heroin and methamphetamine abuses which attack the global and local information transfer of morphological brain networks, respectively.

neuroscience↗

Curcumin attenuates microglia-mediated chronic neuropathic pain through CDK5 /p35 signaling pathway

Curcumin is a phenolic compound derived from turmeric, one of the main ingredients of curry powder, which is widely used for its antioxidant, anti-inflammatory and immunomodulatory effects. Curcumin has been reported to help relieve pain, such as neuropathic pain caused by injury or disease, but the specific mechanism of its antinociceptive effect on pathological pain is unclear. Cyclin-dependent kinase 5 (Cdk5) is a key control point for the release of neurotransmitters from presynaptic vesicles. Cdk5 and its activator p35 couple to regulate key signaling cascades, thereby participating in the pain process. In this study, we established a NP model by chronic constriction injury (CCI) of the bilateral sciatic nerve in rats and evaluated behavioral hyperalgesia using mechanical and hot and cold tests. Protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that Iba-1 and Cdk5/p35 were co-localized in the dorsal horn and dorsal root ganglia, respectively. After CCI, the expression of Cdk5 and p35 was upregulated in the dorsal horn and dorsal root ganglia, while intraperitoneal injection of curcumin significantly reversed the activation of Cdk5/p35 protein and alleviated the hyperalgesia in rats. In addition, the injection of curcumin reduced the co-localization expression of Iba-1 and Cdk5/p35, indicating that curcumin inhibited the activation of Cdk5/p35 protein in the dorsal horn and dorsal root ganglia, thereby affecting the activation of microglia, thereby having a destructive effect on the neuronal cell plasticity and synaptic structure remodeling in the development of NP. Our study provides new evidence that Cdk5/p35 in the dorsal horn and dorsal root ganglia is related to the occurrence of NP, introduces microglia as the basis for the long-term maintenance of NP, and provides insights into the molecular mechanisms involved in the analgesic effect of curcumin. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/623498v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@125fc20org.highwire.dtl.DTLVardef@cba7d3org.highwire.dtl.DTLVardef@772291org.highwire.dtl.DTLVardef@17e87e3_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Older is Order: Entropy reduction in cortical spontaneous activity marks healthy aging

Entropy trajectories remain unclear for the aging process of human brain system due to the lacking of longitudinal neuroimaging resource. We used open data from an accelerated longitudinal cohort (PREVENT-AD) that included 24 healthy aging participants followed by 4 years with 5 visits per participant to establish cortical entropy aging curves and distinguish with the effects of age and cohort. This reveals that global cortical entropy decreased with aging, while a significant cohort effect was detectable that people who were born earlier showed higher cortical entropy. Such entropy reductions were also evident for large-scale cortical networks, although with different rates of reduction for different networks. Specifically, the primary and intermediate networks reduce their entropy faster than the higher-order association networks. We conclude two specific characteristics of the entropy of the human cortex with aging: the shift of the complexity hierarchy and the diversity of complexity strengthen.

neuroscience↗

Human skin rejuvenation via mRNA

Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related changes in cellular composition and function across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells. Using our atlas, we have uncovered basal stem cells as a highly variable population across aging, more so than other skin cell populations, such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we developed an innovative mRNA-based treatment to mitigate the effects of skin aging. After treatment with ATF3 mRNA, cell senescence decreased 25%, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found communication between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 mRNA rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%. Furthermore, we validated the efficacy of ATF3 mRNA treatment in ex vivo human skin and in vivo mouse models. In ex vivo human skin, microneedle-mediated delivery of ATF3 mRNA induced robust rejuvenation, expanding the basal stem-cell population and enhancing dermal ECM reconstruction. In a wound healing mouse model, ATF3 mRNA reduced scarring, demonstrating strong regenerative potential for reversing age-related skin decline. We conclude that ATF3 mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.

synthetic biology↗

Integration of Imaging-based and Sequencing-based Spatial Omics Mapping on the Same Tissue Section via DBiTplus

Spatially mapping the transcriptome and proteome in the same tissue section can significantly advance our understanding of heterogeneous cellular processes and connect cell type to function. Here, we present Deterministic Barcoding in Tissue sequencing plus (DBiTplus), an integrative multi-modality spatial omics approach that combines sequencing-based spatial transcriptomics and image-based spatial protein profiling on the same tissue section to enable both single-cell resolution cell typing and genome-scale interrogation of biological pathways. DBiTplus begins with in situ reverse transcription for cDNA synthesis, microfluidic delivery of DNA oligos for spatial barcoding, retrieval of barcoded cDNA using RNaseH, an enzyme that selectively degrades RNA in an RNA-DNA hybrid, preserving the intact tissue section for high-plex protein imaging with CODEX. We developed computational pipelines to register data from two distinct modalities. Performing both DBiT-seq and CODEX on the same tissue slide enables accurate cell typing in each spatial transcriptome spot and subsequently image-guided decomposition to generate single-cell resolved spatial transcriptome atlases. DBiTplus was applied to mouse embryos with limited protein markers but still demonstrated excellent integration for single-cell transcriptome decomposition, to normal human lymph nodes with high-plex protein profiling to yield a single-cell spatial transcriptome map, and to human lymphoma FFPE tissue to explore the mechanisms of lymphomagenesis and progression. DBiTplusCODEX is a unified workflow including integrative experimental procedure and computational innovation for spatially resolved single-cell atlasing and exploration of biological pathways cell-by-cell at genome-scale.

systems biology↗

All-Optical Multimodal Mapping of Single Cell Type-Specific Metabolic Activities via REDCAT

Metabolism underlies cell growth, survival, and function, yet its activities vary widely across cell types and tissue environments. Spatially resolving these processes in situ at single-cell resolution is essential to advance our understanding of cellular function and tissue physiology in health and disease. However, existing approaches are limited by either destructive workflows, insufficient spatial resolution and biochemical specificity, or lack of direct linkage to cell identity. Here, we present Raman Enhanced Delineation of Cell Atlases in Tissues (REDCAT), a multimodal all-optical platform that integrates stimulated Raman scattering, autofluorescence redox imaging, second harmonic generation, and high-plex immunofluorescence to co-map metabolic activities and cell types within the same tissue section. REDCAT achieves subcellular resolution profiling of protein, lipid, redox, and nuclear acid metabolism, together with extracellular matrix composition, in both FFPE and fresh-frozen human tissues. Applied to normal lymph nodes, REDCAT delineated distinct redox and lipid remodeling programs across germinal center B-cell zones and immune subsets, highlighting cell-type-specific metabolic specialization. In lymphoma, it revealed profound metabolic reprogramming, including extensive lipid accumulation, nuclear metabolic heterogeneity, and a transitional metabolic state associated with transformation from chronic lymphocytic leukemia to diffuse large B-cell lymphoma, thereby illuminating tumor evolution in situ. In human liver, REDCAT resolved cell-type-specific lipid droplet diversity and zonation-dependent nuclear metabolic gradients, uncovering new principles of spatial metabolic organization. By directly linking cell identity with spatial metabolic states at single-cell or subcellular resolution, REDCAT establishes a broadly applicable framework for studying immune function, tumor progression, and tissue physiology, and offers a new path to deciphering the metabolic basis of health and disease.

cell biology↗

Structural landscape of AAA+ ATPase motor states in the substrate-degrading human 26S proteasome reveals conformation-specific binding of TXNL1

The 26S proteasome targets many cellular proteins for degradation during general homeostasis, protein quality control, and the regulation of vital processes. A broad range of proteasome-interacting cofactors thereby modulates these functions and aids in substrate degradation. Here, we solved several high-resolution structures of the redox active cofactor TXNL1 bound to the human 26S proteasome at saturating and sub-stoichiometric concentrations by time resolved cryo-EM. We identified distinct binding modes of TXNL1 that depend on the proteasome conformational and ATPase motor states. Together with biophysical and biochemical experiments, our structural studies reveal that the resting-state proteasome prior to substrate engagement with the ATPase motor binds TXNL1 with low affinity and in variable positions on top of the Rpn11 deubiquitinase. In contrast, the actively degrading proteasome shows additional interactions leading to high-affinity TXNL1 binding, whereby TXNL1s C-terminal tail covers the catalytic groove of the Rpn11 deubiquitinase and coordinates the active-site Zn2+. Furthermore, these cryo-EM structures of the degrading proteasome capture the ATPase hexamer in all registers of spiral-staircase arrangements and thus visualize the complete ATP-hydrolysis cycle of the AAA+ motor, indicating temporally asymmetric hydrolysis and conformational changes in bursts during mechanical substrate unfolding and translocation. Remarkably, we catch the proteasome in the act of unfolding the beta-barrel mEos3.2 substrate while the ATPase hexamer is in a particular spiral staircase register. Our findings challenge current models for protein translocation through hexameric AAA+ motors and reveal how the proteasome uses its distinct but broad range of conformational states to coordinate cofactor binding and substrate processing. HighlightsO_LIHigh resolution structures of the redox active cofactor TXNL1 in complex with the human 26S proteasome solved by time-resolved cryo-EM. C_LIO_LITXNL1 binds the catalytic groove of the main proteasomal deubiquitinase Rpn11 and coordinates its active-site Zinc specifically in substrate-degrading states of the proteasome. C_LIO_LIVisualizing a partially unfolded intermediate of the mEos model substrate during processing. C_LIO_LIStructures of the actively degrading human proteasome reveal all spiral-staircase registers of the AAA+ ATPase hexamer with unexpected nucleotide occupancies that indicate asymmetric ATP hydrolysis mechanisms, conformational changes with burst phases, and thus new models for hand-over-hand substrate translocation. C_LI

biochemistry↗

RBPMS and RBPMS2 Cooperate to Safeguard Cardiac Splicing

BackgroundMutations in cardiac splicing factors (SFs) cause cardiomyopathy and congenital heart disease, underscoring the critical role of SFs in cardiac development and disease. Cardiac SFs are implicated to cooperatively regulate the splicing of essential cardiac genes, but the functional importance of their collaboration remains unclear. RNA Binding Protein with Multiple Splicing (RBPMS) and RBPMS2 are SFs involved in heart development and exhibit similar splicing regulatory activities in vitro, but it is unknown whether they cooperate to regulate splicing in vivo. MethodsRbpms and Rbpms2 single or double cardiomyocyte (CM)-specific knockout (KO) mice were generated and analyzed for cardiac phenotypes. RNA sequencing was performed to assess gene expression and splicing changes in single and double KOs. In silico analyses were used to dissect the mechanisms underlying distinct and overlapping roles of RBPMS and RBPMS2 in heart development. ResultsMice lacking both RBPMS and RBPMS2 in CMs died before embryonic day 13.5 and developed sarcomere disarray, whereas Rbpms or Rbpms2 single CM-specific KO mice had normal sarcomere assembly and survived to adulthood. Defective sarcomere assembly is likely owing to the widespread mis-splicing of genes essential for cardiac contraction in double KO mice, underscoring the overlapping role of RBPMS and RBPMS2 in splicing regulation. Mechanistically, we found RBPMS and RBPMS collectively promote cardiac splicing program while repressing non-cardiac splicing programs. Moreover, RNA splicing maps suggested that the binding location of RBPMS and RBPMS2 on pre-mRNA dictates whether they function as splicing activators or repressors. Lastly, the requirement for RBPMS and/or RBPMS2 for splicing regulation arises from intrinsic features of the target exons. ConclusionsOur results demonstrate that RBPMS and RBPMS2 work in concert to safeguard the splicing of genes essential for cardiac contraction, highlighting the importance of SF collaboration in maintaining cardiac splicing signature, which should be taken into consideration when devising future therapeutic approaches through modulating the activity of SFs. Novelty and SignificanceO_ST_ABSWhat Is Known?C_ST_ABSO_LIMutations in cardiac splicing factors (SFs) cause cardiomyopathy and congenital heart disease, and the splicing of cardiac genes is regulated by multiple SFs. However, the functional importance of the collaboration among specific cardiac SFs is unknown. C_LIO_LIRBPMS has emerged as a cardiac SF for sarcomere genes but is not required for sarcomere assembly. C_LIO_LIRBPMS2 can substitute RBPMS in in vitro splicing assays, yet its role in mammalian cardiomyocytes (CMs) remains unclear. C_LI What New Information Does This Article Contribute?O_LIRBPMS and RBPMS2 have both distinct and overlapping roles in CMs. C_LIO_LIRBPMS and RBPMS2 collectively contribute to the maintenance of cardiac splicing program, which is essential for sarcomere assembly and embryonic survival. C_LIO_LIRNA splicing map of RBPMS and RBPMS2 reveals that they can function either as splicing activators or repressors, depending on their binding locations on pre-mRNA. C_LI This study provides compelling evidence of cooperation between cardiac splicing factors during heart development, which, to our knowledge, has not been demonstrated in vivo. Rbpms and Rbpms2 CM-specific double KO mice die in utero and exhibit sarcomere disarray, whereas single KO mice survive to adulthood with normal sarcomere structure but manifest distinct cardiac phenotypes, suggesting RBPMS and RBPMS2 possess both distinct and overlapping functions in CMs. Although mis-splicing in cardiac genes can be seen in all three KOs, the splicing signature of double KO hearts drastically shifts towards non-cardiac tissues, including more prominent mis-splicing in genes related to cardiac contractile function. Our study further reveals that the splicing regulation of RBPMS and RBPMS2 has the characteristics of "positional effects", i.e., the binding location on pre-mRNA dictates whether they function as splicing activators or repressors; and the intrinsic features of the target exon determine the requirement for one or two RBPMS proteins for splicing regulation. Our study sheds light on the functional importance of cardiac SF cooperation in maintaining cardiac splicing signature during heart development.

developmental biology↗

Substrate utilization and cross-feeding synergistically determine microbiome resistance to pathogen invasion

Understanding how microbiomes resist pathogen invasion remains a key challenge in natural ecosystems. Here, we combined genome-scale metabolic models with synthetic community experiments to unravel the mechanisms driving pathogen suppression. We developed curated genome-scale models for each strain, incorporating 48 common resource utilization profiles to fully capture their metabolic capacities. Trophic interactions inferred from models accurately predicted pathogen invasion outcomes, achieving an F1 score of 96% across 620 invasion tests involving diverse microbial communities and nutrient environments. Importantly, considering both substrate and metabolite features provided a more holistic understanding of pathogen suppression. In particular, cross-feeding metabolites within the native community emerged as crucial yet often overlooked predictors of community resistance, disproportionally favoring native species over invaders. This study lays the foundation for designing disease-resistant microbiomes, with broad implications for mitigating pathogen exposure in diverse environments.

ecology↗

KLF7-Regulated ITGA2 as a Therapeutic Target for Inhibiting Oral Cancer Stem Cells

Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. When bound to its ECM ligand, type I collagen, ITGA2 activates several stemness-related pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, which inhibits the ITGA2-collagen interaction, showed a synergistic anti-tumor effect when combined with cisplatin in both in vitro and xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy. Highlights1) KLF7 as a key molecule in maintaining oral cancer stemness. 2) ITGA2as a key downstream gene regulated by KLF7 in the maintenance of stemness. 3) ITGA2 interacts with extracellular matrix type I collagen, activating stemness-related pathways and promoting YAP1 nuclear translocation to sustain OCSCs. 4) ITGA2 as a novel anti-CSC target, providing a new strategy to overcome OSCC drug resistance.

cancer biology↗

Multiple roles for TFG ring complexes in neuronal cargo trafficking

Pathological variants in Trk-fused gene (TFG) have been implicated in a variety of neurodegenerative conditions. In particular, mutations within its amino-terminal PB1 domain have been suggested to cause hereditary spastic paraplegia (HSP), resulting in progressive lower limb spasticity and weakness. The structural basis for this effect is unknown. Here, we combine X-ray crystallography and cryo-electron microscopy to determine a structural model of TFG, demonstrating the mechanism by which it forms octameric ring complexes. A network of electrostatic and hydrophobic interactions defines the interface between protomers. Moreover, we show that mutations identified previously in HSP patients disrupt this interface, destabilizing octamers, which ultimately leads to axonopathy. Surprisingly, the impacts of these variants are not equivalent in vivo, highlighting the existence of multiple, distinct mechanisms by which TFG mutations contribute to neurodegenerative disease.

biochemistry↗

Intelligence and Cognitive Flexibility Selectively Modulate Working Memory Functioning

Working memory is a key component of intelligence, which can be underpinned by task connectome, while cognitive flexibility plays a role in adaptive and executive function that supports working memory processes. However, it remains unknown how intelligence and cognitive flexibility modulate working memory functioning, in terms of behavioural performance and task-related brain hierarchy. Current study investigated the working memory task-related behaviour and brain connectomic gradient in healthy adults together with their intelligence and cognitive flexibility measures. Results showed cognitive flexibility and intelligence were not significantly correlated with each other but with working memory function. Principal component and partial least square analysis revealed that nearly half of variance was explained by their overlap component, which linked with task gradient values of frontoparietal and ventral attention network representing executive, control and cognitive functioning. Individuals with higher intelligence and cognitive flexibility showed less distance between frontoparietal/ventral attention network and unimodal regions in gradient axis during working memory performance. Further analyses demonstrated that task gradient of frontoparietal and ventral attention network was significantly associated with working memory function, and selectively mediated by cognitive flexibility and intelligence, which may suggest partly convergent neural mechanisms for higher order functions that are involved in working memory functioning. In conclusion, current study provides new insight into the relationship among task connectomic gradient, working memory, intelligence, and cognitive flexibility, which helps understand the multi-component model of working memory and underlying task gradient principle.

neuroscience↗