Biology subjects

Fu, Z.

Publications and source records attributed to Fu, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

SPATIAL DISSIMILARITY TRAJECTORIES REVEAL RAPID FUNCTIONAL NETWORK REFINEMENT DURING EARLY INFANCY

The first six months of life mark a critical window for human brain development, characterized by rapid synaptic formation, axonal growth, and network reorganization. During this period, large-scale functional networks progressively mature. Although prior infant fMRI studies have characterized temporal functional connectivity, the spatial organization and refinement of brain networks during early infancy remain underexplored. In this study, we analyzed longitudinal resting-state fMRI from 74 typically developing infants (0-6 months; 137 scans) using group independent component analysis (ICA) with group-information-guided ICA (GIG-ICA) back-reconstruction. Spatial dissimilarity between each infants spatial map and the group-level map was quantified using cosine dissimilarity and Euclidean distance. Generalized additive models were applied to model age-related trends. Both cosine and Euclidean dissimilarity metrics showed significant decreases with age, indicating a progressive convergence of individual network topographies toward the group-level architecture. These findings reveal increasing spatial coherence and refinement of large-scale brain networks during early infancy, suggesting that spatial maturation complements the well-established functional integration observed in temporal connectivity studies.

neuroscience↗

bioRxiv2025

Developmental deviations of structural connectivity in youths with ADHD predict symptom and treatment outcomes

Attention-deficit/hyperactivity disorder (ADHD) lacks validated biomarkers to track symptom development or guide treatment selection in youth. We quantified individual deviations from normative age-related trajectories of white-matter structural connectivity (SC) across two independent cohorts: 6,687 typically developing and 1,114 ADHD scans from the ABCD study, and 292 typically developing and 482 ADHD participants from a Chinese cohort. Youth with ADHD showed pronounced SC deviations, especially in higher-order association pathways. A subset of connections showed ADHD-specific developmental reductions in deviations beyond typical developmental patterns, and these changes mediated the age-related decline in ADHD symptoms. Longitudinal within-individual analyses demonstrated that decreases in deviation over two years tracked symptom improvement. Baseline deviations also predicted 12-week treatment response to atomoxetine, but not methylphenidate, and follow-up imaging revealed treatment-related reductions in deviation. Together, these findings identify SC deviation as a robust developmental biomarker with prognostic and theragnostic relevance for ADHD, supporting precision care through risk stratification, individualized pharmacotherapy selection, and objective monitoring of treatment effects.

neuroscience↗

bioRxiv2025

Infusible Extracellular Matrix Biomaterial Enhances Cell-Specific Pro-Repair Responses Following Acute Myocardial Infarction

To mitigate the pathological effects of myocardial infarction, we developed and investigated pro-reparative decellularized extracellular matrix (ECM) biomaterials: an intravascularly infusible ECM (iECM). However, the cellular and molecular mechanisms by which iECM mediates repair are unknown because investigations have relied on bulk techniques. Here, we leverage single nucleus RNA sequencing (snRNAseq) to measure pro-repair in various cell types across acute timepoints (1, 3 and 7 days post infusion). In iECM, we found pro-reparative macrophage activation, fibroblast remodeling, increased vasculaure development, lymphangiogenesis, cardioprotection, and neurogenesis. These findings were validated through spatial transcriptomics. Thus, we define the pro-reparative nature of decellularized ECM biomaterials on cardiac cell types and elucidate previously undiscovered therapeutic pathways, further demonstrating the potential of iECM as an MI therapy as well as display the wealth of data generated from next-generation sequencing.

bioengineering↗

bioRxiv2025

Maternal SETDB1 enables development beyond cleavage stages by extinguishing the MERVL-driven 2-cell totipotency transcriptional program in the mouse embryo

Loss of maternal SETDB1, a histone H3K9 methyltransferase, leads to developmental arrest prior to implantation, with very few mouse embryos advancing beyond the 8-cell stage, which is currently unexplained. We genetically investigate SETDB1s role in the epigenetic control of the transition from totipotency to pluripotency--a process demanding precise timing and forward directionality. Through single-embryo total RNA sequencing of 2-cell and 8-cell embryos, we find that Setdb1mat-/+ embryos fail to extinguish 1-cell and 2-cell transient genes--alongside persistent expression of MERVL retroelements and MERVL-driven chimeric transcripts that define the totipotent state in mouse 2-cell embryos. Comparative bioinformatics reveals that SETDB1 acts at MT2 LTRs and MERVL-driven chimeric transcripts, which normally acquire H3K9me3 during early development. The dysregulated targets substantially overlap with DUXBL-responsive genes, indicating a shared regulatory pathway for silencing the 2-cell transcriptional program. We establish maternal SETDB1 as a critical chromatin regulator required to extinguish retroelement-driven totipotency networks and ensure successful preimplantation development.

genetics↗

bioRxiv2025

Intrarenal Generation of Aldosterone Contributes to Ischemia-Induced Hypertension and Nephropathy in Mice

BackgroundThe past few years have witnessed a significant advancement in aldosterone (Aldo)-targeted therapies for the management of treatment-resistant hypertension and chronic kidney disease, which often exist in tandem. While Aldo is believed to predominantly originate from the adrenal glands, this study provides evidence to support the involvement of intrarenal Aldo biosynthesis in the pathogenesis of ischemic nephropathy and hypertension in a two-kidney, one-clip (2K1C) model. MethodsWe generated inducible renal tubule-specific deletion of C11B2 (RT C11B2 KO) and characterized the phenotype during the 2K1C procedure. We investigated the underlying mechanisms involving the use of mice with collecting duct-specific (pro)renin receptor (CD PRR KO) or renin (CD renin KO). ResultsRT C11B2 KO induced a partial blockade of the hypertensive response but a much greater improvement in renal fibrosis and inflammation four weeks post-2K1C. This phenotype was associated with an effective blockade of intrarenal generation of Aldo contrasting to unchanged circulating Aldo concentrations. Furthermore, clipping-induced acute kidney injury was also attenuated 24 hours post-2K1C, at which point blood pressure (BP) did not increase. Similarly, sodium nitroprusside effectively lowered BP in C57BL/6j/2K1C mice but failed to improve renal injury. Additionally, we identified CD) PRR and renin as key upstream regulators of intrarenal Aldo biosynthesis following the 2K1C procedure. ConclusionsTogether, these results support the idea that CD PRR/renin-dependent generation of intrarenal Aldo may play a primary role in the pathogenesis of ischemic nephropathy and a secondary role in hypertension development during renovascular constriction. Therefore, targeting intrarenal Aldo biosynthesis may represent a more effective and safer intervention than existing Aldo-targeted therapy to manage ischemic nephropathy as well as hypertension.

physiology↗

bioRxiv2025

Glycemia Shift Pancreatic Islets Rhythmicity via δ-α Cell in vivo, Impairment in Diabetes

Blood glucose homeostasis relies on the well-coordinated rhythmic activity of millions of islets throughout the pancreas. Islet rhythmicity is triggered by glucose elevation and mediated by paracrine interactions. However, the dynamics of islet population rhythmicity in healthy and diabetic pancreases in vivo remain poorly understood. Using simultaneous multi-islet Ca2+ imaging (20-100 islets per experiment) in both live mice and pancreatic tissue slices, we systematically studied how glycemia fluctuations and intra-islet paracrine signaling collectively shape the islet rhythmicity. In this study, we report that a transition from Hyperglycemia to Euglycemia induces a coordinated shift from slow to fast islet Ca2+ oscillations (HESF) in vivo. HESF is conserved in pancreatic tissue slices and isolated islets, however, not dispersed single cells in vitro, suggesting a mechanistic link with paracrine interactions. We found HESF arises from -cell activation, which is inhibited by {delta} cells upon glucose elevation. The autonomous islets mostly differ in phase and period at high glucose level. Diabetic mice with disrupted glycemic stability lost HESF both in vivo and in vitro. Interestingly, HESF is preserved in {beta}-cell knockout Gcgr transgenetic mice, both in vivo and in vitro, suggesting HESFs dependence on Glp1r. Indeed, HESF was restored in semaglutide-treated diabetic mice with stabilized glycemic stability. These findings offer a comprehensive understanding of how {delta} and cells influence islet rhythmicity and precisely maintain the stability of blood glucose.

physiology↗

bioRxiv2025

A Paracrine-to-Autocrine Shunt of GREM1 Fuels Colorectal Cancer Metastasis via ACVR1C

Tumor cells typically rely on paracrine stromal signals to guide malignant behaviors, but whether they acquire signaling autonomy to support metastasis remains unclear. We elucidate this in colorectal cancer (CRC) by uncovering a paracrine-to-autocrine shunt of Gremlin1 (GREM1), a canonical stromal-secreted antagonist of bone morphogenetic proteins (BMPs). We demonstrate that while GREM1 remains restricted to stromal cells in earlier-stage (I-III) CRC, its ectopic expression in tumor epithelium increases markedly in stage IV. Mechanistically, we identify ACVR1C as a novel, high-affinity epithelial receptor for GREM1. Their interaction activates SMAD2/3 signaling, which upregulates SNAI1 and GREM1, establishing a feedback loop that amplifies epithelial-mesenchymal transition (EMT). Disrupting this loop impairs CRC metastasis in vivo. Clinically, epithelial GREM1 or ACVR1C expression predicts metastasis and poor survival. These findings define a paradigm in which tumor cells hijack stromal GREM1 to establish a GREM1-ACVR1C autocrine loop that sustains EMT and metastasis, marking a shift toward signaling autonomy and revealing a targetable vulnerability in advanced CRC.

cancer biology↗

bioRxiv2025

Uncovering the Regional and Cell Specific Bioactivity of Injectable Extracellular Matrix Biomaterials in Myocardial Infarction through Spatial and Single Nucleus Transcriptomics

Myocardial infarction (MI) remains a global health concern. To mitigate MI pathophysiology, we previously investigated a pro-reparative decellularized extracellular matrix (ECM) hydrogel for treating subacute and chronic MI. Despite increasing interest in biomaterial scaffolds, single cell and spatially resolved transcriptomics have not been used to probe their therapeutic activity in the heart. Here, we utilize spatial transcriptomics and single nucleus RNA sequencing to delineate the regional and cell-specific bioactivity of ECM biomaterials. ECM hydrogel subacute treatment induced cardiac resident macrophage preservation, fibroblast activation, and increased lymphatic, vasculature, smooth muscle and cardiomyocyte development as well as neurogenesis. Chronic treatment elicited macrophage polarization, cardiomyocyte and vasculature development, alongside fibroblast development. When comparing treatment timepoints, subacute administration had stronger immune modulation, while the chronic timepoint demonstrated higher cardiac development markers. Both subacute and chronic administration were associated with fibroblast activation and vasculature development. Thus, we elucidate undiscovered therapeutic targets of the ECM hydrogel, further demonstrating the potential of ECM biomaterials as an MI therapy.

bioengineering↗

bioRxiv2025

Semantics across the globe: A universal neurocognitive semantic structure adaptive to climate

Thousands of languages are used worldwide as the primary means of human thought communications. While both similarities and variations in word meaning (semantics) across different languages are well recognized, the underlying mechanisms remain enigmatic without a coherent theoretical model for semantic representation. Given that semantic representation is a product of the human brain, we address this issue through the lens of neurocognitive theories, with the consensus framework that semantics are derived from sensory experiences, with a set of dimensions being identified as biologically salient in neuroscientific studies. We operationalized word semantic representations with this set of specific dimensions, using computational models (53 languages word embedding data; Study 1), human behavioral ratings (253 subjects, 8 languages; Study 2), and brain activity data (86 subjects, 45 languages; Study 3), and analyzed the similarity and variation patterns of concepts across different languages. These three approaches converge on the finding that, across diverse language samples, word semantic representations along the neurocognitive dimensional structures exhibit strong commonalities, with variations along this structure being significantly and uniquely explained by climate, beyond sociocultural-centered variables. These results present a universal, biologically constrained semantic structure that is adaptive to environmental inputs, reconciling the classical universality and relativity debate.

neuroscience↗

bioRxiv2025

aNy-way ICA and its application to estimate cortico-thalamo-cerebellar functional links in schizophrenia

Disrupted large-scale brain network interactions are a hallmark of schizophrenia, yet the circuit-level mechanisms underlying cognitive deficits remain incompletely understood. In particular, cortico-thalamo-cerebellar circuitry has been implicated in "cognitive dysmetria," but its functional organization across subdomains has not been fully characterized. Here, we apply a flexible multimodal data fusion framework (aNy-way independent component analysis) to integrate 4D domain-specific resting-state fMRI data from the cortex, thalamus, and cerebellum. Using a large discovery cohort (FBIRN, N=311) and two independent replication datasets (COBRE, N=148; MPRC, N=364), we identify a robust cortico-thalamo-cerebellar circuit involving higher-order thalamic nuclei, visual cortex, default mode network, and cerebellar posterior regions. This circuit shows altered connectivity in schizophrenia, characterized by reduced anticorrelation between thalamus and cortex, and is consistently associated with cognitive impairments, including processing speed, working memory, and reasoning deficits across cohorts. Importantly, these findings are largely replicated across independent cohorts. Together, these results provide data-driven evidence for a cortico-thalamo-cerebellar mechanism underlying cognitive dysfunction in schizophrenia, supporting the cognitive dysmetria hypothesis. This work also demonstrates the utility of aNy-way independent component analysis for identifying clinically relevant brain circuits in psychiatric disorders. HighlightsO_LIIdentified cortico-thalamo-cerebellar circuits in schizophrenia C_LIO_LIAltered thalamocortical interactions differentiated schizophrenia C_LIO_LICircuit alterations were associated with cognitive impairment C_LIO_LIFindings are replicated across three independent multisite datasets C_LIO_LIMultidomain fusion enabled subdomain-specific circuit characterization C_LI

neuroscience↗

bioRxiv2025

Structural basis for membrane microdomain formation by a human Stomatin complex

Biological membranes are not just passive barriers--they actively sense and respond to mechanical forces, in part through specialized proteins embedded within them. Among these are Stomatin-family proteins, which are known to influence membrane stiffness and regulate ion channels, yet how they achieve these functions at the molecular level has remained elusive. Here, we report the 2.2 [A] cryo-electron microscopy structure of the human Stomatin complex in a native membrane environment. We find that Stomatin assembles into a 16-subunit ring-shaped homo-oligomer, forming a [~]12 nm-wide cage that defines a mechanically distinct, curvature-resistant membrane microdomain. While the majority of the complex exhibits C16 symmetry, the C-terminal domains adopt two alternating conformations, producing a symmetry-broken hydrophobic {beta}-barrel pore with local C8 symmetry. The membrane beneath the complex remains flat despite surrounding curvature, indicating localized membrane stiffening. The structure reveals a conserved network of inter-subunit salt bridges that stabilize the assembly. These findings provide a molecular framework for how Stomatin oligomers shape membrane architecture and mechanics, offering new insight into their roles in mechanotransduction and diseases such as nephrotic syndrome.

biophysics↗

bioRxiv2025

Mechanisms of resistance to active state selective tri-complex RAS inhibitors

Tri-complex inhibitors (TCIs) act as molecular glues to recruit cyclophilin A (CYPA) to the active (GTP-bound or ON) conformation of RAS, which in turn prevents the activation of downstream effector proteins like RAF and PI3K. Emerging data demonstrate clinical activity, including tumor regressions, in patients with RAS driven cancers. Despite being promising therapeutic interventions, the mechanisms of resistance in patients treated with these inhibitors remain unknown. Here we studied matched baseline and post-progression specimens from patients treated with the RAS(ON) multi-selective inhibitor daraxonrasib (RMC-6236). Tissue or cell-free DNA specimens were collected from 40 patients with RAS-mutant non-small cell lung, colorectal, or other cancers. Eighteen patients (45%) were found to have acquired alterations in RAS signaling intermediates, including recurrent alterations in KRAS, BRAF, RAF1, MAP2K1/2 and PIK3CA. Preclinical resistance models mirrored the alterations observed in patients. We found that secondary KRAS Y64X mutations caused resistance by disrupting an important pi-pi interaction between KRAS and the indole ring of daraxonrasib, which lowers the affinity of the daraxonrasib:CYPA binary complex for active KRAS. We also identified kinase-dead and low-activity BRAF mutations in samples with acquired resistance. This is puzzling, because TCIs are expected to prevent the interaction between RAS and BRAF, which is needed for hypoactive mutants to dimerize and signal. We now show that RAF dimers are harder to displace from active RAS, as compared to their monomeric forms. Indeed, enhanced RAF dimerization attenuated the ability of TCIs to recruit CYPA to active RAS, resulting in diminished inhibition of oncogenic signaling and tumor growth. Thus, several clinical resistance alterations converge at attenuating the formation of the RAS:daraxonrasib:CYPA tri-complex, either by preventing daraxonrasib binding or by inducing RAF dimers.

cancer biology↗

bioRxiv2025

Abnormal Lipid Metabolism and Altered Neuronal Support by Astrocytes Lacking Akap11, a Risk Gene for Schizophrenia and Bipolar Disorder

A-Kinase Anchoring Protein 11 (AKAP11) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains and cultured astrocytes, we identified significant transcriptomic, proteomic, and metabolomic alterations. Key findings include the upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid species such as cholesteryl esters, triacylglycerols, ceramides, and glycerophospholipids, and elevated levels of 3,5-cyclic AMP and protein kinase A (PKA) signaling. These metabolic perturbations manifested as increased lipid droplet accumulation in Akap11 mutant astrocytes, highlighting AKAP11s critical role in regulating intracellular lipid homeostasis. Mechanistically, AKAP11 functions as an autophagy receptor mediating PKA degradation and interacts with endoplasmic reticulum-resident proteins VAP-A and VAP-B through its FFAT motif, providing possible molecular insight into AKAP11s regulation of lipid metabolism. Co-culture experiments with mouse astrocytes and human induced pluripotent stem cell-derived neurons demonstrated that loss of Akap11 in astrocytes, relative to wild-type, increases excitatory neurotransmission and neuronal activity. Collectively, these findings link AKAP11-mediated lipid and synaptic dysregulation to psychiatric disease risk and highlight the potential role of astrocytes in these disorders.

cell biology↗

bioRxiv2025

LILRA5 functions to induce ROS production on innate immune cells

Activating immune receptors provide mechanisms for phagocytes to elicit important effector functions that promote the killing of microbes. Leukocyte immunoglobulin-like receptor A5 (LILRA5) an orphan immune receptor expressed by human phagocytes and co-localising with FcR{gamma}, remains poorly characterised. To address this, we developed a highly-specific anti-LILRA5 monoclonal antibody that has agonistic properties. Using a specific anti-LILRA5 antibody, we show LILRA5 expression on naive monocytes and neutrophils, and that ligation of LILRA5 stimulates ROS production. While increased LILRA5 transcript copy numbers have been associated with sepsis, we also observed increased levels in patients with systemic infection but without sepsis complications. Ex vivo bacterial infection of whole blood did not alter surface LILRA5 expression, but LPS stimulation changed expression levels. This indicates that surface LILRA5 expression is dynamic and likely regulated posttranscriptionally, changing responses to different stimuli or over time. Soluble (s)LILRA5 was enhanced in sera from sepsis patients and in supernatants of monocytes that were LPS-stimulated, indicative that shedding of LILRA5 from cell surfaces or that expression of sLILRA5 isoforms provides a mechanism to regulate surface LILRA5 expression levels. Finally, we show that altered surface LILRA5 expression influences LILRA5-induced ROS production capacity. We propose that LILRA5 is a dynamically regulated activating receptor expressed on phagocytes that can stimulate ROS production.

immunology↗

bioRxiv2025

Tarloxotinib targets tumor hypoxia to improve therapeutic efficacy of immune checkpoint inhibition in a TLR9 dependent manner

Immune checkpoint inhibitors can elicit deep and durable immune responses although most cancer patients fail to experience long-term remission. There is consensus that tumor hypoxia coordinates a multitude of underlying resistance mechanisms that contribute to treatment failure. Here we show that the clinical-stage hypoxia-activated prodrug tarloxotinib lowers tumor hypoxia 8-fold in the EGFR-dependent MB49 syngeneic tumor model, attracting a effector CD8+ T cell infiltrate into an oxygen enriched tumor microenvironment, leading to potentiation of checkpoint inhibitor activity. Various methodologies, including CD8+ T cell depletion and exogenous T cell priming confirmed that tarloxotinib has a positive impact on the function of activated CD8+ T cells. Whilst anti-PD-L1, anti-PD-1 and anti-CTLA-4 treatments all benefited from the remodeled tumor microenvironment, anti-PD-L1 was most responsive to tarloxotinib coadministration, providing a 100% complete response rate and >360% improvement in tumor growth delay (day 19; p<0.0001). This robust interaction was associated with MB49 tumor enrichment of CD8+ T cell infiltrate from 8% to 43% of the total CD45+ population. To further understand these promising observations, comparative RNA transcript analysis of 770 cancer/immune related genes in naive and tarloxotinib treated tumors highlighted the strong induction of gene clusters related to co-stimulatory signaling, cytokine/chemokine signaling, interferon signaling, immune cell adhesion/migration, antigen presentation and the lymphoid/myeloid compartments. Serum protein analysis confirmed upregulation of a mixture of cytokines/chemokines, including IL-6, IL-12p40, IFN{gamma}, G-CSF and MIP-1{beta}, amongst others. The source of this broad immunogenic response was identified as toll-like receptor 9 (TLR9) dependent, with the positive interaction between anti-PD-L1 and tarloxotinib blocked in MyD88 or TLR9 knockout mice. Further, the observed therapeutic interaction was still evident in MC38 and EG7.OVA syngeneic tumor models, both refractory to tarloxotinib by virtue of EGFR-signal independence. Consistent with the clinical experience of minimal systemic toxicities related to EGFR inhibition (e.g. diarrhea), mouse body weight loss was minimal across all in vivo studies and histopathology screening for evidence of lung fibrosis proved negative. Tarloxotinib therefore represents a systemically administered small molecule with an established clinical safety profile that is capable of activating TLR9 signaling within tumors whilst remodeling the microenvironment to facilitate efficacy of checkpoint blockade. What is already known on this topicSolid tumor resistance to immune checkpoint inhibitors (ICI) is orchestrated through a diverse collection of hypoxia-driven mechanisms. In preclinical models modifying the tumor microenvironment (TME) to lessen hypoxia typically improves responses to ICI. What this study addsTarloxotinib is a hypoxia-activated prodrug (HAP) of an irreversible EGFR/HER2 TKI that profoundly remodels the TME, both eliminating tumor hypoxia and elevating cytokine/chemokine production via a TLR9 dependent effect. Together, this results in a marked tumor influx of activated CD8+ T cells (and other TILs), that results in major improvements in the efficacy of ICIs, particularly anti-PD-L1. How this study might affect research, practice or policyTarloxotinib is the first example of a tumor-targeted small molecule TLR9 stimulant that restores ICI sensitivity in a range of syngeneic tumor models. Phase I/II data has demonstrated that tarloxotinib is well tolerated, with few EGFR-dependent (on-target) side-effects, reflecting minimization of normal tissue exposure with the tumor-targeted HAP approach. Importantly, it also optimizes tumor selective exposure, offering a compelling clinical rationale for evaluation of this combination in cancer patients experiencing ICI relapse or resistance.

immunology↗

bioRxiv2025

Building Multivariate Molecular Imaging Brain Atlases Using the NeuroMark PET Independent Component Analysis Framework

Molecular imaging analyses using positron emission tomography (PET) data often rely on macro-anatomical regions of interest (ROI), which may not align with chemo-architectural boundaries and obscure functional distinctions. While methods such as independent component analysis (ICA) have been useful to address this limitation, the fully data-driven nature can make it challenging to compare results across studies. Here, we introduce the NeuroMark PET approach, utilizing spatially constrained independent component analysis to define overlapping regions that may reflect the brains molecular architecture. We first generate an ICA template for the PET radiotracer florbetapir (FBP), targeting amyloid-{beta} (A{beta}) accumulation in the brain, using blind ICA on large datasets to identify replicable independent components. Only components that targeted A{beta} were included in this study, defined as A{beta} networks (A{beta}Ns), by omitting components targeting myelin or other non-A{beta} targets. Next, we use the A{beta}Ns as priors for spatially constrained ICA, resulting in a fully automated ICA pipeline called NeuroMark PET. This NeuroMark pipeline, including its A{beta}Ns, was validated against a standard neuroanatomical PET atlas, using data from the Alzheimers Disease Neuroimaging Initiative (ADNI). The study included 296 cognitively normal participants with FBP PET scans and 173 with florbetaben (FBB) PET scans, an analogue radiotracer also targeting A{beta} accumulation. Our results show that NeuroMark PET captures biologically meaningful, participant-specific features, such as subject specific loading values, consistent across individuals, and also shows higher sensitivity and power for detecting age-related changes compared to traditional atlas-based ROIs. Using this framework, we also highlight some of the advantages of using ICA analysis for PET data. In this study, an A{beta}N consists of weighted voxels and forms a pattern throughout the entire brain. For example, components may have weighted values at every voxel and can overlap with one another, enabling the separation of artifacts which may coincide with the A{beta}Ns of interest. In addition, this approach allows for the differentiation, separating white matter components, which may overlap in complex ways with the A{beta}Ns, mainly residing in the neighboring gray matter. Results also showed that the most age associated A{beta}N (representing the cognitive control network, CC1) exhibited a stronger association with age compared with macro-anatomical regions of interest. This may suggest that each NeuroMark FBP A{beta}N represents a spatial network following chemo-architectural uptake with greater biological relevance compared with anatomical ROIs. In summary, the proposed NeuroMark PET approach offers a fully automated framework, providing accurate and reproducible brain A{beta}Ns. This approach enhances our ability to investigate the molecular underpinnings of brain function and pathology, offering an alternative to traditional ROI-based analyses.

neuroscience↗

bioRxiv2025

Spatial distribution of the proteome in human body and cancers

A comprehensive spatial distribution of the proteome in human body and cancers is fundamental for understanding human biology and diseases including cancers. Here, we present an anatomically resolved human proteome derived from 1781 benign and malignant samples from 58 major tissue types encompassing 251 specific tissues and 25 carcinomas. Based on a spectral library covering over 75% of the human protein-coding genes with 208 understudied and 82 missing proteins characterized, we quantified over 13,000 proteins in these samples using data-independent acquisition proteomics. This data resource presents the so far most comprehensive quantitative proteomic landscape of human tissues and common carcinomas. It allows systematic evaluation of tissue-specific drug responses, identification of drug candidates that may be repurposed as antineoplastics, and discovery of novel targets for anticancer therapy. This resource, available as an online knowledgebase, refines our knowledge of spatial distribution of the human proteome and tumor-specific protein modulation.

systems biology↗

bioRxiv2025

Altered Functional Network Energy Across Multiscale Brain Networks in Preterm vs. Full-Term Subjects: Insights from the Adolescent Brain Cognitive Development (ABCD) Study

Infants born prematurely, or preterm, can experience altered brain connectivity, due in part to incomplete brain development at the time of parturition. Research has also shown structural and functional differences in the brain that persist in these individuals as they enter adolescence when compared to peers who were fully mature at birth. In this study, we examined functional network energy across multiscale functional connectivity in approximately 4600 adolescents from the Adolescent Brain Cognitive Development (ABCD) study who were either preterm or full term at birth. We identified three key brain networks that show significant differences in network energy between preterm and full-term subjects. These networks include the visual network (comprising the occipitotemporal and occipital subnetworks), the sensorimotor network, and the high cognitive network (including the temporoparietal and frontal subnetworks). Additionally, it was demonstrated that full-term subjects exhibit greater instability, leading to more dynamic reconfiguration of functional brain information and increased flexibility across the three identified canonical brain networks compared to preterm subjects. In contrast, those born prematurely show more stable networks but less dynamic and flexible organization of functional brain information within these key canonical networks. In summary, measuring multiscale functional network energy offered insights into the stability of canonical brain networks associated with subjects born prematurely. These findings enhance our understanding of how early birth impacts brain development.

neuroscience↗