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Xu, Y.

Publications and source records attributed to Xu, Y..

At least 109 records · Page 6Linked to original sources

Functional genomic map of local adaptation in sorghum to guide allele mining

Genomic data from genebanks could be exploited to find alleles adapted to target environments for resilience breeding, but it can be difficult to prioritize among the thousands of accessions and millions of genomic variants. There are competing hypotheses for the molecular basis and architecture of local adaptations: e.g. whether cis-regulatory versus amino acid changing variants are more important; or whether small-effect, low pleiotropy versus large-effect, high pleiotropy variants are more important. Here, we compare a range of variant types and genomic contexts thought to influence effect size, pleiotropy, and selection for their role in local adaptation in 443 whole genome resequenced African sorghum landraces. We used genotype-environment associations (GEAs) as evidence of local adaptation. We found that GEA were particularly enriched in the vicinity of genes and depleted elsewhere. However, enrichment was strongest in likely cis-regulatory contexts: accessible chromatin, unmethylated regions, and in transposable elements close to genes. Near genes, there were clear peaks in GEAs at the transcription start site, where mutations are demonstrated to have the largest expression effects. Additionally, GEAs in accessible chromatin and unmethylated regions were better predictors of genetic variation in response to experimental drought than comparable loci. Having tested hypotheses about the variants underlying local adaptation, we can now use this knowledge of the importance of cis-regulatory variation in the search for new environmentally-adaptive alleles for plant improvement.

evolutionary biology↗

Dynamic Reprogramming of Fungal Cell Walls Underlies Germination and Immune Exposure in Zygomycetous Fungal Pathogens

Fungal germination is a critical developmental transition that underlies environmental adaptation and pathogenicity, yet how the cell wall is molecularly reprogrammed during this process remains poorly understood. Here we show that germination of Rhizopus delemar involves a developmentally programmed transition from a {beta}-1,3-glucan-rich dormant scaffold to a chitin-chitosan-dominated polarized wall. Using solid-state nuclear magnetic resonance spectroscopy and cytochemistry approaches, we show that resting conidia contains a rigid {beta}-1,3-glucan- and chitosan-rich core beneath a persistent melanin layer. During swelling, this architecture is largely maintained, but germ tube emergence triggers complete shutdown of {beta}-1,3-glucan synthesis and extensive chitin-chitosan enrichment. Distinct chitosan polymorphs are selectively enriched, while mobile polysaccharides are progressively incorporated into the rigid scaffold. This remodeling enhances neutrophil recognition of swollen and germinating conidia. Our study reveals a molecular mechanism linking fungal morphogenesis, cell wall remodeling, and morphotype-specific immune exposure during mucormycosis.

biochemistry↗

Multimodal profiling reveals the centromedian nucleus of thalamus as a dynamic hub orchestrating staged consciousness recovery

Consciousness recovery from general anesthesia represents a fundamental brain state transition. The absence of objective, continuous metrics to monitor the shift from unconsciousness to full awareness has left its dynamic, multidimensional nature unresolved, fracturing consciousness theoretical framework and posing clinical risks due to unreliable assessment of emergence. To address this, we developed a multiscale framework integrating AI-driven behavioral analysis, continuous neuro-physiology recording, and whole-brain functional imaging. This decodes recovery into three hierarchical stages, reflex restitution, level restoration, and content re-establishment, each with unique multimodal signatures. We identified heart rate stabilization as a potential noninvasive biomarker for the restoration of consciousness level. Crucially, the centromedian nucleus of thalamus acts as a dynamic hub, actively orchestrating staged whole-brain reconfiguration via stage-dependent network routing. These findings resolve the temporal orchestration of consciousness recovery, ground disparate theories within a unified mechanistic sequence, and open transformative paths for real-time monitoring and neuromodulation in anesthesiology. HighlightsA multimodal framework decodes consciousness recovery into three hierarchical stages Recovery stages span from reflex restitution, to level restoration, and finally to content re-establishment Heart rate stabilization serves as a noninvasive biomarker for consciousness level restoration The CM paces this staged reconfiguration as a dynamic network hub In BriefZhang et al. develop a multiscale framework that delineates consciousness recovery from anesthesia as a three-stage process, identifies heart rate stabilization as a biomarker for the restoration of consciousness level, and reveals the CM as a dynamic hub orchestrating this progression. These findings clarify the temporal orchestration of consciousness recovery, pave the way for real-time monitoring and neuromodulation in anesthesiology and other fields.

neuroscience↗

Three-Dimensional Photoacoustic Tomography with Ultrasound Localization Priors

Three-dimensional photoacoustic tomography (3D-PAT) enables noninvasive structural and functional imaging with optical absorption contrast and ultrasonic detection depth. However, its spatial resolution is limited by acoustic diffraction, and incomplete detection geometry can substantially degrade image fidelity and quantitative accuracy. Here, we present a ULM-guided model-based reconstruction framework, termed 3D-PAULMprior that incorporates sub-diffraction vascular priors from concurrent ultrasound localization microscopy (ULM) into 3D photoacoustic reconstruction. The method uses weighted regional Laplacian regularization to integrate high-resolution vascular information into the inverse problem, thereby enhancing vascular sharpness, suppressing limited-view artifacts, and improving blood oxygen saturation estimation. We validated 3D-PAULMprior using numerical simulations, tissue-mimicking phantoms, and in vivo mouse brain imaging. Compared with conventional reconstruction, 3D- PAULMprior improved spatial resolution by over 50%, increased contrast-to-noise ratio by 261.2%, and enhanced structural similarity index by 24.6%. In vivo, 3D-PAULMprior recovered vascular structures that were poorly resolved or missing in conventional reconstructions and produced more spatially confined sO2 maps. These results establish 3D-PAULMprior as a robust multimodal reconstruction strategy for high-resolution structural and functional photoacoustic imaging.

bioengineering↗

Hippocampal Glucuronyl C5-epimerase promotes stress resilience by directly engaging PI3K through a non-enzymatic mechanism

Major depressive disorder (MDD) seriously affects human physical and mental health and causes global socioeconomic burdens. Stress-induced depressive etiology is linked to dendritic atrophy in the hippocampus, however, the underlying mechanism was poorly understood. Here, we identify that glucuronyl C5-epimerase (Glce), a heparan sulfae-modifying enzyme, as a critical regulator of hippocampal dendritic integrity and stress resilience. Genetic ablation of Glce in the hippocampal excitatory neurons is sufficient to induce dendritic atrophy and depressive-like behaviors, whereas its restoration rescues these deficits. Notably, Glce levels are reduced in the plasma of depressed individuals. We further find that Glce functions independently of its enzymatic activity, instead binding directly to and activating PI3K (p85/p110), thereby triggering an Akt/CREB/BDNF signaling cascade. Together, our findings uncover a non-canonical role for Glce and establish that Glce-PI3K-BDNF axis is essential for maintaining hippocampal structure and behavioral resilience, thereby highlighting a critical role of Glce in the pathophysiology of depression.

neuroscience↗

3D-PAULM: Integrated Photoacoustic Tomography and Ultrasound Localization Microscopy for Multiparametric Brain and Tumor Imaging

Understanding processes such as blood-brain barrier (BBB) disruption and tumor progression can greatly benefit from simultaneous molecular, functional, and hemodynamic imaging in deep tissue, yet few existing imaging modalities can provide all three in a single system. Here, we present an integrated imaging platform that combines 3D photoacoustic tomography with ultrasound localization microscopy (3D-PAULM) to enable intrinsically co-registered, multiparametric imaging. 3D-PAULM unifies multispectral photoacoustic molecular imaging, ultrasound B-mode imaging, microbubble-enhanced power Doppler, and ultrasound localization microscopy, and concurrently measures blood oxygenation, blood perfusion, microvascular flow dynamics, and molecular probes from near-infrared dyes and photoswitchable phytochromes. We apply 3D-PAULM to quantify BBB leakage in focal ischemia and systemic inflammation, and to perform high-sensitivity molecular imaging of solid tumors alongside functional mapping of tumor hypoxia and super-resolved vascular remodeling. Together, these results establish 3D-PAULM as a versatile platform for integrated functional and molecular imaging in deep tissue.

bioengineering↗

SpatialBench: Comparative cross-platform benchmarking of high-resolution spatial transcriptomics using matched mouse lymphoid tissue

Spatial transcriptomics (ST) has rapidly expanded with the introduction of multiple high-resolution platforms, yet cross-platform benchmarking remains limited and largely focused on technical performance. Here we present SpatialBench, a matched multi-platform resource comprising Visium HD, Xenium and MERSCOPE data together with single-cell and single-nucleus references from a malaria-challenged wild-type and B cell-specific Tbx21 knockout mouse spleen model. In this system, loss of T-bet in B cells disrupts germinal center (GC) polarization and antibody maturation, providing a biologically grounded benchmark for technology comparison. We leveraged this system to systematically evaluate ST platform performance using technical and biological readouts. Across platforms, immune organization and Tbx21-associated programs were consistently recovered, indicating robustness of major biological signals. Platforms instead differed in the level of biological resolution accessible. Visium HD enabled transcriptome-scale GC characterization and, together with Xenium, resolved dark and light zone organization, whereas GC zonation was not resolved in MERSCOPE, consistent with differences in transcript detection sensitivity. SpatialBench provides a biologically defined reference dataset for evaluation of ST technologies, method development, computational benchmarking, and studies of GC spatial organization in lymphoid tissue.

bioinformatics↗

Spatial Multi-Omics Reveals Extracellular Matrix Remodeling and VSMC Phenotypic Switching in Moyamoya Disease

BackgroundMoyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by steno-occlusive lesions and intimal hyperplasia. Although vascular smooth muscle cell (VSMC) phenotypic switching is implicated in its pathogenesis, the precise spatial interplay between extracellular matrix (ECM) remodeling and local metabolic alterations within the distinct vascular microenvironments remains unknown. MethodsSuperficial temporal artery (STA) samples from patients with MMD and controls were analyzed by histology, immunofluorescence, spatial transcriptomics, spatial proteomics, and spatial metabolomics. Single cell RNA sequencing was used to profile the cellular landscape of STA tissues. To functionally validate the identified pathway, human brain vascular smooth muscle cells (HBVSMCs) were stimulated with fibronectin 1 (FN1), and patient derived induced pluripotent stem cell smooth muscle cells (iPSC-SMCs) were generated for migration and protein expression assays following ITGA5 silencing or focal adhesion kinase (FAK) inhibition. ResultsMMD STA samples exhibited marked intimal hyperplasia with medial thinning and intimal accumulation of -SMA positive cells. Spatial transcriptomic and proteomic analyses identified an intimal remodeling program characterized by increased FN1, EFEMP1, fibronectin, ITGA5, and FAK, together with reduced MYH11. FN1 stimulation promoted smooth muscle cell migration, ECM associated protein expression, and FAK phosphorylation, whereas ITGA5 knockdown or FAK inhibition attenuated these effects. Patient derived MMD iPSC-SMCs showed similar abnormalities, including enhanced migration, increased FAK activation, reduced contractile markers, and increased ECM associated proteins. Spatial metabolomics and integrated multi-omics analyses further revealed that these changes were coupled to a metabolically depleted intimal niche enriched for reduced acyl-CoA related metabolites. ConclusionsIntegrated spatial multi-omics identifies coupled ECM remodeling and metabolic alteration in the hyperplastic intima of MMD. Within this context, the FN1-ITGA5-FAK axis emerges as a plausible mediator of smooth muscle remodeling that warrants further validation. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/721225v1_ufig1.gif" ALT="Figure 1"> View larger version (90K): org.highwire.dtl.DTLVardef@3f6e19org.highwire.dtl.DTLVardef@554d49org.highwire.dtl.DTLVardef@451dd9org.highwire.dtl.DTLVardef@1aac1e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

EnzCast: Prediction of Patient-Specific Enzymatic Kinetics through Multi-Modal Deep Learning and Isoform-Resolved Bayesian Inference based on Single-Cell Transcriptomics

Enzyme kinetic parameters underpin mechanistic biology but remain sparse in physiological context. We present EnzCast, a multi-modal framework jointly predicting Km, kcat, kcat/Km, and Ki from protein sequence, 3D structure, substrate chemistry, and experimental conditions, paired with IsoKin, an isoform-resolved Bayesian framework converting EnzCast priors into patient-specific in vivo kinetics. Trained on KinBench, the largest curated kinetics database, task-adaptive EnzCast achieved R2 = 0.413, 0.455, 0.227, and 0.105 for Km, Ki, kcat, and kcat/Km, surpassing all baselines on catalytic tasks. Systematic condition scans recovered compartment-specific pH direction inversion and pathway-level temperature responses. In a 20-patient colorectal cancer single-cell cohort, IsoKin reduced posterior uncertainty by 73.3% and 77.3%, revealing cell-type-specific rewiring. Orthogonal validation--scFEA flux, DepMap essentiality (permutation P = 0.0008) and TCGA survival-- provided mixed but directionally consistent support. Together, EnzCast and IsoKin bridge in vitro prediction, condition-aware biochemical interrogation and patient-resolved in vivo inference.

bioinformatics↗

Reciprocal repulsions enforce heterotypic dendrite segregation in an olfactory circuit

How dendrites of different neurons segregate into discrete spatial domains during neural circuit assembly is poorly understood. Here, using the Drosophila olfactory system, we found that heterophilic interactions between two cell-surface proteins Teneurin-m (Ten-m) and Capricious (Caps) drive dendrite segregation. Ten-m and Caps are expressed in largely inverse patterns across projection neuron (PN) types when PNs are establishing their dendritic territories. Loss of Ten-m in Ten-m+ PNs causes their dendrites to invade Caps+ territories, whereas loss of Caps in Caps+ PNs causes dendrite invasion into Ten-m+ territories. Structure-guided mutations that abolish Ten- m-Caps binding disrupt dendrite segregation, whereas the same mutation on Ten-m preserves its homophilic attraction in a synaptic partner matching assay. These results support a model in which mutual repulsions between two inversely expressed cell-surface proteins drive dendrite segregation into discrete glomerular territories.

neuroscience↗

OneGenomeRice (OGR): A Genomic Foundation Model for Rice

The transition of genomics to a predictive intelligence discipline is driven by the advent of genomic foundation models. While substantial progress has been observed in all-life and human-centric models, plant species, particularly for the staple crops, remains hindered by a lack of models. Here we introduce OneGenome-Rice (OGR), a rice (Oryza sativa) genomic foundation model pre-trained on a genomic dataset comprising 422 high-quality genomes of cultivated and wild rice. OGR is engineered upon a Mixture of Experts (MoE) transformer architecture with 1.25-billion parameters and supports an ultra-long context window of up to 1 million base (Mb) pairs at single-nucleotide resolution. A comprehensive benchmark demonstrated that OGR significantly outperforms existing state-of-the-art multi-plant or all-life genome models in 11 categories (e.g. motif identification, sweep detection, etc). We further demonstrated the utility of OGR in several downstream applications, such as indica-japonica subspecies introgression analysis, identification of agronomy trait-associated functional loci and prediction of gene expression from DNA sequences. These results establish OGR as a promising foundational computational infrastructure for rice functional genomics and precision breeding. The OGR and its fine-tuned models, including pretrained weights, training code and the rice genomic benchmark suit, have been fully opened.

genomics↗

A sequence-based proactive intelligence for influenza antigenic profiling improves vaccine strain selection

Seasonal influenza viruses accumulate antigenic changes, eroding population immunity and necessitating recurrent vaccine updates. Hemagglutination inhibition (HI) assays are the standard for measuring antigenic relationships between circulating and vaccine strains; however, their limited throughput constrains the scale and timeliness of surveillance. Here, we present fluProfiler, a foundation-model-based framework that learns a stable mapping from viral sequences to antigenic space and uses this representation to support influenza antigenic prediction, vaccine strain evaluation, and diversity-driven sampling. fluAgPredictor aligns hemagglutinin (HA) and neuraminidase (NA) sequence representations with HI-derived antigenicity, enabling accurate and consistent inference of pairwise antigenic distances across surveillance-aligned evaluation settings. Without prior annotation of antigenic sites, it identifies key residues in immunodominant epitopes and reveals the cooperative contributions of HA and NA to antigenic variation. Building on this antigenic-space representation, fluVacSelector provides antigenic coverage scores that are concordant with World Health Organization (WHO) vaccine recommendations while also flagging potential candidates that may offer broader coverage ahead of formal consultations. fluAgEnhancer further leverages the same representation to prioritize antigenically informative and diverse strains for experimental characterization, achieving comparable predictive accuracy with approximately 25% fewer HI measurements than random sampling. Together, these modules provide a high-throughput and interpretable complement to HI testing, converting routine genomic surveillance into a more proactive, data-driven support system for antigenic monitoring and vaccine strain selection.

bioinformatics↗

Generation and long-term expansion of human pancreatic islet organoids in vitro

The scarcity of expandable, functional human islet cells remains a major barrier to diabetes therapy. Here, we identify PROCR+ cells within adult human islets and establish a defined culture system to generate pancreatic islet organoids. These organoids self-organize into -, {beta}-, {delta}-, and PP cells at near-native ratios, exhibit regulated insulin and glucagon secretion, and support exponential in vitro expansion. Single-cell transcriptomics reveals a unique progenitor-like cell population that is transcriptionally primed for endocrine differentiation but shares molecular features with fetal trunk cells and endocrine progenitors. When transplanted, the organoids rapidly ameliorate hyperglycemia in diabetic mice. Importantly, in a non-human primate model, intraportal transplantation of these organoids reduced exogenous insulin requirements, restored glucose-stimulated C-peptide secretion, and achieved sustained glycemic control-representing a critical step toward clinical translation. This study provides a strategy for expanding human islet organoids, offering a scalable platform for diabetes treatment, disease modeling, and regenerative medicine.

cell biology↗

An EEG-fMRI Jointly Constrained Digital Twin Brain and Its Application in Alzheime's Disease

Current digital twin brain (DTB) models are typically optimized using single-modality functional neuroimaging data, which restricts their ability to simulate brain dynamics across multiple spatiotemporal scales. Here, we bridged this gap by developing a two-stage DTB (TS-DTB) modeling framework jointly constrained by functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) data. Validation in both the healthy young and Alzheimers disease (AD) cohorts demonstrated that the TS-DTB model simultaneously captures subject-specific features of multi-scale brain dynamics. In particular, the TS-DTB models of AD patients successfully recapitulated spectral-temporal signatures of cognitive decline, mechanistically linking these deficits to excitation-inhibition (E-I) imbalances. By simulating responses to repetitive transcranial magnetic stimulation (rTMS), we further revealed that cognitive recovery in AD patients can be driven by E-I rebalancing via synaptic reconfiguration and background suppression. Overall, these findings underscore the potential of the TS-DTB to advance the mechanistic understanding of the brain and inform personalized digital therapeutics.

neuroscience↗

Emergence of rigidity percolation and critical behavior in tunable protein condensates

Multivalent proteins are known to form complex networks within biomolecular condensates, yet the mechanisms governing the emergence and evolution of these networks remain poorly understood. Here, we utilize a synthetic protein chimera system with tunable interactions to investigate the transition from liquid-like droplets to networked condensates. By employing single-amino-acid substitutions, we generated a series of mutants with varying protein-binding strengths. As the interaction strength increases, the condensates undergo a sharp rigidity percolation transition, characterized by a more than 200-fold increase in both elastic modulus and viscosity. Near this transition, we identify a critical scaling relation in the condensate elasticity, providing robust evidence for a percolation-driven assembly mechanism. Furthermore, we demonstrate that this network architecture is fundamentally linked to biological functions. The introduction of disease-associated mutations disrupts the network, significantly softening the condensates and rendering them fluid-like. Our findings reveal that network percolation and criticality in protein condensates can be sensitively regulated by single-amino-acid substitutions, underscoring their essential role in maintaining structural integrity and supporting physiological function.

biophysics↗

Curvature-mediated prewetting organize mitochondrial nucleoid

The emergence of spatiotemporal order in diffusive cellular environments requires physical mechanisms to overcome the entropic drive toward disorder. While the organizing role of chemical signaling is well characterized, how complex membrane curvature regulate soluble molecular organization remains a fundamental open question. Here, we establish membrane curvature as a thermodynamic control parameter for the condensation of soluble proteins through prewetting. Using the mitochondrial transcription factor TFAM, we demonstrate that intrinsic membrane curvature locally drives a prewetting transitiona surface-mediated phase separation distinct from bulk condensation. By combining in vitro reconstitution, live-cell super-resolution imaging, cryo-electron tomography, and thermodynamic theory, we show that negatively high-curvature regions lower the nucleation energy barrier of Tfam, driving localized protein condensation at physiological concentrations. These results reveal that membrane curvature does not merely scaffold cellular machinery but manipulates the local free energy landscape, establishing a geometric principle for the spatial control of biological processes.

biophysics↗

IEKB: a comprehensive knowledge base for inner ear genetics integrating curated associations, cochlear interactions, Bayesian candidate prioritisation, explainable dark-gene support relations, and a scientific entity network

Inner-ear genetics has expanded rapidly, yet the supporting evidence remains dispersed across a vast literature and across resources that typically emphasise loci, variants, or expression data rather than integrated biological interpretation. Here we present the Inner Ear Knowledge Base (IEKB; https://earkb.org), an open database that unifies curated associations, cochlear interaction evidence, candidate prioritisation, explainable support relations, and network exploration for inner-ear research. IEKB was built with an automated agent-assisted curation workflow that combines schema-constrained literature extraction, continuous human monitoring, and final expert review by inner-ear genetics researchers. By systematically analysing 250,696 PubMed-indexed records retrieved across 16,563 screened genes, IEKB curates 6,051 gene-phenotype-disease associations from 2,494 genes across 43 phenotype categories and 4,102 cochlear gene-gene interactions with pathway, cell-type, and experimental context. IEKB further includes a Bayesian "dark matter" module that prioritises 243,071 candidate gene-phenotype associations for 13,229 genes across all 43 phenotypes (global AUC-ROC = 0.8603; global AUC-PR = 0.1674), together with a supervised dark-relation layer that ranks phenotype-specific known-gene support for each candidate and a multi-entity scientific network containing nearly 4,000 entities, 28,616 deterministic edges, and 83,712 literature-derived relational links. The web resource supports interactive search, multi-parameter filtering, gene-detail pages, bibliometric exploration, domain-specific enrichment against IEKB phenotype and disease gene sets, network visualisation, bulk download in CSV, JSON, SQLite, and XLSX formats, and natural-language evidence-grounded question answering through a companion conversational interface (IEKB QA). To our knowledge, IEKB is the first openly accessible inner-ear resource that integrates curated associations, cochlear interactions, probabilistic candidate prioritisation, auditable known-gene support relations for novel candidates, and a multi-entity scientific network within a single database. All data are released without registration under the CC BY 4.0 license.

bioinformatics↗

A Non-Classical Neuroactive Steroid Exhibiting Potent, Efficacious GABA A Receptor Agonism and NMDA Receptor Inhibition

Neuroactive steroids modulate GABAA and NMDA receptors allosterically, typically requiring specific structural features for their activity. In this study, we characterize YX84, a novel neuroactive steroid bearing a 3{beta} sulfate and p-trifluoroacetylbenzyl alcohol attached in an ether linkage to a hydroxyl group at steroid carbon 17. This compound and similar analogues exhibit an atypical pharmacological profile, with three distinct actions at GABAA receptors. First, YX84 is a full agonist, with EC50 near 1 {micro}M and comparable efficacy to GABA at GABAA receptors in native hippocampal neurons. It presents as a full agonist relative to GABA at 4/{delta} subunit-containing receptors. Second, YX84 acts as a slow-onset, potent positive allosteric modulator (PAM) of GABAA receptors at concentrations below those that gate a response. Finally, YX84 exhibits rapid desensitizing and/or blocking kinetics; voltage dependence is consistent with a contribution of channel block. Structure- activity relationship analyses reveal that both functional groups are essential for gating activity, while classical requirements such as carbon 3 hydroxyl stereoselectivity and carbon 5 reduction are dispensable. YX84 also modestly inhibits NMDA receptor currents, suggesting weak negative allosteric modulation. Behavioral assays show that intraperitoneal administration of YX84 (30 mg/kg) does not impair sensorimotor function, unlike allopregnanolone. These findings identify YX84 as a structurally distinct neuroactive steroid with dual receptor activity and favorable behavioral tolerability, offering a promising scaffold for therapeutic development targeting excitatory/inhibitory imbalance in neuropsychiatric disorders if pharmacokinetic considerations can be overcome.

neuroscience↗