Biology subjects

Kim, H.

Publications and source records attributed to Kim, H..

At least 199 records · Page 11Linked to original sources

bioRxiv2025

Probing the effect of PEG-DNA interactions and buffer viscosity on tethered DNA in shear flow

DNA flow-stretching is a widely employed, powerful technique for investigating the mechanisms of DNA-binding proteins involved in compacting and organizing chromosomal DNA. We combine single-molecule DNA flow-stretching experiments with Brownian dynamics simulations to study the effect of the crowding agent polyethylene glycol (PEG) in these experiments. PEG interacts with DNA by an excluded volume effect, resulting in compaction of single, free DNA molecules in PEG solutions. In addition, PEG increases the viscosity of the buffer solution. By stretching surface-tethered bacteriophage lambda DNA in a flow cell and tracking the positions of a quantum dot labeled at the free DNA end using total internal reflection fluorescence (TIRF) microscopy, we find that higher PEG concentrations result in increased end-to-end length of flow-stretched DNA and decreased fluctuations of the free DNA end. To better understand our experimental results, we perform Brownian dynamics simulations of a bead-spring chain model of flow-stretched DNA in a viscous buffer that models the excluded volume effect of PEG by an effective attractive interaction between DNA segments. We find quantitative agreement between our model and the experimental results for suitable PEG-DNA interaction parameters.

biophysics↗

bioRxiv2025

Strain-specific differences in toxT expression and virulence gene activation in Vibrio cholerae

The transcriptional activator ToxT is a key regulator of Vibrio cholerae virulence, controlling the expression of cholera toxin (CT) and the toxin co-regulated pilus (TCP). Insights into the regulation and function of toxT have largely come from studies on the classical biotype strain O395, which exhibits robust toxT expression. However, toxT expression is not fully consistent across V. cholerae strains. Here, we show that toxT transcription and protein production differ significantly among strains, particularly in El Tor biotype, which exhibit allele-dependent regulatory constraints. Using qRT-PCR and Western blotting, we demonstrate that alternative toxT alleles confer distinct transcriptional activator functions across El Tor biotype strains. Notably, IB5230, a pandemic El Tor strain, exhibits enhanced toxT and virulence gene expression even at 37{degrees}C, suggesting a potential adaptation for increased pathogenicity. Our results suggest that toxT autoregulatory feedback plays a more critical role in virulence gene activation than previously recognized. This study underscores previously unrecognized complexity in toxT regulation, emphasizing the need to reassess virulence control mechanisms in epidemic and emerging V. cholerae strains. Understanding these strain-specific differences is essential for refining models of cholera pathogenesis. Author SummaryCholera is a severe diarrheal disease caused by the bacterium Vibrio cholerae, which continues to pose a major threat to global health. The ability of V. cholerae to cause disease depends on the expression of two key virulence factors--cholera toxin (CT) and the toxin-coregulated pilus(TCP)-- controlled by the transcriptional activator ToxT. While much of our understanding of ToxT regulation is based on classical biotype strains, most recent cholera outbreaks have been driven by El Tor biotype strains. In this study, we demonstrate that toxT expression and its ability to activate virulence genes vary markedly across V. cholerae strains, depending on both the specific toxT allele and the genetic background. Using isogenic strains engineered to express different toxT alleles, we show that some alleles are transcriptionally silent in certain El Tor strains while others are active, despite having similar functional capabilities when expressed. Notably, a hypervirulent strain linked to the Haitian cholera outbreak maintained high toxT expression even at human body temperature, hinting at possible adaptive mechanisms for enhanced pathogenicity. Our findings suggest that virulence regulation in V. cholerae may be more variable than previously recognized, highlighting strain- and allele-specific differences in toxT expression. Understanding these strain- and allele-specific differences in virulence gene regulation is crucial for improving models of cholera pathogenesis and could inform the development of more effective interventions and vaccines against this evolving pathogen.

microbiology↗

bioRxiv2025

Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells

Brain endothelial cells experience mechanical forces in the form of blood flow-mediated shear stress and underlying matrix stiffness, but intersectional contributions of these factors towards blood-brain barrier (BBB) impairment and neurovascular dysfunction have not been extensively studied. Here, we developed in vitro models to examine the sensitivity of primary human brain microvascular endothelial cells (BMECs) to substrate stiffness, with or without exposure to fluid shear stress. Using a combination of molecular profiling techniques, we show that BMECs exhibit an inflammatory signature at both the mRNA and protein level when cultured on gelatin substrates of intermediate stiffness ([~]30 kPa) versus soft substrates ([~]6 kPa). Exposure to modest fluid shear stress (1.7 dyne/cm2) partially attenuated this signature, including reductions in levels of soluble chemoattractants and surface ICAM-1. Overall, our results indicate that increased substrate stiffness promotes an inflammatory phenotype in BMECs that is dampened in the presence of fluid shear stress.

neuroscience↗

bioRxiv2025

Amyloid-β-regulated gene circuits for programmable Alzheimer's disease therapy

Alzheimer's disease (AD) is a neurodegenerative disease characterized in part by the accumulation of the protein amyloid-{beta} (A{beta}). Monoclonal antibodies (mAbs) that target A{beta} for clearance from the brain have received FDA approval; however, these therapies are accompanied by serious side effects, and their cognitive benefit for patients remains of tremendous debate. Here, we present a potential engineered cell therapy for AD in which we enlist cells of the central nervous system as programmable agents for sculpting the neurodegenerative niche toward one that mitigates glial reactivity and neuronal loss. We constructed a suite of A{beta}-sensitive synthetic Notch (synNotch) receptors from clinically tested anti-A{beta} mAbs and show that cells expressing these receptors can recognize synthetic A{beta}42 and A{beta}40 with differential sensitivity. We express these receptors in astrocytes, cells native to the brain that are known to become dysfunctional in AD. These synNotch astrocytes, which upregulate selected transgenes upon exposure to synthetic and human brain-derived amyloid, were engineered to express potential therapeutic transgenes in response to A{beta}, including brain-derived neurotrophic factor and antagonists of the cytokines tumor necrosis factor and interleukin-1. SynNotch astrocytes that express such antagonists in response to A{beta} partially attenuate a cytokine-induced reactive astrocyte phenotype and promote barrier properties in brain microvascular endothelial cells. Additionally, engineered A{beta}-synNotch cells potently upregulate transgene expression in response to A{beta} deposited in the 5xFAD mouse brain, demonstrating the capacity to recognize A{beta} in situ. Overall, our work supports A{beta}-synNotch receptors as promising tools to generate a cell-based therapy for AD with targeted functionalities to positively influence the AD niche.

bioengineering↗

bioRxiv2025

Comparing Vibrotactile Stimulation to Combined Visual and Auditory Stimulation for 40 Hz Gamma Entrainment

There is significant interest in combined visual and auditory stimulation to entrain 40 Hz gamma oscillations for the treatment of Alzheimers disease and other neurological conditions such as stroke and insomnia. In this work, we compared another sensory modality--vibrotactile stimulation delivered with a glove--to visual and auditory stimulation in 15 healthy participants in terms of electroencephalogram (EEG) responses and subjective experience. We found that vibrotactile stimulation from the glove could evoke 40 Hz EEG responses in the central, frontal and, to a lesser extent, occipital cortices. We also observed distinct patterns of functional connectivity between the two stimulation modalities. Participants preferred the vibrotactile stimulation over the visual and auditory stimulation. Our study supports future investigations on vibrotactile stimulation for the treatment of neurological conditions.

bioengineering↗

bioRxiv2025

Sub-second Fluctuation between Top-Down and Bottom-Up Modes Distinguishes Diverse Human Brain States

Information continuously flows between regions of the human brain, exhibiting distinct patterns that dynamically shift across states of consciousness, cognitive modes, and neuropsychiatric conditions. In this study, we introduce Relative Phase Analysis (RPA), a method that leverages phase-lead/lag relationships to reveal the real-time dynamics of dominant directional patterns and their rapid transitions. We demonstrate that the human brain switches on a sub-second timescale between a top-down mode-where anterior regions drive posterior activity-and a bottom-up mode, characterized by reverse directionality. These dynamics are most pronounced during full consciousness and gradually become less distinct as awareness diminishes. Furthermore, we find from simultaneous EEG-fMRI recordings that the top-down mode is expressed when higher-order cognitive networks are more active while the bottom-up mode is expressed when sensory systems are more active. Moreover, comparisons of an attention deficit hyperactivity disorder (ADHD) inattentive cohort with typically developing individuals reveal distinct imbalances in these transition dynamics, highlighting the potential of RPA as a diagnostic biomarker. Complementing our empirical findings, a coupled-oscillator model of the structural brain network recapitulates these emergent patterns, suggesting that such directional modes and transitions may arise naturally from inter-regional neural interactions. Altogether, this study provides a framework for understanding whole-brain dynamics in real-time and identifies sub-second fluctuations in top-down versus bottom-up directionality as a fundamental mechanism underlying human information processing.

neuroscience↗

bioRxiv2025

Dual agonist and antagonist muscle vibration produces a bias in end point with no change in variability

Muscle spindles provide critical proprioceptive feedback about muscle length to the central nervous system (CNS). Single muscle tendon vibration can stimulate muscle spindles, causing participants to misjudge limb position, while dual muscle tendon vibration is thought to produce a noisy proprioceptive system. It is currently unclear exactly how the CNS uses kinesthetic feedback from the agonist and antagonist muscles during target-directed reaches. The purpose of the current project was to investigate the effects of agonist, antagonist, and dual agonist/antagonist during target-directed reaching. Using an elbow extension task, we found that antagonist muscle vibration produced an undershooting effect relative to the no-vibration control, while agonist muscle vibration produced an overshooting effect relative to the no-vibration control. Neither of the single muscle vibrations produced any change in the variable error of the movements. While it was originally hypothesized that dual agonist/antagonist vibration would increase participants variable error with no change in bias, the opposite was found. Participants undershot relative to the no-vibration control with no change in variable error. Overall, the results from this study suggest that dual vibration does not necessarily create a noisy proprioceptive system but can produce a bias in end point.

neuroscience↗

bioRxiv2025

Antibody-Free Immunopeptide Nano-Conjugates for Brain-Targeted Drug Delivery in Glioblastoma Multiforme

Glioblastoma Multiforme (GBM) represents a significant clinical challenge amongst central nervous system (CNS) tumors, with a dismal mean survival rate of less than 8 months, a statistic that has remained largely unchanged for decades (National Brain Society, 2022). The specialized intricate anatomical features of the brain, notably the blood-brain barrier (BBB), pose significant challenges to effective therapeutic interventions, limiting the potential reach of modern advancements in immunotherapy to impact these types of tumors. This study introduces an innovative, actively targeted immunotherapeutic nanoconjugate (P12/AP-2/NCs) designed to serve as an immunotherapeutic agent capable of traversing the BBB via LRP-1 receptor-mediated transcytosis. P12/AP-2/NCs exert its immune-modulating effects by inhibiting the PD-1/PD-L1 axis through a small-size PD-L1/ PD-L2 antagonist peptide Aurigene NP-12 (P12). P12/AP-2/NCs are synthesized from completely biodegradable, functionalized high molecular weight {beta}-poly(L-malic acid) (PMLA) polymer, conjugated with P12 and Angiopep-2 (AP2) to yield P12/AP-2/NCs. Evaluating nanoconjugates for BBB permeability and 3-D tumor model efficacy using an in vitro BBB-Transwell spheroid based model demonstrating successful crossing of the BBB and internalization in brain 3D tumor environments. In addition, the nanoconjugate mediated T cells cytotoxicity on 3D tumor region death in a U87 GBM 3-D spheroid model. AP2/P12/NCs is selectively inhibited in PD1/PDL1 interaction on T cells and tumor site, increasing inflammatory cytokine secretion and T cell proliferation. In an in-vivo murine brain environment, rhodamine fluorophore-labeled AP2/P12/NCs displayed significantly increased accumulation in the brain during 2-6 h time intervals post-injection with a prolonged bioavailability over unconjugated peptides. AP2/P12/NCs demonstrated a safety profile at both low and high doses based on major organ histopathology evaluations. Our findings introduce a novel, programmable nanoconjugate platform capable of penetrating the BBB for directed delivery of small peptides and significant immune environment modulation without utilizing antibodies, offering promise for treating challenging brain diseases like glioblastoma multiforme and beyond.

immunology↗

bioRxiv2025

The graphene-based affinity cryo-EM grid for the endogenous protein structure determination

Following recent advancements in cryo-electron microscopy (cryo-EM) instrumentation and software algorithms, the next bottleneck in achieving high-resolution cryo-EM structures arises from sample preparation. To overcome this, we developed a graphene-based affinity cryo-EM grid, the Graffendor (GFD) grid, to target low-abundance endogenous protein complexes. To maintain grid quality and consistency within a single batch of 36 grids, we established a one-step crosslinking batch-production method using genetically modified ALFA nanobody as affinity probe (GFD-A grid). Using low concentrations of {beta}-galactosidase-2xALFA, we demonstrated the GFD-A grids efficiency in capturing tagged proteins and resolving its cryo-EM structure at 2.71 [A]. To test its application for endogenous proteins, we engineered yeast cells with a C-terminal tandem affinity tag (3xALFA-Tev-3xFlag: ATF) at Pop6, a shared component of RNase MRP and RNase P. Cryo-EM structures of RNase MRP and RNase P were resolved at 3.3 [A] and 3.0 [A] from cell lysates, and 3.6 [A] and 3.9 [A] from anti-flag elution, respectively. Notably, additional densities were observed in the structures obtained from cell lysates, which were absent in those from the anti-FLAG eluate. These findings establish the GFD-A grid as a robust platform for investigating endogenous proteins, capable of capturing transient interactions and enhancing the resolution of challenging cryo-EM structures with greater efficiency.

biochemistry↗

bioRxiv2025

Autism-associated ASPM variant causes macrocephaly and social-cognitive deficits in mice

In autism spectrum disorder (ASD), a neurodevelopmental disorder with social-cognitive deficits, macrocephaly occurs in 20% of patients with severe symptoms. However, the role of macrocephaly in ASD pathogenesis remains unclear. Here, we address the mechanistic link between macrocephaly and ASD by investigating a novel ASD-associated gain-of-function A1877T mutation in ASPM (abnormal spindle-like microcephaly-associated). ASPM is a key regulator of cortical size and cell proliferation expressed in both excitatory and inhibitory neuronal progenitors but not in differentiated neurons. We found that Aspm gain-of-function knock-in mice exhibit macrocephaly, excessive embryonic neurogenesis with expanded outer radial glia, an increased excitatory-inhibitory (E-I) ratio, brain hyperconnectivity, and social-cognitive deficits with male specificity. Our results suggest that macrocephaly in ASD is not a proportional expansion of excitatory and inhibitory neurons, but a shift in the E-I ratio, independent of the expression patterns of the causative gene. Thus, macrocephaly alone can cause a subset of ASD-like symptoms.

neuroscience↗

bioRxiv2025

Cholesterol efflux protein, ABCA1, supports anti-cancer functions of myeloid immune cells

Although immune therapy has seen significant advances, the majority of breast and other solid tumors do not respond or quickly develop de novo resistance. One factor driving resistance is highly immune suppressive myeloid cells (MCs) such as macrophages. Previous work has established clinical links between cholesterol and cancer outcome, and that MC function can be regulated through disruption in cholesterol metabolism. Thus, we screened for proteins that were expressed in MCs, involved in cholesterol homeostasis and whose expression was associated with survival; we identify the cholesterol efflux protein ABCA1. Preclinical studies revealed that ABCA1 activity resulted in increased anti-cancer functions of macrophages: enhanced tumor infiltration, decreased angiogenic potential, reduced efferocytosis, and improved support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K dependent and independent mechanisms. Assessment of human blood and breast tumors revealed correlations between ABCA1 in macrophages and angiogenic potential, VEGFA, and CD8 T cell abundance and activity, highlighting the clinical relevance of our findings. The culmination of the effects of ABCA1 on MC function were demonstrated through increased tumor growth and metastasis in mice with MC specific knockout of ABCA1. Therefore, modulating ABCA1 activity within MCs may represent a novel approach to immune therapy.

cancer biology↗

bioRxiv2025

A dual mechanism of sensitivity to PLK4 inhibition by RP-1664 in neuroblastoma

A novel therapeutic strategy was recently proposed for high-risk neuroblastoma carrying copy number gain of the TRIM37 gene: centriole loss upon inhibition of polo-like kinase 4 (PLK4), while tolerated by normal cells, induces aberrant mitotic spindle formation and p53-dependent cell death in TRIM37-overexpressing cells. Interestingly, while full PLK4 inhibition causes centriole loss, partial inhibition is known to elevate centriole numbers. Here we show using a novel selective PLK4 inhibitor RP-1664 that both centriole loss and amplification contribute to hypersensitivity of neuroblastoma cells. Whereas inactivation of TRIM37 and TP53 rescues neuroblastoma cell death at higher concentrations of RP-1664, at lower doses cell death is TRIM37/TP53-independent. With CRISPR screens and live cell imaging we demonstrate that upon centriole amplification, neuroblastoma cells succumb to multipolar mitoses due to inability to cluster or inactivate supernumerary centrosomes. In vivo, RP-1664 shows robust efficacy in neuroblastoma xenografts at doses consistent with centriole amplification. STATEMENT OF SIGNIFICANCEHigh-risk neuroblastoma is associated with poor outcomes in pediatric patients and novel therapies need to be developed. We show that neuroblastoma cells are remarkably sensitive to PLK4 inhibitors due to a combination of two complementary mechanisms, supporting the evaluation of PLK4 inhibitors in clinical trials of high-risk neuroblastoma.

cancer biology↗

bioRxiv2025

SoEM-Web: a user-friendly platform for the analysis and visualization of small-organelle-enriched metagenomics data

BackgroundMarine microeukaryotes play a crucial role in global biogeochemical cycles and ecosystem functioning. However, their diversity and distribution patterns remain poorly understood. To improve the biodiversity assessment of environmental samples, we recently developed a PCR-free, small-organelle-enriched metagenomics (SoEM) method, accompanied by a bioinformatics workflow for analyzing SoEM metagenomic data. However, the complexity of these analyses typically requires extensive bioinformatics expertise, potentially limiting their broader adoption. MethodsTo address this challenge, we present SoEM-Web, a user-friendly web application for the interactive analysis, classification, and visualization of SoEM metagenomic data. SoEM-Web integrates all necessary procedures, including raw sequencing data preprocessing, paired-end read merging, automated taxonomic identification, and diversity visualization, into a streamlined workflow accessible through an intuitive interface. This application is designed to facilitate SoEM data analysis for researchers who may not have advanced bioinformatics skills. ResultsWe demonstrated the capabilities of SoEM-Web by reanalyzing previously published datasets. This reanalysis not only confirmed the utility of the platform but also revealed additional taxa, emphasizing the value of updated reference datasets. The application successfully simplifies complex bioinformatics processes, enhancing accessibility and reproducibility in marine microeukaryote diversity research. SoEM-Web aims to enhance accessibility and reproducibility in marine microeukaryote diversity research. The web server is freely available at http://compsysbio.re.kr/soem-web/.

bioinformatics↗

bioRxiv2025

Lineage plasticity of the integrated stress response is a hallmark of cancer evolution.

The link between the "stress phenotype"-a well-established hallmark of cancer-and its role in tumor progression and intratumor heterogeneity remains poorly defined. The integrated stress response (ISR) is a key adaptive pathway that enables tumor survival under oncogenic stress. While ISR has been implicated in promoting tumor growth, its precise role in driving tumor evolution and heterogeneity has not been elucidated. In this study, using a genetically engineered mouse models, we demonstrate that ISR activation--indicated by elevated levels of phosphorylated eIF2 (p-eIF2) and ATF4--is essential for the emergence of dedifferentiated, therapy-resistant cell states. ISR, through the coordinated actions of ATF4 and MYC, facilitates the development of tumor cell populations characterized by high plasticity, stemness, and an epithelial-mesenchymal transition (EMT)-prone phenotype. This process is driven by ISR-mediated expression of genes that maintain mitochondrial integrity and function, critical for sustaining tumor progression. Importantly, genetic, or pharmacological inhibition of the p-eIF2-ATF4 signaling axis leads to mitochondrial dysfunction and significantly impairs tumor growth in mouse models of lung adenocarcinoma (LUAD). Moreover, ISR-driven dedifferentiation is associated with poor prognosis and therapy resistance in advanced human LUAD, underscoring ISR inhibition as a promising therapeutic strategy to disrupt tumor evolution and counteract disease progression.

cancer biology↗

bioRxiv2025

Multivariate Neural Markers of Individual Differences in Thought Control Difficulties

Difficulties in controlling thought, including pathological rumination, worry, and intrusive thoughts, occur in a range of mental health disorders. Here we identify specific patterns of brain activity distributed within and across canonical brain networks that are associated with self-reported difficulties in controlling ones thoughts. These activity patterns were derived using multivariate pattern analysis on fMRI data recorded while participants engaged in one of four operations on an item in working memory: maintaining it, replacing it with another, specifically suppressing it, or clearing the mind of all thought. Individuals who reported greater difficulties exhibited brain activation patterns that were more variable and less differentiated across the four operations in frontoparietal and default mode networks, and showed less distinct patterns of connectivity within the default mode network. These activity profiles were absent during rest but serve as promising task-based neural markers, explaining over 30% of the variance in thought control difficulties.

neuroscience↗

bioRxiv2025

The CFDE Workbench: Integrating Metadata and Processed Data from Common Fund Programs

The NIH Common Fund Data Ecosystem (CFDE) program was established to facilitate data accessibility and interoperability across multiple Common Fund (CF) programs and promote collaborations and new discoveries by combining data from different CF programs. The CFDE Data Resource Center (DRC) was tasked with developing two web-based portals: an Information Portal to serve information about the CFDE, and a Data Portal to host harmonized metadata and processed data contributed by participating CF Data Coordination Centers (DCCs) and other sources. To achieve these goals, the CFDE DRC developed the CFDE Workbench, a web-based platform that hosts highly processed data, metadata, tools, use cases, and analyses developed by the CFDE. The Crosscut Metadata Model (C2M2) and several other processed data formats are hosted by the CFDE Workbench, including set libraries (XMTs), Knowledge Graph (KG) assertions, and attribute tables. These processed data formats make information derived from CF programs more findable, accessible, interoperable, and reusable (FAIR) and artificial intelligence (AI)-ready for cross-DCC knowledge discovery. In addition to these processed data formats, several other assets are served by the Workbench, including Extract Transform Load (ETL) pipelines, OpenAPI-documented and SmartAPI-registered Representational State Transfer (REST) Application Programming Interfaces (APIs), entity pages such as gene, drug, disease, or tissue landing pages, Playbook Workflow Builder (PWB) metanodes which are codified workflow steps involving DCC APIs, and chatbot specifications which are prompts helping chatbots to use DCC APIs to answer a wide range of user queries. Besides serving data, metadata, and code assets, the CFDE Workbench also has several tools that use these data, metadata, and code assets to enable cross-CF-program knowledge discovery use cases. Overall, the CFDE Workbench is a platform that consolidates efforts toward making CF programs funded resources harmonized, FAIR, and AI-ready. The CFDE Workbench website is available from: https://cfde.info/.

bioinformatics↗

bioRxiv2025

Physiological analysis of the mechanism of Ci transcription factor activation through multiple Fused phosphorylation sites in Hedgehog signal transduction

Hedgehog (Hh) proteins elicit dose-dependent transcriptional responses by binding Patched receptors to activate transmembrane Smoothened (Smo) proteins. Activated Smo inhibits Ci/Gli transcription factor phosphorylation by Protein Kinase A (PKA) and consequent proteolytic processing to repressor forms; it also promotes nuclear transport and activity of full-length Ci/Gli proteins to induce Hh target genes. Smo-activated Fused (Fu) kinase drives Ci activation in Drosophila, while Suppressor of Fused (Su(fu)) counters full-length Ci/Gli activity and stabilizes full-length Ci/Gli by direct binding to at least three surfaces. Here, we used CRISPR-generated designer ci alleles to investigate alterations to Fu phosphorylation sites and to regions around Ci-Su(fu) interfaces under physiological conditions in Drosophila imaginal wing discs. Surprisingly, we identified alterations that activate Ci without significant loss of stabilization by Su(fu) and contributions of multiple Fu target sites to Ci activation in the absence of Su(fu), suggesting that the affected sites mediate Ci activation by regulating Ci-Ci, rather than Ci-Su(fu) interactions. We propose that those interactions maintain full-length Ci in a closed conformation that also facilitates, and is stabilized by, cooperative Ci-Su(fu) binding. Access to binding partners necessary for Ci activation is promoted through phosphorylation of at least four Fu sites on Ci, likely by directly disrupting Ci-Ci contacts and one Ci-Su(fu) interface without substantial Ci-Su(fu) dissociation, contrary to previous proposals. We also found that the Ci binding partner, Costal 2 (Cos2), which silences Ci in the absence of Hh, can facilitate Ci activation by Fu kinase.

developmental biology↗

bioRxiv2025

Classifying Mild Cognitive Impairment from Normal Cognition: fMRI Complexity Matches Tau PET Performance

BackgroundTau protein accumulation is closely linked to synaptic and neuronal loss in Alzheimers disease (AD), resulting in progressive cognitive decline. Although tau-PET imaging is a direct biomarker of tau pathology, it is costly, carries radiation risks, and is not widely accessible. Resting-state functional MRI (rs-fMRI) complexity--an entropy-based measure of BOLD signal variation--has been proposed as a non-invasive surrogate biomarker of early neuronal dysfunction associated with tau pathology. ObjectivesTo determine whether fMRI-based brain complexity (sample entropy and multiscale entropy) can match or exceed tau-PET in classifying cognitively normal (CN) versus cognitively impaired (MCI/AD) individuals. And to investigate and compare the most influential network regions-of-interest (ROIs) for classification between fMRI complexity and tau-PET, thereby identifying key neuroanatomical correlates of AD-related changes. DesignA cross-sectional study employing 3D convolutional neural network (CNN) classification with five-fold cross-validation and leave-one-network-out analysis. SettingData from the Alzheimers Disease Neuroimaging Initiative (ADNI) database. ParticipantsOne hundred forty-seven older adults (age 72.5 {+/-} 7.5 years), including 95 CN, 45 MCI, and 7 AD. MeasurementsWe created whole-brain complexity maps from rs-fMRI and standardized uptake value ratio (SUVR) maps from tau-PET. Each modality was separately fed into CNN classifiers. Region-based analyses (leave-one-network-out) were performed to identify critical ROIs for classification. ResultsfMRI complexity showed classification accuracy comparable to tau-PET yet surpassed it in F1-score (0.64 vs. 0.61) and area under the curve (AUC; 0.73 vs. 0.67). Salience and dorsal attention networks contributed most to fMRI-based classification, and a dorsal attention network contributed most to tau-PET-based classification. ConclusionsfMRI complexity performs similarly to tau-PET in detecting cognitive impairment related to AD and identifies partially distinct critical ROIs, suggesting an alternative, radiation- free imaging biomarker for earlier detection and broader clinical application.

neuroscience↗