Biology subjects

Lin, W.

Publications and source records attributed to Lin, W..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2024

Electron-density informed effective and reliable de novo molecular design and lead optimization with ED2Mol

Generative drug design opens new avenues for discovering novel compounds within the vast chemical space rather than conventional screening against limited compound libraries. However, the practical utility of the generated molecules is frequently constrained, as many designs prioritize a narrow range of pharmacological properties while neglecting physical reliability, which hinders the success rate of subsequent wet-lab evaluations. To address this, we propose ED2Mol, a deep learning-based approach that leverages fundamental electron density information to improve de novo molecular generation and lead optimization. The extensive evaluations across multiple benchmarks demonstrate that ED2Mol surpasses existing methods in terms of generation success rate and >97% physical reliability. It also facilitates automated lead optimization that is not fully implemented by other methods using fragment-based strategies. Furthermore, ED2Mol exhibits generalizability to more challenging, unseen allosteric pocket benchmarks, attaining consistent performance in both de novo molecule generation and lead optimization. More importantly, ED2Mol has been applied to various real-world essential targets, successfully identifying wet-lab validated bioactive compounds, ranging from FGFR3 orthosteric inhibitors to CDC42 allosteric inhibitors and GCK allosteric activators. The directly generated binding modes of these compounds with target proteins are close to predictions through molecular docking and further validated via the X-ray co-crystal structure. All these results highlight ED2Mols potential as a useful tool in realistic drug design with enhanced effectiveness, physical reliability, and practical applicability.

bioinformatics↗

bioRxiv2024

Covalent inhibitors of the RAS binding domain of PI3Ka impair tumor growth driven by RAS and HER2

Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3Ks role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110 and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.

cancer biology↗

bioRxiv2024

Local Gradients of Functional Connectivity Enable Precise Fingerprinting of Infant Brains During Dynamic Development

Brain functional connectivity patterns exhibit distinctive, individualized characteristics capable of distinguishing one individual from others, like fingerprint. Accurate and reliable depiction of individualized functional connectivity patterns during infancy is crucial for advancing our understanding of individual uniqueness and variability of the intrinsic functional architecture during dynamic early brain development, as well as its role in neurodevelopmental disorders. However, the highly dynamic and rapidly developing nature of the infant brain presents significant challenges in capturing robust and stable functional fingerprint, resulting in low accuracy in individual identification over ages during infancy using functional connectivity. Conventional methods rely on brain parcellations for computing inter-regional functional connections, which are sensitive to the chosen parcellation scheme and completely ignore important fine-grained, spatially detailed patterns in functional connectivity that encodes developmentally-invariant, subject-specific features critical for functional fingerprinting. To solve these issues, for the first time, we propose a novel method to leverage the high-resolution, vertex-level local gradient map of functional connectivity from resting-state functional MRI, which captures sharp changes and subject-specific rich information of functional connectivity patterns, to explore infant functional fingerprint. Leveraging a longitudinal dataset comprising 591 high-resolution resting-state functional MRI scans from 103 infants, our method demonstrates superior performance in infant individual identification across ages. Our method has unprecedentedly achieved 99% individual identification rates across three age-varied sub-datasets, with consistent and robust identification rates across different phase encoding directions, significantly outperforming atlas-based approaches with only around 70% accuracy. Further vertex-wise uniqueness and differential power analyses highlighted the discriminative identifiability of higher-order functional networks. Additionally, the local gradient-based functional fingerprints demonstrated reliable predictive capabilities for cognitive performance during infancy. These findings suggest the existence of unique individualized functional fingerprints during infancy and underscore the potential of local gradients of functional connectivity in capturing neurobiologically meaningful and fine-grained features of individualized characteristics for advancing normal and abnormal early brain development.

neuroscience↗

bioRxiv2024

Tardigrade Dsup: Interactions with DNA and protection of cells from oxidative stress

The remarkable capability of Tardigrade to survive under extreme conditions has been partially attributed to Dsup, an intrinsically disordered, highly positively charged protein. Dsup has been shown to bind to DNA in vitro, a property that has been associated with the capability of Dsup to exhibit stress-protective effects when expressed in mammalian cells. However, DNA binding of Dsup has not been visualized in living cells and expression of Dsup in different cell types was associated with either protective or detrimental effects. In addition, the effect of Dsup expression has not been clearly demonstrated at the organism level. Here we combined molecular dynamics (MD) simulations and fluorescence lifetime imaging microscopy (FLIM)-Forster resonance energy transfer (FRET) to interrogate Dsup-DNA interactions and demonstrated Dsup binding to DNA in living mammalian cells. Furthermore, Dsup expression in both HEK293T cells and yeast enhanced cell survival in the presence of hydrogen peroxide, suggesting that the presence of Dsup allows both mammalian and yeast cells to better cope with oxidative stress conditions. This study provides a better understanding of the property and functional role of Dsup and lays a foundation to explore new approaches to enhance stress resistance.

biophysics↗

bioRxiv2024

Habenula-ventral tegmental area functional coupling and risk-aversion in humans

Maladaptive responses to uncertainty, including excessive risk avoidance, are linked to a range of mental disorders. One expression of these is a pro-variance bias (PVB), wherein risk-seeking manifests in a preference for choosing options with higher variances/uncertainty. Here, using a magnitude learning task, we provide a behavioural and neural account of PVB in humans. We show that individual differences in PVB are captured by a computational model that includes asymmetric learning rates, allowing differential learning from positive prediction errors (PPEs) and negative prediction errors (NPEs). Using high-resolution 7T functional magnetic resonance imaging (fMRI), we identify distinct neural responses to PPEs and NPEs in value-sensitive regions including habenula (Hb), ventral tegmental area (VTA), nucleus accumbens (NAcc), and ventral medial prefrontal cortex (vmPFC). Prediction error signals in NAcc and vmPFC were boosted for high variance options. NPEs responses in NAcc were associated with a negative bias in learning rates linked to a stronger negative Hb-VTA functional coupling during NPE encoding. A mediation analysis revealed this coupling influenced NAcc responses to NPEs via an impact on learning rates. These findings implicate Hb-VTA coupling in the emergence of risk preferences during learning, with implications for psychopathology.

neuroscience↗

bioRxiv2024

Spatially global effects of feature-based attention in functional subdivisions of human subcortical nuclei

Attention can prioritize the processing of non-spatial features throughout the visual field. While human subcortical nuclei are known to play important roles in spatial attention, the subcortical mechanisms of feature-based attention remain elusive. Using high-resolution 7T fMRI, we investigated the spatially global effects of color-based attention in functional subdivisions of human subcortical nuclei. Paying attention to a color matching the unattended stimulus across the visual field selectively modulated BOLD signals in the parvocellular (P) layers of the lateral geniculate nucleus (LGN) of the thalamus, enhancing the response to the unattended stimulus while reducing the response to the attended stimulus. The spatially global effects of color-based attention were also found in the deeper layers of the superior colliculus (SC), early visual cortices, and the intraparietal sulcus (IPS) of the parietal lobe. Effective connectivity analyses further revealed enhanced feedforward and feedback connectivity between LGN and V1, along with top-down modulation from IPS through the SC and ventral pulvinar. Finally, attended color can be decoded from multi-voxel response patterns in frontoparietal regions. These findings demonstrate that color-based attention selectively modulates color processing in P subdivisions of the LGN of the thalamus throughout the visual field, controlled by top-down signals from the parietal cortex through the SC and pulvinar. HighlightsO_LIColor-based attention selectively modulates parvocellular activity in the LGN throughout the visual field. C_LIO_LISpatially global effect of feature-based attention significantly modulates activity in the deeper layers of the SC. C_LIO_LIFeature-based attention enhances both feedforward and feedback connectivity between the LGN and V1. C_LIO_LITop-down signals from IPS through the SC and pulvinar controls feature-based attention. C_LI

neuroscience↗

bioRxiv2024

Utilizing data imbalance to enhance compound-protein interaction prediction models

Identifying potential compounds for target proteins is crucial in drug discovery. Current compound-protein interaction prediction models concentrate on utilizing more complex features to enhance capabilities, but this often incurs substantial computational burdens. Indeed, this issue arises from the limited understanding of data imbalance between proteins and compounds, leading to insufficient optimization of protein encoders. Therefore, we introduce a sequence-based predictor named FilmCPI, designed to utilize data imbalance to learn proteins with their numerous corresponding compounds. FilmCPI consistently outperforms baseline models across diverse datasets and split strategies, and its generalization to unseen proteins becomes more pronounced as the datasets expand. Notably, FilmCPI can be transferred to unseen protein families with sequence-based data from other families, exhibiting its practicability. The effectiveness of FilmCPI is attributed to different optimization speeds for diverse encoders, elucidating optimization imbalance in compound-protein prediction models. Additionally, these advantages of FilmCPI do not depend on increasing parameters, aiming to lighten model design with data imbalance.

biochemistry↗

bioRxiv2024

The Growing Little Brain: Cerebellar Functional Development from Cradle to School

Despite the cerebellums crucial role in brain functions, its early development, particularly in relation to the cerebrum, remains poorly understood. Here, we examine cerebellocortical connectivity using over 1,000 high-quality resting-state functional MRI scans of children from birth to 60 months. By mapping cerebellar topography with fine temporal detail for the first time, we show the hierarchical organization of cerebellocortical functional connectivity from infancy. We observe dynamic shifts in cerebellar network gradients, which become more focal with age while generally maintaining stable anchor points similar to adults, highlighting the cerebellums evolving yet stable role in functional integration during early development. Our findings provide the first evidence of cerebellar connections to higher-order networks at birth, which generally strengthen with age, emphasizing the cerebellums early role in cognitive processing beyond sensory and motor functions. Our study provides insights into early cerebellocortical interactions, reveals functional asymmetry and sex-specific patterns in cerebellar development, and lays the groundwork for future research on cerebellum-related disorders in children.

neuroscience↗

bioRxiv2024

Diversification mitigates pesticide but not microplastic effects on bees without compromising rapeseed yield in China

Humanity depends on agriculture for food, fiber and energy provisioning, but input-intensive agricultural production is impacting ecosystem services such as pollination. Pollution effects from neonicotinoid insecticides on pollinators receive much attention, but nothing is known on the synergistic effects with emerging plastic contaminants and the mitigation potential of agricultural diversification. Here, we conduct the first large-scale and full-factorial mesocosm study to understand two-generation effects of diversified floral resources (diversification treatment), neonicotinoid and microplastic pollution (pollution treatments) on Osmia cornifrons bees in 72 mesocosms. In our three-year experiment, we found that diversification can mitigate individual neonicotinoid effects. We did not find any individual or synergistic effects of microplastic on reproductive performance of solitary bees. None of our treatments affected rapeseed yield. Our results confirm the benefits of diversified flower resources to mitigate pesticide effects on bees in China and suggest that microplastics have no acute individual or interaction toxicity in semi-natural environment at realistic exposure levels. Diversified flower resources in Chinese agricultural landscapes to mitigate pesticide pollution effects on pollinators is an important policy argument for pollinator protection with downstream implications for food security.

ecology↗

bioRxiv2024

A Unified Theory of Response Sparsity and Variability for Energy-Efficient Neural Coding

Understanding how cortical neurons use dynamic firing patterns to represent sensory signals is a central challenge in neuroscience. Decades of research have shown that cortical neuronal activities exhibit high variance, typically quantified by the coefficient of variation (CV), suggesting intrinsic randomness. Conversely, substantial evidence indicates that cortical neurons display high response sparseness, indicative of efficient encoding. The apparent contradiction between these neural coding properties--stochastic yet efficient--has lacked a unified theoretical framework. This study aims to resolve this discrepancy. We conducted a series of analyses to establish a direct relational function between CV and sparseness, proving they are intrinsically correlated or equivalent across different statistical distributions in neural activities. We further derive a function showing that both irregularity and sparsity in neuronal activities are positive functions of energy-efficient coding capacity, quantified by Information-Cost Efficiency (ICE). This suggests that the observed high irregularity and sparsity in cortical activities result from a shared mechanism optimized for maximizing information encoding capacity while minimizing cost. Furthermore, we introduce a CV-maximization algorithm to generate kernel functions replicating the receptive fields of the primary visual cortex. This finding indicates that the neuronal functions in the visual cortex are optimal energy-efficient coding operators for natural images. Hence, this framework unifies the concepts of irregularity and sparsity in neuronal activities by linking them to a common mechanism of coding efficiency, offering deeper insights into neural coding strategies.

neuroscience↗

bioRxiv2024

Diversification and conservation of DNA binding specificities of SPL family of transcription factors

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/612952v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1154c42org.highwire.dtl.DTLVardef@1419f5borg.highwire.dtl.DTLVardef@1454a7aorg.highwire.dtl.DTLVardef@1cbd5f_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGRAPHICAL ABSTRACTC_FLOATNO C_FIG SQUAMOSA Promoter-Binding Protein-Like (SPL) transcription factors are key regulators of plant development and stress responses. Here, we present a comprehensive DNA affinity purification sequencing (DAP-seq) analysis of 14 of the 16 SPL members in Arabidopsis thaliana, revealing two major classes based on distinct DNA-binding motifs. Gene Ontology enrichment of target genes indicated both shared and specialized functions among AtSPLs, including roles in hormone signaling, metal ion homeostasis, and developmental transitions. Comparative analysis of closely related paralogs, AtSPL9 and AtSPL15, uncovered divergence in their genomic binding locations and target gene regulation, particularly in auxin and abscisic acid pathways. These differences were supported by motif analysis and protoplast reporter assays. Extending our study across species, we analyzed DAP-seq data from maize (Zea mays) and wheat (Triticum aestivum) SPL homologs, identifying conserved target genes but species-specific DNA motifs. Notably, wheat SPLs preferentially bind to longer, palindromic motifs distinct from the GTAC core motif in Arabidopsis. Using AlphaFold3 structure modeling, we show that these motif differences may arise from enhanced protein-protein interactions that stabilize dimeric binding. Our results highlight how SPL family members diversify through DNA-binding evolution and suggest that transcription factor dimerization contributes to motif complexity and regulatory specialization across plant genomes.

plant biology↗

bioRxiv2024

OsWHY1/OsTRXz/OsMORFs complex is essential for RNA modification and early chloroplast development in rice

WHIRLY (WHY) proteins are single-stranded DNA/RNA-binding proteins that play multifaceted roles in various plant species. The regulatory mechanisms of WHY proteins in rice remains blank. Here we demonstrate that OsWHY1 in rice is required for early chloroplast development. CRISPR/Cas9-generated oswhy1 knockout lines displayed albino seedling phenotypes, abnormal chloroplast structure and comprised redox balance in leaves. OsWHY1 interacts with multiple plastid proteins, including the thioredoxin OsTRXz and two multiple organellar RNA editing factors (OsMORF8 and OsMORF9) in chloroplasts. Accordingly, several plastid genes dependent on plastid-encoded RNA polymerase (PEP) in the oswhy1 mutants were significantly depressed at both transcript and protein levels. The editing of rps14 transcripts and splicing of rpl2, along with their protein expression, were defective in the oswhy1 mutants. OsWHY1 exhibited RNA-binding activity, specifically binding to rps14 and rpl2 precursor RNAs, which underscores its role as a post-transcriptional regulator essential for normal protein synthesis in chloroplasts. Loss-of- function mutants of either OsWHY1 or OsMORF9 and OsTRXz displayed albino phenotypes, disrupted H2O2 homeostasis, and defective RNA processing in rps14 and rpl2, suggesting the OsWHY1-OsTRXz-OsMORFs regulatory module is vital for maintaining chloroplast stability and integrity through its RNA-binding activity and its role in recruiting OsTRXz and OsMORFs to ensure proper RNA modification. One sentence summaryOsWHY1 is integral to chloroplast development in rice through its RNA-binding activity and its role in recruiting OsTRXz and OsMORFs to ensure proper RNA modification.

plant biology↗

bioRxiv2024

Involvement of OsS40-14 in ROS and plastid organization related regulatory networks of dark-induced senescence in rice

Dark-induced senescence triggers significant metabolic changes that recycle resources and ensure plant survival. In this study, we identified a transcription factor OsS40-14 in rice, which can form homo-oligomers. The oss40-14 knockout mutants exhibited stay-green phenotype of primary leaf and flag leaf during dark-induced condition, with substantial retention of chlorophylls and photosynthetic capacity as well as remarkably reduced reactive oxygen species (ROS), while OsS40-14 overexpressing transgenic lines (oeOsS40-14) showed an accelerated senescence phenotype under dark-induced leaf senescence conditions. Transcriptome analysis revealed that when the detached leaves of oss40-14 and WT were treated in darkness condition for 72 hours, 1585 DEGs (|Log2FC| [≥]1, P value<0.05) were reprogrammed in oss40-14 relative to WT. CUT&Tag-seq analysis in protoplast transient expression of OsS40-14 system showed that OsS40-14 was 40.95% enriched in the transcription start site (TSS) of the genome. Sequence clustering analysis showed that OsS40-14 protein was mainly enriched and bound to TACCCACAAGACAC conserved elements. The seed region "ACCCA" of OsS40 proteins was identified by single nucleotide mutagenesis EMSA. The integrative analysis of transcriptome and CUT&Tag-seq datasets showed 153 OsS40-14-targeted DEGs, they mainly enriched in plastid organization and photosynthesis process at dark-induced condition in oss40-14 relative to WT. Among them, eleven candidate targets of OsS40-14 such as Glucose 6-phosphate/phosphate translocator, Na+/H+ antiporter, Catalase, Chitinase 2, Phosphate transporter 19, OsWAK32, and OsRLCK319 were directly targeted and upregulated confirmed by ChIP-PCR and RT-qPCR. It demonstrates a novel model of OsS40-14 mediating macromolecule metabolism and nutrient recycling controls the plastid organization during dark-induced leaf senescence. Significant statementInvolvement of OsS40-14 in macromolecule catabolism, nutrient recycling, and ROS homeostasis revealed a plastid organization defection of dark-induced senescence in rice

plant biology↗

bioRxiv2024

Effects of clinically relevant radionuclides on the activation of a type I interferon response by radiopharmaceuticals in syngeneic murine tumor models

Radiopharmaceutical therapies (RPT) activate a type I interferon (IFN1) response in tumor cells. We hypothesized that the timing and amplitude of this response varies by isotope. We compared equal doses delivered by 90Y, 177Lu, and 225Ac in vitro as unbound radionuclides and in vivo when chelated to NM600, a tumor-selective alkylphosphocholine. Response in murine MOC2 head and neck carcinoma and B78 melanoma was evaluated by qPCR and flow cytometry. Therapeutic response to 225Ac-NM600+anti-CTLA4+anti-PD-L1 immune checkpoint inhibition (ICI) was evaluated in wild-type and stimulator of interferon genes knockout (STING KO) B78. The timing and magnitude of IFN1 response correlated with radionuclide half-life and linear energy transfer. CD8+/Treg ratios increased in tumors 7 days after 90Y- and 177Lu-NM600 and day 21 after 225Ac-NM600. 225Ac-NM600+ICI improved survival in mice with WT but not with STING KO tumors, relative to monotherapies. Immunomodulatory effects of RPT vary with radioisotope and promote STING-dependent enhanced response to ICIs in murine models. TeaserThis study describes the time course and nature of tumor immunomodulation by radiopharmaceuticals with differing physical properties.

cancer biology↗

bioRxiv2024

A long non-coding RNA LINC00094 regulates the transcriptional expression of lipid metabolism-related genes as a new member of core regulatory circuitry in esophageal squamous cell carcinoma

LINC00094 as a new supper-enhancer (SE)-related long non-coding RNA is associated with poor overall survival of patients with esophageal squamous cell carcinoma (ESCC). However, the transcriptional regulatory mechanism of LINC00094 and the molecular mechanisms by which LINC00094 affects the phenotype of ESCC remains unclear. Here, we found that LINC00094 promoted the proliferation of ESCC cells both in vitro and in vivo. LINC00094 knockdown significantly reduced the expression profiles of transcription activators including transcription factor 3 (TCF3) and Kruppel like factor 5 (KLF5) and lipid metabolism-related genes. Mechanically, TCF3 and KLF5 formed a core regulatory circuitry (CRC) that bound to the SEs of LINC00094 and to their own SEs to regulate the transcriptional expression in a positive feedback loop. LINC00094 recruited TCF3 and KLF5 to form a ternary complex, which forms a new CRC with TCF3 and KLF5 that regulated its own transcription as well as lipid metabolism-related genes. Knockdown of any or all three genes inhibited the expression of genes related to lipid synthesis and consistently reduced total lipid droplet levels. Treatment with SEs inhibitors (THZ1 and JQ1) effectively inhibited the formation of this CRC and the production of lipid droplets in ESCC cells. The high-risk group of CRC-associated signatures were closely associated with poor prognosis in patients with ESCC. Our findings suggest that LINC00094 is involved in the CRC by forming a complex with TCF3 and KLF5, and this regulation model can affect the phenotype of ESCC cells by controlling the expression of lipid metabolism-related genes. HighlightsO_LIWe identified a novel functional lncRNA-LINC00094 for esophageal squamous cell carcinoma. C_LIO_LILINC00094 forms a complex with the core transcription factors TCF3 and KLF5, thereby forming a core regulatory circuitry to participate in transcriptional regulation in ESCC. C_LIO_LIA core regulatory circuitry mediated by LINC00094 regulates lipid metabolism in ESCC. C_LI

cancer biology↗

bioRxiv2024

Hierarchical global and local auxin signals coordinate cellular interdigitation in Arabidopsis

The development of multicellular tissues requires both local and global coordination of cell polarization, however, the mechanisms underlying their interplay are poorly understood. In Arabidopsis, leaf epidermal pavement cells (PC) develop a puzzle-piece shape locally coordinated through apoplastic auxin signaling. Here we show auxin also globally coordinates interdigitation by activating the TIR1/AFB-dependent nuclear signaling pathway. This pathway promotes a transient maximum of auxin at the cotyledon tip, which then moves across the leaf activating local PC polarization, as demonstrated by locally uncaged auxin globally rescuing defects in tir1;afb1;afb2;afb4;afb5 mutant but not in tmk1;tmk2;tmk3;tmk4 mutants. Our findings show that hierarchically integrated global and local auxin signaling systems, which respectively depend on TIR1/AFB-dependent gene transcription in the nucleus and TMK-mediated rapid activation of ROP GTPases at the cell surface, control PC interdigitation patterns in Arabidopsis cotyledons, revealing a mechanism for coordinating a local cellular process with the development of whole tissues.

plant biology↗

bioRxiv2024

Functional Hierarchy of the Human Neocortex from Cradle to Grave

Recent evidence indicates that the organization of the human neocortex is underpinned by smooth spatial gradients of functional connectivity (FC). These gradients provide crucial in-sight into the relationship between the brains topographic organization and the texture of human cognition. However, no studies to date have charted how intrinsic FC gradient archi-tecture develops across the entire human lifespan. In this work, we model developmental trajectories of the three primary gradients of FC using a large, high-quality, and temporally-dense functional MRI dataset spanning from birth to 100 years of age. The gradient axes, denoted as sensorimotor-association (SA), visual-somatosensory (VS), and modulation-representation (MR), encode crucial hierarchical organizing principles of the brain in development and aging. By tracking their development throughout the human lifespan, we provide the first ever comprehensive low-dimensional normative reference of global FC hierarchical architecture. We observe significant age-related changes in global network features, with global markers of hierarchical organization increasing from birth to early adulthood and decreasing there-after. During infancy and early childhood, FC organization is shaped by primary sensory processing, dense short-range connectivity, and immature association and control hierarchies. Functional differentiation of transmodal systems supported by long-range coupling drives a convergence toward adult-like FC organization during late childhood, while adolescence and early adulthood are marked by the expansion and refinement of SA and MR hierarchies. While gradient topographies remain stable during late adulthood and aging, we observe decreases in global gradient measures of FC differentiation and complexity from 30 to 100 years. Examining cortical microstructure gradients alongside our functional gradients, we observed that structure-function gradient coupling undergoes differential lifespan trajectories across multiple gradient axes.

neuroscience↗