Biology subjects

Kim, A. J.

Publications and source records attributed to Kim, A. J..

At least 19 recordsLinked to original sources

bioRxiv2026

Distinct spatial organization of human hippocampal perfusion and microvascular pulsatility across age

Arterial pulsation can modulate neuronal activity through mechanosensitive pathways in mice, but whether vascular pulsatility is similarly related to neural organization in humans remains unclear. Here, using 7T MRI in 35 young and older adults, we mapped cerebral perfusion and microvascular volumetric pulsatility index (mvPI) across the unfolded hippocampus and integrated these measures with histological, electrophysiological, and transcriptomic reference maps. Perfusion and mvPI exhibited distinct spatial organization and age-related differences. In young adults, perfusion preferentially corresponded to parvalbumin-interneuron density and beta/gamma distribution, whereas mvPI was associated with theta-band distribution. A number of associations detected in young adults were not detected in the older adults maps. Spectral simulations showed qualitative similarity to heartbeat-related phase resetting as one possible explanation for the mvPI-theta relationship, while spatial transcriptomics revealed perivascular enrichment of PIEZO2, a candidate mediator of vascular mechanotransduction. Together, these findings establish perfusion and tissue-level pulsatility as distinct dimensions of human hippocampal vascular organization and provide a framework for investigating their relationships with neural dynamics across aging.

neuroscience↗

bioRxiv2026

Connectome analysis reveals brain-wide processing of visual features in Drosophila

Sensory processing relies on an intricate interplay between specialized sensory circuits and the broader brain. Leveraging the whole-brain Drosophila melanogaster connectome, we analyzed long-range projections linking the optic lobe (OL)--the principal visual center--reciprocally with the central brain and the contralateral OL to determine how visual features are computed by a brainwide network. By quantifying synaptic polarity and connectivity, we classified the projection neurons into feedforward, feedback, and bilateral groups. Feedforward neurons form an information bottleneck, consolidating diverse visual features from the OL and distributing them through modular pathways for higher-order processing. Feedback neurons densely innervate OL structures, conveying contextual signals in the central brain via precise recurrent loops. Bilateral neurons link local visual circuits across the two OLs, providing a substrate for inter-ocular processing. These findings reveal how early visual pathways interface with brainwide circuits to support diverse brain functions and enable context-dependent flexibility in sensory computation. HighlightsO_LIWhole-brain connectome analysis identifies three streams of brainwide visual processing C_LIO_LIFeedforward neurons form a bottleneck and distribute features for higher processing C_LIO_LIFeedback neurons modulate early vision via layer-specific recurrent loops C_LIO_LIBilateral neurons bridge both optic lobes to enable inter-ocular processing C_LI

neuroscience↗

bioRxiv2026

Fibroblast-specific Deletion of Yap/Taz Impairs Mouse Postnatal Dermal Development by Suppressing Collagen Production and Deposition

The Hippo pathway effectors YAP and TAZ are key regulators of cell proliferation, apoptosis, and differentiation, thereby maintaining tissue homeostasis and controlling organ size. While their roles in epithelial tissues and cancer are well established, their role in dermal fibroblast extracellular matrix (ECM) regulation is less understood. Here, we investigated the role of Yap/Taz during postnatal skin dermis development. During postnatal growth, mouse skin steadily grows and undergoes significant surface expansion. Postnatal deletion of Yap/Taz in dermal fibroblasts, the primary cells responsible for dermal ECM homeostasis, significantly impaired dermal maturation, as evidenced by marked deficiencies in collagen synthesis and deposition. Isolated fibroblasts from Yap/Taz knockout mice showed reduced proliferation and diminished expression of Yap/Taz target genes (Ccn2, Col1a1), which were rescued by reintroduction of active Yap/Taz. RNA-seq, and spatial transcriptomics and proteomics of Yap/Taz knockout skin revealed substantial downregulation of matrisome genes, including type I (Col1a1, Col1a2) and type III (Col1a3) collagens, which together constitute more than 90% of the skins collagen content. These findings demonstrate that Yap/Taz are essential for dermal ECM homeostasis, highlighting their therapeutic potential in skin regeneration, fibrosis, and aging-related ECM decline.

cell biology↗

bioRxiv2026

Cruciform-forming AT/TA repeats are acted upon by structure selective endonucleases and Rad51 prior to repositioning to the nuclear periphery for repair

Structure-forming DNA repeats can pose a barrier to DNA replication and repair, creating chromosomal fragile sites. An AT/TA DNA repeat, derived from the Flex1 region of human common fragile site FRA16D, can form hairpin and cruciform structures which interfere with DNA replication. When inserted into the S. cerevisiae genome, the Flex1(AT)34 repeat stimulates chromosome deletions in a manner dependent on the Mus81-Mms4 nuclease and the SLX4 nuclease scaffold. It was previously found that hairpin forming CAG/CTG repeats move to the nuclear periphery to maintain genomic stability. Here, we show that a structure forming AT/TA repeat also relocalizes to the nuclear periphery in late S/G2 phase in a replication and length-dependent manner. In contrast to the CAG repeat, this shift in nuclear positioning is dependent on polySUMOylation and the activity of the Mus81-Mms4 nuclease. Processing by the Mre11 nuclease and Rad51-dependent strand exchange occurs prior to repositioning. Replication analysis indicates that the replisome likely bypasses the AT/TA repeat leaving behind a DNA structure that initiates relocation to the nuclear periphery. We conclude that AT/TA repeats form post-replicative DNA structures that are targeted for nuclease cleavage and require hairpin processing and repositioning to the nuclear periphery for homologous recombination-dependent repair.

genetics↗

bioRxiv2025

Assessing molecular, cellular and transcriptomic bases of laminar perfusion and cytoarchitecture coupling in the human cortex

Understanding how cellular architecture organizes cortical function requires mesoscopic approaches that resolve structure-function coupling in vivo. Here we introduce cerebral blood flow (CBF) and cell-body staining intensity (CSI) similarity index (CCSI), a localized similarity index between the CBF estimates from ultra-high-field 7T arterial spin labeling images and CSI from the BigBrain histology images to serve as a quantitative marker of laminar perfusion-cytoarchitecture coupling. CCSI revealed a reproducible, region- specific alignment between laminar vascular and cellular profiles across the cortex. Going beyond CBF, CCSI selectively tracked mitochondrial respiratory capacity and colocalized with capillary endothelial and mature non-myelination oligodendrocyte populations forming neurovascular interfaces. Transcriptomic enrichment highlighted pathways related to vascular remodeling, oxidative metabolism, and lipid-myelin homeostasis, indicating that CCSI reflects integrated metabolic-structural specialization. At the systems level, CCSI strengthened structure-function gradient correspondence in transmodal cortices, such as the default mode network. Together, these findings establish CCSI as a physiologically grounded, non-invasive marker of perfusion-cytoarchitecture alignment, providing a cross-scale framework linking cortical microstructure, metabolism, and functional organization.

neuroscience↗

bioRxiv2025

Arousal increases locus coeruleus blood flow, salience-related brain responses, and modulates negative-valence attentional biases

The amygdala helps prioritize emotional over neutral information. However, it responds similarly to positive and negative stimuli, and so is unlikely to be the source of valence-specific effects within affective networks. We hypothesized that the locus coeruleus (LC) is a key contributor to negative biases in attention. Using ultra-high field 7T magnetic resonance imaging, we tested how arousal modulates processing of emotional faces during an oddball task in twenty-two young adults during two separate sessions. Arousal induced by isometric handgrip increased LC cerebral blood flow and amplified brain responses to target and angry faces, but not to happy faces. The amygdala exhibited valence-general responses that were not modulated by arousal. LC connectivity with the default mode network decreased during processing target and angry faces, and arousal further modulated responses in the salience network and visual cortex. Behaviorally, arousal enhanced recognition of angry faces only when allocating attentional resources and memory performance was linked to left LC brain activity. These findings highlight the LC as a key structure through which arousal shapes valence processing, biases attention, and informs mechanisms related to affective disorders.

neuroscience↗

bioRxiv2025

Electroencephalography, pupillometry, and behavioral evidence for locus coeruleus-noradrenaline system related tonic hyperactivity in older adults

Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampers the development of targeted preventative interventions. In this study, we tested the hypothesis that cognitively healthy older adults sustain tonic LC hyperactivity, by acquiring electrophysiological, pupillometric, and behavioral measures during a passive and active auditory oddball paradigm. We capitalized on the LC-NA systems role in arousal regulation and manipulated state arousal using the unpredictable threat of electric shock. We hypothesized that if older adults maintain elevated LC activity compared with young adults, task-evoked noradrenergic responses would be less responsive to arousal in older adults. Consistent with this hypothesis, arousal elicited weaker behavioral responses, pupil dilation responses, and P300 event-related potentials in older adults compared with young adults. Linear mixed models revealed an arousal by modality interaction, showing that arousal differentially modulated attentional control to salient but task-irrelevant distractors between both age groups. Collectively, these findings support the hypothesis that aging is associated with tonic LC-NA system hyperactivity in humans, with neuromodulatory consequences for mechanisms of attentional control. Furthermore, the multimodal approach underscores the potential of non-invasive physiological markers to assess LC-NA system function throughout aging and identify individuals at elevated risk for neurodegenerative progression prior to the emergence of clinical biomarkers. Highlights- Behavioral, pupil and EEG data indicate LC-NA tonic hyperactivity in older adults. - Arousal modulates attentional control differently in young vs. older adults. - Older adults show increased distractibility from reduced habituation. - Arousal differentially modulates alpha power and aperiodic activity across age groups. - Phasic noradrenergic responses are modulated by state, arousal, and attention.

neuroscience↗

bioRxiv2025

Identification of novel interacting proteins of FUZ and GPR161.

Proteins modulate signaling pathways through dynamic protein-protein interactions, which provide critical insights into the underlying mechanisms of cellular processes leading to human diseases. Our previous study revealed the biochemical and genetic interactions between FUZ and GPR161 that regulate sonic hedgehog signaling during spinal neural tube development. This study aimed to identify novel co-interacting proteins of FUZ and GPR161 and explore their biochemical and functional associations. We performed affinity-based liquid chromatography-tandem mass spectrometry on immunoprecipitated FUZ and GPR161 proteins. Using this approach, we identified 159 co-interacting proteins, of which 289 proteins that interacted exclusively with FUZ and 617 proteins that interacted exclusively with GPR161. Gene Ontology (GO) analysis of the FUZ and GPR161 co-interactome revealed an enrichment of proteins associated with proteasomal catabolic processes and trafficking. GO analysis of the exclusive FUZ and GPR161 interactomes identified cell cycle progression, mitochondrial membrane, RNA metabolism, receptor complex, and Endoplasmic Reticulum-Golgi transport. These findings were further validated using STRING network analysis. Among the identified proteins, we prioritized FKBP8 and confirmed its biochemical interactions with both FUZ and GPR161 exclusively. In summary, our proteomic profiling uncovered the protein network of FUZ and GPR161, revealing their individual and cooperative functions in multiple cellular processes. Statement of Significance- The functional link between FUZ and GPR161 remains unknown, while our previous study showed their genetic and biochemical link in regulating sonic hedgehog signaling during spinal neural tube development. - This study identified the protein network involving FUZ and GPR161 using affinity- based mass spectrometry combining with gene ontology and STRING analysis, providing the novel molecular regulatory role of FUZ and GPR161. - We prioritized the proteins, FKBP8, as a co-interacting partners of FUZ and GPR161, and validated their biochemical interaction. We identified the FUZ-GPR161-FKBP8 forms protein complex, and their interaction was not exclusive, suggesting those three proteins located in the same signaling pathway potentially regulating spinal neural tube development.

biochemistry↗

bioRxiv2025

Machine learning enables de novo multi-epitope design of plasmodium falciparum circumsporozoite protein to target trimeric L9 antibody

AbstractCurrently approved vaccines for the prevention of malaria provide only partial protection against disease, due to high variability in the quality of induced antibodies. These vaccines present the unstructured central repeat region, as well as the C-terminal domain, of the circumsporozoite protein (PfCSP) of the malaria parasite, Plasmodium falciparum (1). A recently discovered protective monoclonal antibody, L9, recognizes three structured copies of the PfCSP minor repeat. Similarly to other highly potent anti-malarial antibodies, L9 relies on critical homotypic interactions between antibodies for its high protective efficacy (2, 3). Here, we report the design of immunogens scaffolding one copy of PfCSPs minor repeat capable of binding L9. To design immunogens capable of presenting multiple, structure-based epitopes in one scaffold, we developed a machine-learning-driven structural immunogen design pipeline, MESODID, tailored to focus on multi-epitope vaccine targets. We use this pipeline to design multiple scaffolds that present three copies of the PfCSP minor repeat. A 3.6 [A] cryo-EM structure of our top design, minor repeat targeting immunogen (M-TIM), demonstrates that M-TIM successfully orients three copies of L9, effectively recapitulating its critical homotypic interactions. The wide prevalence of repeated epitopes in key vaccine targets, such as HIV-1 Envelope, SARS-CoV-2 spike, and Influenza Hemagglutinin, suggests that MESODID will have broad utility in creating immunogens that incorporate such epitopes, offering a new powerful approach to developing vaccines against a range of challenging infections, including malaria. Significance StatementIn this study, we present a machine learning driven, structure-guided protein design pipeline built specifically for the design of multi-epitope vaccine immunogens. We employ the pipeline here to design and solve the cryo-EM structure of a de novo immunogen that binds and properly orients three copies of the anti-malarial monoclonal antibody L9, producing a promising next-generation malaria vaccine immunogen. This design pipeline could be employed to design any number of structurally constrained multi-epitope immunogens, as well as other proteins designed to bind multiple targets.

biophysics↗

bioRxiv2025

Data-driven feedback augments ultrasound nanotheranostics in brain tumors

The blood-brain barrier (BBB) renders the delivery of nanomedicine in the brain ineffective and the detection of circulating disease-related DNA from the brain unreliable. Here, we show that the acoustic emission content of focused ultrasound-controlled microbubble dynamics (MB-FUS) incorporates precursor signals that allow large-data models to predict sonication regimens for safe and effective BBB opening. Crucially, closed-loop MB-FUS controller augmented by machine learning (ML-CL) expands the treatment window (4-fold), as compared to conventional controllers, by persistently and proactively maximizing the BBB permeability while preventing tissue damage. By successfully scaling up from mice to rats and from healthy to diseased brains (glioma), ML-CL rendered the BBB permeable to large nanoparticles and markedly improved the release and detection of tumor DNA in plasma. Together, our findings reveal the potential of data-driven feedback to support the development of next-generation AI-powered ultrasound systems for safe, robust, and efficient nanotheranostic targeting of brain diseases.

bioengineering↗

bioRxiv2024

UPR deficiency in budding yeast reveals a trade-off between ER folding capacity and maintenance of euploidy

The Unfolded Protein Response (UPR) was discovered in budding yeast as a mechanism that allows cells to adapt to ER stress. While the Ire1 branch of this pathway is highly conserved, it is not thought to be important for cellular homeostasis in the absence of stress. Surprisingly, we found that removal of UPR activity led to pervasive aneuploidy in budding yeast cells, suggesting selective pressure resulting from UPR-deficiency. Aneuploid UPR-deficient cells grew better than euploid cells, but exhibited heightened general proteostatic stress, a hallmark of aneuploidy in wild-type cells. Modulation of key genes involved in ER proteostasis that were encoded on aneuploid chromosomes, could phenocopy the effects of aneuploidy, indicating that the reason cells require UPR activity to maintain euploidy is to counteract protein folding stress in the ER. In support of this model, aneuploidy in UPR-deficient cells can be prevented by expression of a UPR-independent general ER chaperone. Overall, our results indicate an unexpected role for the UPR in basal cell growth that is sufficiently important for cells to accept the costly trade-off of aneuploidy in the absence of UPR activity.

molecular biology↗

bioRxiv2024

PLK-1 regulates MEX-1 polarization in the C. elegans zygote

The one-cell C. elegans embryo undergoes an asymmetric cell division during which germline factors such as the RNA-binding proteins POS-1 and MEX-1 segregate to the posterior cytoplasm, leading to their asymmetric inheritance to the posterior germline daughter cell. Previous studies found that the RNA-binding protein MEX-5 recruits polo-like kinase PLK-1 to the anterior cytoplasm where PLK-1 inhibits the retention of its substrate POS-1, leading to POS-1 segregation to the posterior. In this study, we tested whether PLK-1 similarly regulates MEX-1 polarization. We find that both the retention of MEX-1 in the anterior and the segregation of MEX-1 to the posterior depend on PLK kinase activity and on the interaction between MEX-5 and PLK-1. Human PLK1 directly phosphorylates recombinant MEX-1 on 9 predicted PLK-1 sites in vitro, four of which were identified in previous phosphoproteomic analysis of C. elegans embryos. The introduction of alanine substitutions at these four PLK-1 phosphorylation sites (MEX-1(4A)) significantly weakened the inhibition of MEX-1 retention in the anterior, thereby weakening MEX-1 segregation to the posterior. In contrast, mutation of a predicted CDK1 phosphorylation site had no effect on MEX-1 retention or on MEX-1 segregation. MEX-1(4A) mutants are viable and fertile but display significant sterility and fecundity defects at elevated temperatures. Taken together with our previous findings, these findings suggest PLK-1 phosphorylation drives both MEX-1 and POS-1 polarization during the asymmetric division of the zygote.

developmental biology↗

bioRxiv2024

Murine aortic valve cell heterogeneity at birth

Heart valve function requires a highly organized extracellular matrix (ECM) network that provides the necessary biomechanical properties needed to withstand pressure changes during each cardiac cycle. Lay down of the valve ECM begins during embryogenesis and continues throughout postnatal stages when it is remodeled into stratified layers and arranged according to blood flow. Alterations in this process can lead to dysfunction and if left untreated, heart failure. Despite this, the mechanisms that establish structure-function relationships of the valve, particularly during postnatal maturation, are poorly understood. To address this, single cell transcriptomics was performed on murine aortic valve structures at postnatal day one (PND1). Overall, 18 clusters of 7 diverse cell populations were identified, including a novel VEC subpopulation unique to PND1, and three previously unappreciated VIC subpopulations defined as "primitive", "remodeling" and "bioactive". Additional lineage tracing of the "primitive" VIC subpopulation in mice uncovered a temporal and spatial trajectory throughout postnatal maturation. In summary, this work highlights the heterogeneity of cell types within the aortic valve structure at birth that contribute to establishing and maintaining structure and function throughout life.

cell biology↗

bioRxiv2024

Eye movements reveal age differences in how arousal modulates saliency priority but not attention processing speed

The arousal-biased competition theory posits that inducing arousal increases attentional priority of salient stimuli while reducing priority of non-pertinent stimuli. However, unlike in young adults, older adults rarely exhibit shifts in priority under increased arousal, and prior studies have proposed different neural mechanisms to explain how arousal differentially modulates selective attention in older adults. Therefore, we investigated how the threat of unpredictable shock differentially modulates attentional control mechanisms in young and older adults by observing eye movements. Participants completed two oculomotor search tasks in which the salient distractor was typically captured by attention (singleton search) or proactively suppressed (feature search). We found that arousal did not modulate attentional priority for any stimulus among older adults nor affect the speed of attention processing in either age group. Furthermore, we observed that arousal modulated pupil sizes and found a correlation between evoked pupil responses and oculomotor function. Our findings suggest age differences in how the locus coeruleus-noradrenaline system interacts with neural networks of attention and oculomotor function. Highlights- Increased arousal modulates attention saliency priority but not processing speed - Older adults do not exhibit shifts in stimulus priority under elevated arousal - Proactive suppression of salient stimuli persists even during increased arousal - Threat of unpredictable shock increases pupil sizes and decreases evoked responses - Eye movements may be able to help assess locus coeruleus function

neuroscience↗

bioRxiv2024

Reliably Measuring Learning-Dependent Distractor Suppression with Eye Tracking

In the field of psychological science, behavioral performance in computer-based cognitive tasks often exhibits poor reliability. The absence of reliable measures of cognitive processes contributes to non-reproducibility in the field and impedes investigation of individual differences. Specifically in visual search paradigms, response time-based measures have shown poor test-retest reliability and internal consistency across attention capture and distractor suppression, but one study has demonstrated the potential for oculomotor measures to exhibit superior reliability. Therefore, in this study, we investigated three datasets to compare the reliability of learning-dependent distractor suppression measured via distractor fixations (oculomotor capture) and latency to fixate the target (fixation times). Our findings reveal superior split-half reliability of oculomotor capture compared to that of fixation times regardless of the critical distractor comparison, with the reliability of oculomotor capture in most cases falling within the range that is acceptable for the investigation of individual differences. We additionally find that older adults have superior oculomotor reliability compared with young adults, potentially addressing a significant limitation in the aging literature of high variability in response time measures due to slower responses. Our findings highlight the utility of measuring eye movements in the pursuit of reliable indicators of distractor processing and the need to further test and develop additional measures in other sensory domains to maximize statistical power, reliability, and reproducibility.

neuroscience↗

bioRxiv2023

Mapping of multiple neurotransmitter receptor subtypes and distinct protein complexes to the connectome

Neurons express different combinations of neurotransmitter receptor (NR) subunits and receive inputs from multiple neuron types expressing different neurotransmitters. Localizing NR subunits to specific synaptic inputs has been challenging. Here we use epitope tagged endogenous NR subunits, expansion light-sheet microscopy, and EM connectomics to molecularly characterize synapses in Drosophila. We show that in directionally selective motion sensitive neurons, different multiple NRs elaborated a highly stereotyped molecular topography with NR localized to specific domains receiving cell-type specific inputs. Developmental studies suggested that NRs or complexes of them with other membrane proteins determines patterns of synaptic inputs. In support of this model, we identify a transmembrane protein associated selectively with a subset of spatially restricted synapses and demonstrate through genetic analysis its requirement for synapse formation. We propose that mechanisms which regulate the precise spatial distribution of NRs provide a molecular cartography specifying the patterns of synaptic connections onto dendrites.

neuroscience↗

bioRxiv2022

Commercial influenza vaccines vary in both the structural arrangements of HA complexes and in induction of antibodies to cross-reactive HA epitopes

Influenza virus infects millions of people annually and can cause global pandemics. Hemagglutinin (HA) is the primary component of commercial influenza vaccines (CIV), and antibody to HA is a primary correlate of protection. Persistent antigenic variation of HA requires that CIV be reformulated for new strains yearly. Differences in structural organization of HA has not been correlated with induction of broadly reactive antibodies, and CIV formulations can vary in how HA is organized. Using electron microscopy to study four current CIV, we found that these different formulations contained a variety of structures including: individual HAs, starfish-like structures with up to 12 HA molecules, and novel "spiked nanodisc" structures that displayed over 50 HA molecules along the complexs perimeter. These spiked nanodiscs uniquely exposed conserved stem epitopes and elicited the highest levels of heterosubtypic cross-reactive antibodies. Overall, we found that HA structural organization can be an important CIV parameter and can be associated with the induction of cross-reactive antibodies to conserved HA epitopes.

microbiology↗

bioRxiv2021

A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding

Dystonia is a disabling disease that manifests as prolonged involuntary twisting movements. DYT-THAP1 is an inherited form of isolated dystonia caused by mutations in THAP1 encoding the transcription factor THAP1. The phe81leu (F81L) missense mutation is representative of a category of poorly understood mutations that do not occur on residues critical for DNA binding. Here, we demonstrate that the F81L mutation (THAP1F81L) impairs THAP1 transcriptional activity and disrupts CNS myelination. Strikingly, THAP1F81L exhibits normal DNA binding but causes a significantly reduced DNA binding of YY1, its transcriptional partner that also has an established role in oligodendrocyte lineage progression. Our results suggest a model of molecular pathogenesis whereby THAP1F81L normally binds DNA but is unable to efficiently organize an active transcription complex.

neuroscience↗