Protein kinases are the most intensively targeted protein family for small-molecule drugs, and the large volume of inhibitory-assay data reported for them makes the family particularly well suited to data-driven and machine-learning approaches to drug discovery. This data, however, is scattered across heterogeneous assays, reports and publications, and its reuse for modeling requires substantial curation. Here, we present Kinoteca, a curated database of kinase inhibitory-activity data derived from ChEMBL and accessible through a web interface for browsing, filtering, visualization and download. Kinoteca reconciles the multiple raw independent measurements reported for each combination of compound, kinase and activity type into a single fused activity value, together with a dispersion score based on the mean unsigned error (MUE) that quantifies how consistent the underlying measurements were. The database currently organizes curated data for 585 kinases and arranges them along biologically meaningful groupings such as kinome family, pathway and source organism. Curated activities can be filtered by the physicochemical properties of the assayed molecules or by measurement quality, explored through summary statistics, activity distributions and structural clustering, and exported either as curated or semi-raw data tables or as molecular structure files. These data formats are suitable for the direct training of machine learning models, such as activity prediction models. By delivering reconciled, analysis-ready data with its provenance preserved, Kinoteca aims to lower the barrier to reproducible, data-driven kinase drug discovery.
Osteoarthritis (OA) remains a challenging disease due to the increased rate of incidence in the older population and the lack of a disease-modifying drug. BMP signaling plays a crucial role in chondrogenic differentiation and in the stability of articular cartilage. However, because BMP-2 also induces chondrocyte hypertrophy, it is not a viable drug for OA treatment. In contrast, the Bmpr1a biomimetic peptide can repair articular cartilage without inducing chondrocyte hypertrophy in the OA mouse model and in chondrocytes derived from patients diagnosed with OA. Despite this benefit, the mechanism by which the peptide drives chondrogenesis remains elusive. To explore this, we use a phosphoproteomics approach to identify pathways differentially activated by CK2.1. Specifically, we identified differentially phosphorylated phosphosites by CK2.1. Based on these phosphosites that we identified, we propose a molecular mechanism by which CK2.1 activates chondrogenesis. Notably, we predict that the mitogen-activated protein kinase (MAPK) pathway is regulated by CK2.1 to induce proteoglycan synthesis in C3H10T1/2 cells.
Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR), whose folding, trafficking, and stability are tightly controlled by ubiquitination-dependent protein quality control (PQC) pathways. Although CFTR modulators have transformed CF therapy, their efficacy remains limited by persistent ubiquitination and degradation of rescued CFTR. This limitation is particularly evident in class I mutations, where premature termination codons (PTCs) reduce full-length CFTR protein production and no approved mutation-specific therapies are broadly available for canonical PTC variants. Recent advances highlight ubiquitination as a critical and druggable determinant of CFTR stability. The E3 ligase RFFL regulates peripheral CFTR PQC, restricting the stability of rescued CFTR at the plasma membrane (PM). Inhibition of RFFL, including via antisense oligonucleotides (ASO) and small molecules, enhances CFTR rescue and improves outcomes in combination with modulators and translational readthrough therapies. In parallel, deubiquitinase (DUB)-targeting chimeras (DUBTACs) have emerged as a novel modality to stabilize proteins by reversing ubiquitination. Here, we review current advances in targeting CFTR ubiquitination, with a focus on RFFL inhibition and DUBTAC-based strategies, and discuss their opportunities and translational limitations as components of next-generation CF therapies.
During development, stem cells rapidly proliferate and differentiate to form the embryo and the placenta, requiring intensive increases in cellular protein synthesis and changes to the cell architecture. Chaperone proteins, including the small heat shock proteins (HSPs), are critical assistants to protein folding, preventing protein aggregation, and promoting autophagy. Mitogen-activated protein kinase kinase kinase 4 (MAP3K4) is a stress-activated kinase that promotes fetal and placental growth. MAP3K4 directly activates p38 and JNK in trophoblast stem (TS) cells by phosphorylating MAP2K3 and MAP2K4/7, respectively. In addition, MAP3K4 promotes activation of the Akt signaling pathway by controlling Igf1r expression. TS cells differentiate to placental trophoblasts comprising the junctional zone (JZ) and labyrinth (LAB) placental layers. In this study, we demonstrate that JZ differentiation transiently increases JNK activity, whereas LAB differentiation induces sustained p38, JNK, and Akt activation. Each of these pathways is inhibited in MAP3K4 kinase-inactive (KI) LABKI trophoblasts. JZ and LAB differentiation also induces HSP22 and HSP27 expression and HSP27 phosphorylation; these are also reduced in TSKI and LABKI cells. JZ and LAB differentiation induces GABARAP-positive autophagosomes that are deficient in KI cells. Altogether, our findings demonstrate that MAP3K4 is critical for responses during differentiation in placental trophoblasts.
Oleanolic acid (OA) is a pentacyclic triterpenoid with broad biological activity, but its primary molecular points of engagement remain incompletely resolved. Most available studies describe OA through selected pathway markers, particularly within PI3K/AKT/mTOR, AMPK/mTOR, MAPK, NF-κB, and Nrf2 signaling, without clearly distinguishing direct target engagement from downstream adaptive responses. This limits mechanistic interpretation and weakens translational prioritization. This review focuses specifically on phosphoproteomics-centered and multi-omics-assisted target deconvolution of OA rather than providing a comprehensive catalog of all reported biological effects of OA. We examine why phosphoproteomics is particularly informative for capturing early signaling events, how it can be integrated with total proteomics, transcriptomics, metabolomics, and chemoproteomic approaches, and why orthogonal target-engagement methods remain essential for stronger causal inference. We also organize the current signaling evidence for OA and its derivatives, distinguishing pathway association, kinase/phosphatase activity inference, target prioritization, and direct target validation. The strongest mechanistic support for the parent compound currently concerns AMPK/mTOR-linked regulation of autophagy and apoptosis, whereas evidence for several other pathways remains more heterogeneous, derivative-dependent, or marker-based. Finally, we propose a stepwise workflow for OA target deconvolution based on time-resolved phosphoproteomics, informative phosphosite subsets, multi-omics integration, kinase/phosphatase activity inference, and experimental target validation. This framework may help move OA research from descriptive pathway pharmacology toward mechanism-based target prioritization and more rational derivative development.
Protein kinase inhibition can be achieved through various mechanisms, including blocking phosphorylation activity or disrupting regulatory interactions. While small molecule inhibitors have shown promise, their selectivity remains challenging due to the structural similarities among kinase catalytic sites. To design selective kinase inhibitors based on peptide terminal tail interactions with the activation segment, focusing on five kinases with different conformational states: GSK3, PAK4, TTN (OUT conformation) and PKB, FLT3 (IN conformation). Three-dimensional structures from RCSB PDB were optimized using MODELLER version 9.0. Peptide sequences were designed with PeptiDerive (Rosetta) and RosettaDesign version 3.5, followed by pharmacophore modeling based on key interaction residues. Virtual screening was then conducted with PyRx 0.8 and molecular docking with AutoDock Vina 1.1.2. Molecular dynamics simulations were performed using Desmond v6.6 (Schrödinger Suite 2016, Multisim v3.8.5.19) (100 ns, NPT ensemble, 300 K). Analysis of the five kinases revealed distinct interaction profiles with designed peptidomimetic compounds. Kinases displaying the IN conformation of the activation segment (PKB and FLT3) consistently showed superior stability and stronger interaction profiles compared to those in the OUT conformation. The designed compounds formed key hydrogen bonds and hydrophobic interactions with critical residues in the activation segment binding pocket. The most promising inhibitors demonstrated stability throughout the molecular dynamics simulations, with IN conformation kinases maintaining more consistent conformational profiles than their OUT conformation counterparts. Kinases with IN conformation of the activation segment demonstrated superior stability and interaction profiles compared to OUT conformations. These findings contribute to our understanding of selective kinase inhibition and provide a framework for developing novel inhibitors, particularly for PKB and FLT3. The implications of this study extend to rational drug design approaches that leverage natural regulatory mechanisms for therapeutic intervention, though further optimization is needed for GSK-3β, PAK4, and TTN to improve stability and binding affinity.
Chronic lymphocytic leukemia (CLL) exhibits marked clinical heterogeneity that is closely associated with genomic instability. Although cytogenetic abnormalities are widely used for risk stratification, they do not fully capture the biological complexity of the disease. Telomere dysfunction and alterations in DNA damage response pathways have been implicated in disease progression, but their relationship with cytogenetic risk in CLL remains incompletely characterized. In this study, peripheral blood mononuclear cells (PBMCs) from 48 CLL patients were analyzed. The analyzed PBMC fractions were enriched in leukemic B cells, with an estimated median tumor content above 85–90%. Cytogenetic profiles were obtained by conventional karyotyping following in vitro immunostimulation with DSP30 and interleukin-2 and classified according to ERIC and Döhner criteria. Telomere length was assessed by quantitative PCR, and CHEK1 and CHEK2 expression levels were quantified by RT–qPCR. Molecular parameters were compared across cytogenetic risk groups. Distinct molecular profiles were observed across cytogenetic categories. Favorable-risk CLL cases showed preserved telomere length, low CHEK1 expression, and maintained CHEK2 levels. Intermediate-risk cases, predominantly characterized by trisomy 12, exhibited moderate telomere shortening accompanied by increased CHEK1 expression and partial reduction of CHEK2. High-risk CLL cases, defined by del(11q), del(17p), or complex karyotypes, displayed pronounced telomere shortening, marked CHEK1 upregulation, and strong suppression of CHEK2. Telomere length was inversely correlated with cytogenetic risk (Spearman’s ρ = −0.68, p < 0.0001), and the CHEK1/CHEK2 expression ratio increased progressively with genomic complexity. These findings indicate that telomere length and CHEK1/CHEK2 expression patterns are closely associated with cytogenetic risk in CLL and may provide complementary biological information for risk stratification.
Janus kinase 2 (JAK2) occupies a central position in cytokine signaling and plays essential roles in hematopoiesis, immune regulation, and cancer. Although recent advances in structural biology, cryo-EM, receptor modeling, and biophysical analysis have substantially expanded current views of JAK2 function, key mechanistic questions remain regarding how receptor geometry, JH2-mediated autoinhibition, and disease-associated mutations are structurally integrated. In this review, we discuss the multidomain organization of JAK2 and examine how the FERM–SH2 module, the pseudokinase domain (JH2), and the catalytic kinase domain (JH1) cooperate to govern receptor specificity, allosteric control, and cytokine-induced activation. We further analyze how pathogenic mutations rewire this regulatory system by weakening autoinhibitory contacts, altering linker-mediated communication, or stabilizing active dimeric conformations. Finally, we assess current and emerging therapeutic strategies, from ATP-competitive inhibitors to macrocyclic and JH2-selective allosteric modulators, with emphasis on how structural insight can guide next-generation drug design. These advances support a more integrated view of JAK2 regulation and define new opportunities for selective therapeutic intervention.
The tumor suppressor protein phosphatase 2A (PP2A) plays a crucial role in regulating oncogenic signaling. Its inactivation, specifically through inhibitory phosphorylation at Tyr307 mediated by SET and CIP2A, contributes to breast cancer (BC) progression. Modulation of these interactions represents a promising pharmacological strategy to restore PP2A function. We integrated computational approaches with experimental validation to analyse SET/CIP2A mechanisms and explore how PP2A reactivation suppresses tumor progression. Molecular docking and dynamics simulations showed that the SET inhibitor/FTY-720 forms stable hydrogen bond networks with SET, disrupting its interaction with PP2A. In contrast, CIP2A suppressor/erlotinib interacts with CIP2A through weaker hydrophobic and π-interactions. Protein–protein interaction analyses indicate reduced SET/CIP2A binding to PP2A upon treatment, supporting a structural basis for PP2A reactivation. Gene expression analyses revealed upregulation of PP2A, SET, CIP2A, and cytoskeletal markers in tumor and metastatic tissues. Studies on Triple Negative Breast Cancer (TNBC) cells showed that FTY-720 and erlotinib significantly reduce PP2A-Tyr307 phosphorylation, restoring its activity. Additionally, both compounds decreased c-Myc levels and inhibited Src/FAK/paxillin/PAK1 and ERK signaling, attenuating migratory and proliferative pathways. Our findings identify the SET/CIP2A–PP2A axis as a pharmacological target for the design of next-generation PP2A activators, highlighting the potential of inhibition as a therapeutic strategy to counteract TNBC progression.
Pediatric gastrointestinal (GI) cancers are rare malignancies that differ fundamentally from their adult counterparts in molecular drivers, histology, and clinical behavior. While adult GI cancers are frequently driven by recurrent oncogenic mutations, pediatric tumors often exhibit pathway-level dysregulation involving developmental signaling networks. Among these, the RAS/MAPK pathway emerges as a central convergent axis integrating growth factor signaling, developmental programs, inflammatory cues, and post-translational regulatory mechanisms. Increasing evidence suggests that aberrant phosphorylation dynamics result from imbalanced kinase activation and phosphatase-mediated signal attenuation, which contribute to sustained MAPK signaling in pediatric GI malignancies, even in the absence of canonical RAS or RAF mutations. This review synthesizes current knowledge on RAS/MAPK signaling in pediatric GI cancers, emphasizing the role of kinase–phosphatase imbalance, signal duration, and regulatory failure in shaping oncogenic outcomes. We highlight how altered phosphorylation control may influence tumor differentiation, therapeutic responsiveness, and resistance mechanisms, and discuss emerging opportunities for targeting signaling dynamics rather than single genetic lesions. This signaling-centric framework provides a biologically grounded rationale for functional biomarker-driven precision therapy in pediatric GI malignancies.
Plant–pathogen interactions are shaped by dynamic regulatory processes that control immune signaling. Among these, post-translational modifications (PTMs) play central roles in modulating protein activity, stability, and interaction networks. Increasing evidence indicates that Phytophthora effectors target PTM-dependent regulatory systems to suppress host immunity and promote infection. Here, we synthesize current knowledge on how Phytophthora virulence factors manipulate post-translational regulation through two mechanistically distinct strategies: (i) canonical mechanisms, involving direct enzymatic modification of host proteins or the recruitment of host PTM-modifying enzymes, and (ii) non-canonical mechanisms, in which effectors alter the activity, organization, or localization of PTM-associated regulatory systems without directly inducing covalent modification. These processes frequently involve protein–protein interactions and oligomerization-dependent regulation that reshape signaling complexes and enzymatic accessibility. By distinguishing effector-mediated PTM induction from regulatory interference, we provide a mechanistic framework for interpreting how diverse virulence strategies converge on the control of immune signaling pathways, including those governing reactive oxygen species production, transcriptional regulation, hormone signaling, and cell death. We further highlight current limitations in mechanistic understanding and emphasize the need for integrative approaches combining structural biology and proteomics to resolve how effectors reprogram host signaling systems.
Trypanosoma cruzi is the protozoan parasite responsible for Chagas disease, a neglected tropical disease caused by trypanosomatids. Its success as pathogen relies on remarkable metabolic adaptability, stress tolerance, and complex interactions with mammalian hosts. Among the proteins contributing to these processes, nucleoside diphosphate kinases (NDPKs) and arginine kinase (AK) have emerged as central enzymes for parasite metabolism. NDPKs, beyond their canonical role in nucleotide homeostasis, are implicated in DNA repair and oxidative stress responses and are also secreted enzymes. AK, on the other hand, serves as a unique energy-buffering system absent in mammals, supporting parasite growth and adaptation to oxidative and metabolic stresses, including modulation of host immunity. Both enzymes display distinct subcellular localizations all along the parasite and through the life cycle, linking them to multiple roles important for parasite biology and survival. Recent studies have highlighted the impact of interfering these enzymes with several compounds on the viability of the organisms, suggesting new avenues to explore them as drug targets. This review provides a general overview of NDPKs and AK in T. cruzi, aiming to underline their relevance to a broader context of trypanosomatids. Their study not only broadens our understanding of parasite biology but also opens perspectives for applied research, including therapeutic alternatives for Chagas and related diseases.
Kinases are signaling molecules that are central to all aspects of life. Consequently, their dysregulation is implicated in numerous diseases, making kinases one of the most successful family of drug targets. However, due to the conserved catalytic domain of kinases, these drugs are frequently not selective for a specific target, and selective inhibitors—‘chemical probes’—are therefore necessary to understand the role of specific proteins or isoforms. Through the SGC chemical probe program, selective kinase inhibitors have been made available, focusing on understudied kinases. Here, we discuss recent examples of this effort and showcase how selectivity for these probes has been achieved using different approaches.
Tuberous Sclerosis Complex (TSC) is a genetic disorder caused by mutations that inactivate TSC1 or TSC2 genes. TSC1 or TSC2 mutations activate the mammalian target of rapamycin complex 1 (mTORC1) protein kinase pathway. Although many patients inherit a single copy of a mutant TSC gene, somatic mutations that cause loss of heterozygosity in inhibitory neuroprogenitor cells are hypothesized to be one cause of abnormal development. This may lead to cortical malformations or benign growths along the ventricular-subventricular zone (V-SVZ), cortex, olfactory tract, and olfactory bulbs (OB). This idea is supported by focal single-cell knockout experiments that induce CRE-mediated recombination following neonatal electroporation of conditional Tsc2 or Tsc1 mice. Loss of Tsc2 causes mTORC1 pathway activation and the formation of striatal hamartomas composed of ectopic clusters of abnormal cells and cytomegalic neurons, including within the OB. Neural phenotypes in this model can be partially rescued with Rapalink-1, a bisteric mTOR inhibitor, demonstrating the importance of mTOR in pathogenesis. We previously demonstrated that global V-SVZ neural stem cell (NSC) Tsc2 mutation induced by nestin-CRE-ERT2 causes mTORC1 pathway activation, which is accompanied by transcriptional and translational errors. While we previously described cultured NSCs and OB granule cells from these mice, we did not thoroughly describe changes outside this region. Here, we provide evidence that removal of Tsc2 from neonatal V-SVZ NSCs causes subtle and rare brain malformations. This is exemplified by ectopic clusters of cytomegalic neurons and mTORC1 activation. This data supports that loss of Tsc2 in NSCs during neonatal development leads to heterotopic clusters in the adult brain. This model may be useful to study TSC, but the rarity and stochastic nature of lesions make the use challenging for identifying mechanisms and testing therapies.
CK2α and CK2α’, two paralogous members of the human kinome, are catalytic subunits of protein kinase CK2. Together with the regulatory subunit CK2β, they form heterotetrameric holoenzymes. CK2 is the subject of efforts to develop effective and selective inhibitors. For this, secondary binding sites remote from the canonical ATP/GTP cavity are critical. A crystallographic fragment screening with CK2α’ crystals and an established molecular fragment collection was performed to identify new ligands at known or novel sites. It resulted in fourteen CK2α’/fragment structures. Five fragments were found at the CK2β interface of CK2α’ and three fragments at the established αD pocket, which exhibits subtle differences between CK2α and CK2α’; comparative co-crystallisations with CK2α showed that one of them binds to the αD pocket of CK2α’ exclusively. No fragments bound at the substrate-binding region of CK2α’, but a CK2α’ structure with dp10, a decameric section of the substrate-competitive inhibitor heparin, and the indenoindole-type ATP-competitive inhibitor 4w was determined. A comparison with a published CK2α/dp10 structure revealed features consistent with reports about substrate specificity differences between the isoenzymes: dp10 binds to CK2α’ and CK2α with opposite strand orientations, and the local conformations of the isoenzymes in the helix αD region are significantly different.
Oncogenic kinase pathways, including PI3K/AKT, RAS/ERK/MAPK and JAK/STAT, are central drivers of cancer cell proliferation, survival and metastatic potential. However, excessive activation of these pathways imposes intrinsic cellular stresses, such as oncogene-induced senescence, DNA damage responses and apoptosis. Recent evidence reveals that cancer cells mimic immunoregulatory programs to mitigate these stresses by ectopically expressing inhibitory receptors traditionally found on hematopoietic cells. These receptors recruit phosphatases such as DUSPs, SHP1, SHIP1 and PP2A, which directly counteract hyperactivated kinases. Acting as dynamic homeostatic buffers, these phosphatases attenuate oncogenic signaling intensity, maintaining a balance that permits continued proliferation while preventing the activation of fail-safe tumor-suppressive mechanisms. This mechanism appears particularly relevant in metastasizing cancer populations, where elevated co-expression of inhibitory receptors and phosphatases correlates with survival advantage and adaptation under selective pressures. Understanding the dual roles of phosphatases, not only as classical tumor suppressors but also as modulators of signaling homeostasis, provides insight into cancer cell adaptation to oncogenic stress. Targeting the phosphatase–inhibitory receptor axis may selectively destabilize this balance, exposing vulnerabilities in aggressive, resistant or metastatic cancer cells. This review highlights emerging evidence for the phosphatase-mediated buffering of oncogenic kinase signaling, the molecular mechanisms underlying inhibitory receptor engagement and the clinical implications for tumor progression and therapy resistance.
Receptor protein tyrosine phosphatases (RPTPs) are transmembrane enzymes that counterbalance protein tyrosine kinase activity by catalyzing the removal of phosphate groups from tyrosine residues on target proteins. Despite their critical roles in regulating cellular proliferation, adhesion, differentiation, and survival, RPTPs remain significantly understudied compared to their kinase counterparts. Contrary to early assumptions that PTPs function as constitutive housekeeping enzymes, emerging evidence demonstrates that RPTPs exhibit highly context-dependent roles in cancer, functioning as tumor suppressors, tumor promoters, or displaying dual activities depending on tissue type, cellular environment, and the specific signaling networks involved. This review provides a comprehensive analysis of RPTP structure, catalytic mechanisms, regulatory processes, and interactions with signaling effectors in cancer. Through a systematic examination of RPTP expression patterns across ten cancer types using Clinical Proteomic Tumor Analysis Consortium (CPTAC) and International Cancer Proteogenome Consortium (ICPC) datasets, we identify subfamily-specific and cancer-type-specific expression alterations that correlate with established functional classifications. PTPσ and PTPμ emerge as uniformly downregulated tumor suppressors across diverse malignancies, whereas, PTPα and PTPε, display oncogenic potential by activating Src family kinases. Context-dependent RPTPs, such as LAR and DEP-1, exhibit variable expression patterns that reflect their complex, multifaceted signaling roles. These findings establish RPTPs as critical regulators of cancer signaling with significant therapeutic potential, while underscoring the need to understand tissue-specific signaling architectures when developing RPTP-targeted interventions.
Reversible protein phosphorylation is an important regulatory mechanism in cellular signalling and disease, regulated by the opposing actions of kinases and phosphatases. Modern computer methods predict kinase–substrate or phosphatase–substrate interactions in isolation and lack specificity for biological conditions, neglecting triadic regulation. We present SPINET-KSP, a multi-modal LLM–Graph foundation model engineered for the prediction of kinase–substrate–phosphatase (KSP) triads with contextual awareness. SPINET-KSP integrates high-confidence interactomes (SIGNOR, BioGRID, STRING), structural contacts obtained from AlphaFold3, ESM-3 sequence embeddings, and a 512-dimensional cell-state manifold with 1612 quantitative phosphoproteomic conditions. A heterogeneous KSP graph is examined utilising a cross-attention Graphormer with Reversible Triad Attention to mimic kinase–phosphatase antagonism. SPINET-KSP, pre-trained on 3.41 million validated phospho-sites utilising masked phosphorylation modelling and contrastive cell-state learning, achieves an AUROC of 0.852 for kinase-family classification (sensitivity 0.821, specificity 0.834, MCC 0.655) and a Pearson correlation coefficient of 0.712 for phospho-occupancy prediction. In distinct 2025 mass spectrometry datasets, it identifies 72% of acknowledged cancer-resistance triads within the top 10 rankings and uncovers 247 supplementary triads validated using orthogonal proteomics. SPINET-KSP is the first foundational model for simulating context-dependent reversible phosphorylation, enabling the targeting of dysregulated kinase-phosphatase pathways in diseases.
Protein phosphatase 2A (PP2A) is a highly conserved heterotrimeric enzyme complex present in all eukaryotic cells, consisting of a scaffolding A subunit, a catalytic C subunit, and a regulatory B subunit. The A and C subunits form the core enzyme, which interacts with the B subunit to determine the substrate specificity, subcellular localization, and enzymatic activity of the holoenzyme. The Arabidopsis thaliana genome encodes five C subunits, three A subunits, and 17 B subunits, enabling the formation of diverse holoenzymes with extensive functional versatility. Genetic evidence highlights the essential role of PP2A in regulating various physiological processes in plants, including responses to abiotic and biotic stresses and developmental programs. Notably, PP2A can act as both a positive and negative regulator within the same pathway, while individual subunits often participate in multiple processes. This functional diversity arises from the structural flexibility of PP2A. This review examines the structural diversity of plant PP2A and its regulatory roles across diverse physiological contexts.
