Biology subjects

Ito, T.

Publications and source records attributed to Ito, T..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Sox4 in Treg Cells Suppresses IL-10 Production via c-Maf Degradation and Exacerbates Type 2 Inflammation

The anti-inflammatory cytokine interleukin-10 (IL-10) produced by regulatory T (Treg) cells plays a crucial role in regulating allergic airway inflammation. However, the mechanisms governing IL-10 production in Treg cells remain unclear. In this study, we first identified Sox4 as a gene whose expression is down-regulated in IL-10-producing Treg cells. Comprehensive gene expression profiling of Sox4-deficient Treg cells and Sox4-overexpressing Treg cells revealed specific downregulation of Il10 and Ctla4 by Sox4. Sox4-deficient Treg cells exhibited increased IL-10 production and CTLA-4 expression both in vitro and in vivo and strongly suppressed Th2 cell proliferation compared with Sox4-expressing Treg cells. In a house dust mite (HDM)-induced asthma model, Treg-specific Sox4-deficient (Sox4-cKO) mice exhibited IL-10-dependent reductions in eosinophilic inflammation and Th2 cell infiltration in the airways. A comparison of Sox4-cKO and wild-type Treg cells in the same inflamed environment in mixed bone marrow chimeric mice with HDM-induced asthma revealed that Sox4-mediated suppression of c-Maf is cell-intrinsic. In addition, overexpression of Sox4 in Treg cells repressed the activation of c-Maf-regulated chromatin regions, including those around the Il10 and Ctla4 loci. Moreover, Sox4-induced suppression of IL-10 and CTLA-4 in Treg cells was rescued by forced expression of c-Maf. While Sox4 did not significantly affect Maf mRNA levels, Sox4 degraded c-Maf proteins in Treg cells through its 33 C-terminal residues. Via a domain distinct from its C-terminus, Sox4 physically interacted with c-Maf, subsequently facilitating its degradation through a ubiquitin-proteasome pathway. These findings elucidate a mechanism by which Sox4 influences the asthmatic responses by regulating the c-Maf/IL-10 axis in lung Treg cells.

immunology↗

bioRxiv2025

Aligning transformer circuit mechanisms to neural representations in relational reasoning

Relational reasoning--the capacity to understand how elements relate to one another--is a defining feature of human intelligence, yet its computational basis remains unclear. Here, we combined human neuroimaging (7T fMRI) with artificial neural network modeling to identify circuit-level analogues of human reasoning computations. Using the Latin Square Task, we found that humans and transformers were able to generalize the task reliably, while standard architectures used in cognitive neuroscience could not. Analysing the transformer components revealed distinct computational roles: positional encoding captured the spatial structure of the task and aligned with representations in visual cortex, whereas attention encoded relational structure and mapped onto frontoparietal and default-mode networks. Attention weights tracked the relational complexity of the task, providing a computational analogue of reasoning demands. These results advance knowledge on the core algorithmic computations supporting complex reasoning, highlighting attention-based architectures as powerful models for investigating the neural and computational basis of higher cognition.

neuroscience↗

bioRxiv2025

LOBSTERS: a modular vector series with a diverse set of Cas nucleases and plasmid selection markers for multiplex genome editing in Saccharomyces cerevisiae

The budding yeast Saccharomyces cerevisiae is a central model organism in genetics and synthetic biology, yet efficient multiplex genome editing remains difficult because many toolkits are restricted by limited plasmid selection markers and reduced efficiency when targeting multiple loci. In our previous work, we introduced a CRISPR-based system incorporating three nucleases with distinct PAM specificities but it was available only with the URA3 marker. Here we present LOBSTERS, an expanded modular vector series that retains the PAM-diverse nucleases (SpCas9, SaCas9, and enAsCas12a) while extending marker options to seven. This design enables the simultaneous use of multiple plasmids in one transformation, supporting scalable and flexible genome editing. Proof-of-concept experiments demonstrated efficient ADE2 and ADE3 deletions with colorimetric readouts, coordinated tagging of essential proteins (Cdc3 and Cse4) without compromising function, and recapitulation of three quantitative trait variants (RME1, TAO3, and MKT1) underlying sporulation efficiency. Together these results establish LOBSTERS as a robust and versatile platform for multiplex genome editing in S. cerevisiae. By enabling coordinated modification of essential proteins, genetic interactions, and quantitative trait variants, LOBSTERS provides a broadly applicable resource for functional cell biology and synthetic biology in yeast. Significance StatementO_LILOBSTERS integrates three PAM-diverse nucleases with seven plasmid selection markers, overcoming the single-marker limitation of previous yeast genome editing toolkits. C_LIO_LIThe system enables efficient simultaneous editing at multiple loci, demonstrated by functional tagging of essential proteins and recapitulation of quantitative trait variants. C_LIO_LIBy broadening the editable space and lowering barriers to complex genotype construction, LOBSTERS provides a widely applicable resource for yeast cell biology and synthetic biology. C_LI

molecular biology↗

bioRxiv2025

Arabidopsis epigenetic factor AS2 attenuates nucleolar stress by camptothecin and establishes leaf polarity by repressing a CDK inhibitor

The Arabidopsis thaliana leaf, exhibiting a symmetrically extended flat morphology, consists of two distinct cellular domains: adaxial and abaxial layers. The ASYMMETRIC LEAVES2 (AS2) gene is essential for specifying the adaxial domain, and its protein forms nucleolar structures, termed AS2 bodies, at ribosomal-DNA loci. Numerous nucleolus-related genes have been reported to be cooperatively involved in leaf adaxialization together with AS2. However, the molecular relationships between AS2 and these genes remain unclear. To identify chemical modulators of AS2 function, we screened a chemical library containing natural products and identified eight molecules, including camptothecin, that induced filamentous leaves in the as2 mutant. Camptothecin is an inhibitor of topoisomerase I, which is required for transcription of ribosomal-RNA genes, and induces nucleolar stress. Treatment with 10-hydroxy-camptothecin increased KIP-RELATED-PROTEIN5/INHIBITOR-OF-CYCLIN-DEPENDENT-KINASE3 (KRP5/ICK3) transcript levels, encoding a CDK inhibitor, and caused notable changes in the number and morphology of AS2 bodies. Given its role in leaf morphogenesis, our findings suggest that AS2 is a key factor in establishing leaf adaxial-abaxial polarity by regulating cell proliferation and protecting against nucleolar stress through coordinated interactions with nucleolar proteins.

developmental biology↗

bioRxiv2025

The interferon-stimulated gene product HERC5 inhibits human LINE-1 retrotransposition with an ISGylation-independent mechanism

Text AbstractMobilization of long interspersed element-1 (LINE-1 or L1) compromises genome stability and can cause sporadic genetic disease. Accordingly, cells have evolved multiple mechanisms to restrict L1 retrotransposition. Several interferon-stimulated genes (ISGs) that interact with cytoplasmic L1 ribonucleoproteins (RNPs), which contain the L1-encoded proteins ORF1p and ORF2p, have been identified as suppressors of L1 retrotransposition. We previously reported that the ISG protein HECT and RLD domain containing E3 ubiquitin-protein ligase 5 (HERC5) efficiently inhibits L1 retrotransposition. While HERC5 is known to restrict numerous viruses through ISGylation, how HERC5 inhibits L1 remains to be elucidated. Here, we show that HERC5 inhibits L1 retrotransposition through an ISGylation-independent mechanism. HERC5 interacts with L1 RNA and reduces ORF1p levels, a function that requires the ORF1 coding sequence. We further demonstrate that HERC5 decreases L1 translation efficiency and prevents the assembly of L1 RNPs. Our comparative analysis suggests that HERC5 may have acquired its L1-inhibitory function during the evolution of the small HERC family. These findings uncover a previously unidentified mechanism by which an ISG protein recognizes and inhibits L1 and suggest a role for HERC5 as an evolutionarily adapted restriction factor that expands the repertoire of cellular defenses against retrotransposons.

molecular biology↗

bioRxiv2025

Taurine Transporter SLC6A6 Expression Promotes Mesenchymal Stromal Cell Function

Mesenchymal stromal cell (MSC) differentiation is critical for the development, maintenance, and repair of bone tissue. This occurs within the bone marrow microenvironment, which consists of various stromal populations and structural components that support skeletal growth, repair and homeostasis. MSCs also promote self-renewal of hematopoietic stem cells and regulate their differentiation. Analysis of our own and publicly available single-cell RNA sequencing datasets of the murine non-immune bone and bone marrow indicates that Slc6a6 expression is enriched in MSCs. Slc6a6 encodes for an ion-dependent transporter of taurine (TauT). Although taurine supplements have been shown to mitigate the onset of bone defects in aged populations, the absence of TauT expression in osteolineage cells suggests that taurines effect on bone may be secondary to its function in other populations, such as MSCs. Using young TauT genetic loss-of-function murine models we find that TauT loss impacts MSC populations in vivo and impairs MSC osteogenic differentiation in vitro. This correlates with decreased bone mineral density and bone strength in young TauT knockout mice. Importantly, shRNA-based knockdown of SLC6A6 expression in primary human MSCs reduces osteogenic differentiation, indicating a key role of taurine uptake in human MSC function. Consistent with a decline in MSC function with TauT loss, we find that TauT null MSCs are unable to support self-renewal and expansion of co-cultured hematopoietic stem/progenitor populations. Mechanistically, our RNA-sequencing analysis identifies downregulation of Wnt/beta-catenin signaling in MSCs in the absence of TauT. These cells also show reduced oxidative phosphorylation, and increased ROS levels, indicating that impaired Wnt signaling and elevated oxidative stress may contribute to the observed defects in osteogenic differentiation capacity. Collectively, our data identify taurine uptake as a key regulator of mesenchymal stromal cell maintenance and osteogenic fate determination.

cell biology↗

bioRxiv2025

In vivo cartography of state-dependent signal flow hierarchy in the human cerebral cortex

Understanding the principle of information flow across distributed brain networks is of paramount importance in neuroscience. Here, we introduce a novel neuroimaging framework, leveraging integrated effective connectivity (iEC) and unconstrained signal flow mapping for data-driven discovery of the human cerebral functional hierarchy. Simulation and empirical validation demonstrated the high fidelity of iEC in recovering connectome directionality and its potential relationship with histologically defined feedforward and feedback pathways. Notably, the iEC-derived hierarchy revealed a monotonically increasing level along the axis where the sensorimotor, association, and paralimbic areas are sequentially ordered - a pattern supported by the Structural Model of laminar connectivity. This hierarchy was further demonstrated to flexibly reorganize across brain states: flattening during an externally oriented condition, evidenced by a reduced slope in the hierarchy, and steepening during an internally focused condition, reflecting heightened engagement of interoceptive regions. Our study highlights the unique role of macroscale directed functional connectivity in uncovering a biologically interpretable state-dependent signal flow hierarchy.

neuroscience↗

bioRxiv2025

A Functional Atlas of the Tardigrade Resistome Reveals a Diverse Molecular Toolkit for Extremotolerance

How organisms survive environmental extremes that push life to its physical limits is a fundamental question in biology. Tardigrades are a paradigm for this resilience, entering a state of suspended animation called cryptobiosis to withstand near-complete desiccation and intense radiation. While a few key effectors, including the DNA-shielding protein Dsup and various tardigrade-specific intrinsically disordered proteins (TDPs) have been identified, they constitute only a fraction of a vast, uncharacterized proteome, fundamentally limiting a systems-level understanding of this remarkable biology. Here we overcome this limitation by developing AEGIS, an AI-driven engine that systematically discovers and prioritizes novel guardian proteins constituting the tardigrade molecular shield. Applying AEGIS to the tardigrade proteome, we construct the first functional atlas of the tardigrade resistome, revealing hundreds of novel protein families organized into a diverse and compartmentalized molecular toolkit. This atlas pinpoints new Dsup-like nuclear proteins, suggesting multi-layered genome protection, and a rich cohort of cytoplasmic proteins poised to form protective biological glasses. Our work provides a foundational resource for understanding the evolution of extremotolerance and serves as a blueprint for engineering novel biomolecules with transformative biotechnological potential.

bioinformatics↗

bioRxiv2025

Improved Tumor Blood Flow Enhances the Abscopal Effect: Preclinical Assessment in Mice Treated with Combined Radiation and PD-1 Blockade Therapy

The abscopal effect, where localized radiation therapy induces regression of distant metastatic lesions through immune activation, shows promise for treating metastatic cancer but occurs inconsistently. Here we demonstrate that tumor perfusion critically influences systemic immune responses to combination therapy with radiation and PD-1 blockade. Using multimodal imaging including DCE-MRI, EPR oximetry, and hyperpolarized 13C-MRI, we show that successful abscopal responses in MC38 tumors are characterized by enhanced perfusion, reduced hypoxia, decreased cellularity, and lower glycolytic activity in remote tumors. Notably, pre-treatment perfusion metrics (AUC1min) and extracellular volume (AUC10min) in primary tumors predict subsequent growth of remote tumors, while the same measurements in remote tumors lack predictive value. Based on these findings, we enhanced the abscopal effect by exposing mice to carbogen (95% O2 + 5% CO2) during radiation therapy. Carbogen exposure increased tumor perfusion by 71% (AUC1min) and significantly improved systemic responses in the checkpoint blockade responsive MC38 model but not in the poorly responsive B16.F10 tumors. The enhanced response correlated with increased activation of CD8+ T cells in tumor-draining lymph nodes and elevated serum HMGB-1 levels. RNA sequencing revealed significant extracellular matrix remodeling in carbogen-treated tumors. These results establish tumor perfusion as both a predictive biomarker and a modifiable determinant of systemic immune responses, suggesting that perfusion-based patient stratification and vascular modification strategies could improve outcomes in combination immunotherapy and radiation treatment.

cancer biology↗

bioRxiv2025

Structure-activity relationship of an all-α-helical prenyltransferase reveals a mechanism for indole prenylation.

Enzymes are involved in the biosynthesis of various secondary metabolites found in nature. The catalytic mechanism is regulated by the three-dimensional structure of the enzyme especially at the catalytic site, resulting in the natural products with complicated conformation derived from a regioselective, chemoselective, and stereoselective fashion of the enzyme reaction. Prenyltransferase (PT), which belongs to the prenylsynthase (PS) family, catalyzes the condensation of isoprene to an aromatic compound, consequently producing a terpenoid scaffold structure. Therefore, it plays an important role in which expands the chemical diversity of terpenoids. Although the three-dimensional structures of PS which categorized in the same family were resolved, the catalytic mechanism of the PT has been vailed. In this study, we determined the X-ray crystal structure of a novel prenyltransferase SxPT1 derived from marine Streptomyces. Here we described that SxPT1 analyzed the enzyme reactions and discussed its catalytic mechanism.

biochemistry↗

bioRxiv2025

Concordance of claudin-18.2 expression in biopsy, resection, and recurrent specimens: implications for zolbetuximab therapy in pancreatic ductal adenocarcinoma

Claudin-18.2 is a promising therapeutic target for gastrointestinal cancer. However, its expression pattern in pancreatic ductal adenocarcinoma, especially the concordance between biopsy and resection specimens, is unknown. This study aimed to evaluate the consistency of claudin-18.2 positivity across different specimen types using the clinically validated antibody clone 43-14A employed in ongoing zolbetuximab trials. Immunohistochemical analysis for claudin-18 was conducted on 211 resected pancreatic cancer tissues, 133 matched preoperative biopsy samples, and 60 samples from recurrent lesions. Concordance rates were calculated based on a clinically relevant cutoff ([≥]75% of tumor cells with moderate-to-strong membranous staining). Receiver operating characteristic analysis was used to optimize the biopsy thresholds. Claudin-18.2 positivity was observed in 9.5% of the resection specimens. The concordance rates were 92.5% between biopsy and resection specimens and 83.3% between primary and recurrent lesions. Receiver operating characteristic analysis suggested that a lower cutoff (20%) in biopsy samples achieved 100% sensitivity for detecting positive cases. While overall claudin-18 expression levels were maintained in most recurrent lesions, decreased expression was frequently observed in cases of local recurrence and liver metastasis. Despite intrinsic heterogeneity and limited biopsy yield in pancreatic cancer, claudin-18 expression in small biopsy samples, assessed using the clinical trial-validated clone 43-14A, strongly correlated with that in resection specimens. These results suggest that claudin-18.2 is a clinically stable biomarker for zolbetuximab therapy in patients with pancreatic ductal adenocarcinoma. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/648482v2_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1b822e5org.highwire.dtl.DTLVardef@1fb03f0org.highwire.dtl.DTLVardef@bfa888org.highwire.dtl.DTLVardef@d1a015_HPS_FORMAT_FIGEXP M_FIG C_FIG Core TipsO_LIThis study demonstrated a high concordance (92.5%) of CLDN18.2 positivity between preoperative biopsy and resected pancreatic ductal adenocarcinoma specimens, using the clinical trial-validated antibody clone 43-14A. C_LIO_LICLDN18.2 expression in recurrent lesions generally remained consistent with that in the corresponding primary tumor, although a reduction in expression levels was observed in local recurrence and liver metastases. C_LIO_LIThese findings support the clinical utility of biopsy-based CLDN18.2 evaluation for selecting patients with pancreatic ductal adenocarcinoma who may benefit from zolbetuximab. C_LI

pathology↗

bioRxiv2025

MetDeeCINE: Deciphering Metabolic Regulation through Deep Learning and Multi-Omics

Metabolism, the biochemical reaction network within cells, is crucial for life, health, and disease. Recent advances in multi-omics technologies, enabling the simultaneous measurement of transcripts, proteins, and metabolites, provide unprecedented opportunities to comprehensively analyze metabolic regulation. However, effectively integrating these diverse data types to decipher the complex interplay between enzymes and metabolites remains a significant challenge due to the extensive data requirements of kinetic modeling approaches and the limited interpretability of machine learning approaches. Here, we present MetDeeCINE, a novel explainable deep learning framework that predicts the quantitative relationship between each enzyme and metabolite from proteomic and metabolomic data. We demonstrate that our newly developed Metabolism-informed Graph Neural Network (MiGNN), a core component of MetDeeCINE that is guided by the stoichiometric information of metabolic reactions, outperforms other machine learning models in predicting concentration control coefficients (CCCs) using data obtained from kinetic models of E. coli. Notably, MetDeeCINE, even without explicit information on allosteric regulation, can identify key distant enzymes that predominantly control the steady-state concentrations of specific metabolites. Application of MetDeeCINE to mouse liver multi-omics experimental data further demonstrated its ability to generate biologically meaningful predictions through identifying a rate-limiting enzyme of gluconeogenesis associated with obesity, consistent with existing knowledge. MetDeeCINE offers a scalable and interpretable approach for deciphering complex metabolic regulation from multi-omics data, with broad applications in disease research, drug discovery, and metabolic engineering.

systems biology↗

bioRxiv2025

SMART platform for enzyme engineering: A novel single-molecule display approach for evolution and functional studies of D-amino acid oxidase

This study introduces SMART (Single Molecule Assay on Ribonucleic Acid by Translated Product), an innovative in vitro platform integrating mRNA display, next-generation sequencing, and bioinformatics to address several key challenges in enzyme engineering. The characteristic feature of SMART is its auxiliary unit, attached to the mRNA-displayed enzyme library to mediate the biotinylation of reactive enzyme variants and enable their enrichment by streptavidin beads pull-down. The unit comprises a hairpin single-stranded DNA that hybridizes with the mRNA and anchors a DNA-binding protein, single-chain Cro, which carries functional auxiliary molecules specific to the enzyme of interest. Here, we report on the establishment of SMART for the engineering of oxidases, specifically D-amino acid oxidase (DAAO) from Schizosaccharomyces pombe, with engineered ascorbate peroxidase 2 as its auxiliary enzyme. In a single selection round of a DAAO library with randomized catalytic residue Y232 and D-Alanine as the substrate, we identified several catalytically active enzyme variants with altered substrate specificity in a matter of days. This surpasses traditional enzyme engineering methods in speed, cost, library capacity, and precision. This research underscores the potential of SMART for the engineering of various oxidases, and other enzymes after the corresponding adjustment of the auxiliary unit.

bioengineering↗

bioRxiv2025

Network geometry shapes multi-task representational transformations across human cortex

Flexible cognition requires the brain to generalize across tasks while preserving task-specific information. Previous work showed that task representations are compressed in association cortex and expanded in sensory and motor systems, but the mechanisms underlying these transformations are unclear. Here we test whether the geometry of intrinsic brain connectivity constrains how representations change between cortical regions. We analyzed fMRI acquired during 16 diverse cognitive tasks together with activity flow modelling, finding that connectivity dimensionality predicts representational changes across cortex. Low-dimensional connectivity compressed task representations and increased similarities across tasks, whereas high-dimensional connectivity expanded representations and supported conjunctive coding of task features. Activity flow modelling reproduced the observed compression to expansion pattern along the sensory-association-motor hierarchy and generated representational geometries that more closely matched targets than sources, consistent with transformation rather than transfer of information. These findings identify network geometry as a systems-level principle that shapes cortical representations and supports flexible cognition.

neuroscience↗

bioRxiv2024

Structural basis of transcription-coupled H3K36 trimethylation by Set2 and RNAPII elongation complex in the nucleosome

Trimethylation of the histone H3K36 residue (H3K36me3) plays an indispensable role in ensuring transcription fidelity by suppressing undesired cryptic transcription in chromatin. The H3K36me3 modification is accomplished by Set2/SETD2 during transcription elongation by the RNA polymerase II elongation complex (EC). Here we found that the Set2-mediated H3K36me3 deposition occurs primarily on the nucleosome reassembling behind the EC. Cryo-electron microscopy structures of the transcribing EC complexed with Set2 and the reassembled nucleosome revealed that Set2 is anchored by the Spt6 subunit of the EC and captures an H3 N-terminal tail of the nucleosome. Abrogation of the Set2-Spt6 interaction leads to defective transcription-coupled H3K36me3 deposition. These insights elucidate the structure-based mechanism of transcription-coupled H3K36me3 deposition in chromatin. One-Sentence SummaryCryo-EM structures of the EC-Set2-nucleosome complex reveal the mechanism of H3 Lys36 trimethylation in chromatin.

biochemistry↗

bioRxiv2024

Beyond dichotomy: diversity of rat's ultrasonic vocalizations

Rats emit ultrasonic vocalizations (USVs) in diverse contexts, and these USVs are thought to serve many biological functions, such as socio-coordinating and alarming functions. In particular, rat USVs have been established as a good model for studying emotional expressions. Since the discovery of USVs in rats, it has gradually been revealed that two families of juvenile and adult rat USVs with distinct acoustic features are closely linked to different affective states: 50-kHz (high-short) calls are associated with positive affective states, whereas 22-kHz (low-long) calls are associated with negative affective states. Although various subtypes within high-short and low-long calls have been proposed and used, most studies adopt the dichotomous framework of first dividing USVs into high-short or low-long calls. The diversity of rat USVs may have been overlooked due to this high-short / low-long dichotomous framework, as such labeling could discourage reporting of actual measured acoustic properties. Considering that several recent studies claim to have found new USV categories outside this framework, we conducted a systematic survey of descriptions of rat USVs in the literature. We identified 15 articles reporting USVs that are outside the dichotomous framework. Our results support the existence of diverse USVs beyond the dichotomy, highlighting the importance of research on a broader range of vocalizations that might reflect complex affective states beyond the simple distinction between positive and negative.

animal behavior and cognition↗

bioRxiv2024

Crystal structure of plant γ-glutamyl peptidase 1 with dual roles in sulfur metabolism and implications for oxidative stress regulation

{gamma}-Glutamyl peptidase 1 (GGP1) plays a dual role in primary and secondary sulfur metabolism in Arabidopsis thaliana. During glutathione (GSH) turnover, GGP1 hydrolyzes the isopeptide bond of GSH to degrade the tripeptide into Glu and Cys-Gly. During glucosinolate and camalexin biosynthesis, GGP1 processes GSH conjugates, which have a large substituent at the thiol side chain, by hydrolyzing the same isopeptide bond of {gamma}-Glu. In the present study, we determined the crystal structures of the following GGP1 forms: ligand-free, Glu complex, covalent {gamma}-Glu intermediate, and disulfide-linked S-S inactive forms. The intermediate structure, in which {gamma}-Glu is covalently linked to the nucleophile C100, was trapped by mutating the catalytic His to Asn (H192N). In the Glu complex and {gamma}-Glu intermediate structures, Glu bound to the S1 subsite is extensively recognized by several hydrogen bonds. The substrate recognition of the Cys-Gly moiety at the S1 and S2 subsites was revealed by modeling GSH in the active site. Mutational analysis indicated that R206 plays an important role in substrate binding by forming a salt bridge with Gly at the S2 subsite. An open pocket is present beyond the thiol side chain of Cys in the S1 subsite, which contributed to the dual activity of GGP1 toward GSH and GSH conjugates. The S-S inactive structure was obtained by soaking GGP1 crystals in Cys-Gly, and the catalytic cysteine (C100) partially formed a disulfide bond with a neighboring C154 residue. The partial inactivation of GGP1 in the presence of a pro-oxidant (Cys-Gly) has revealed its possible role in oxidative stress regulation in Arabidopsis.

biochemistry↗

bioRxiv2024

Temporally delayed representations in alpha and beta rhythms in higher-order cortical networks track increasing relational integration demands

Relational reasoning is the ability to infer and understand the relations between multiple elements. In humans, this ability supports higher cognitive functions and is linked to fluid intelligence. Relational complexity (RC) is a cognitive framework that offers a generalisable method for classifying the complexity of reasoning problems. To date, increased RC has been linked to static patterns of brain activity supported by the frontoparietal system, but limited work has assessed the multivariate spatiotemporal dynamics that code for RC. To address this, we conducted representational similarity analysis in two independent neuroimaging datasets (Dataset 1 fMRI, n=40; Dataset 2 EEG, n=45), where brain activity was recorded while participants completed a visuospatial reasoning task that included different levels of RC (Latin Square Task). Our findings revealed that, spatially, RC representations were widespread, peaking in brain networks associated with higher-order cognition (frontoparietal, dorsal-attention, and cingulo-opercular). Temporally, RC was represented in the 2.5 - 4.1 seconds post-stimuli window and emerged in the alpha and beta frequency range. Finally, multimodal fusion analysis demonstrated that shared variability within EEG-fMRI signals within higher-order cortical networks were better explained by the theorised RC model, relative to a model of cognitive effort (CE). Altogether, the results further our understanding of the neural representations supporting relational processing, highlight the spatially distributed coding of RC and CE across cortical networks, and emphasise the importance of late-stage, frequency-specific neural dynamics in resolving RC.

neuroscience↗