Biology subjects

Ahn, S.

Publications and source records attributed to Ahn, S..

34 records · Page 2Linked to original sources

bioRxiv2023

Mind of a dauer: Comparative connectomics reveals developmental plasticity

A fundamental question in neurodevelopmental biology is how flexibly the nervous system changes during development. To address this, we reconstructed the complete connectome of dauer, an alternative developmental stage of nematodes with distinct behavioral characteristics, by volumetric reconstruction and automated synapse detection using deep learning. With the basic architecture of the nervous system preserved, structural changes in neurons, large or small, were closely associated with connectivity changes, which in turn evoked dauer-specific behaviors such as nictation. Graph theoretical analyses revealed significant dauer-specific rewiring of sensory neuron connectivity and increased clustering within motor neurons in the dauer connectome. We suggest that the nervous system in the nematode, probably animals in general, has evolved to respond to harsh environments by reversibly developing a quantitatively and qualitatively differentiated connectome.

neuroscience↗

bioRxiv2022

A brain-inspired object-based attention network for multi-object recognition and visual reasoning

The visual system uses sequences of selective glimpses to objects to support goal-directed behavior, but how is this attention control learned? Here we present an encoder-decoder model inspired by the interacting bottom-up and top-down visual pathways making up the recognitionattention system in the brain. At every iteration, a new glimpse is taken from the image and is processed through the "what" encoder, a hierarchy of feedforward, recurrent, and capsule layers, to obtain an object-centric (object-file) representation. This representation feeds to the "where" decoder, where the evolving recurrent representation provides top-down attentional modulation to plan subsequent glimpses and impact routing in the encoder. We demonstrate how the attention mechanism significantly improves the accuracy of classifying highly overlapping digits. In a visual reasoning task requiring comparison of two objects, our model achieves near-perfect accuracy and significantly outperforms larger models in generalizing to unseen stimuli. Our work demonstrates the benefits of object-based attention mechanisms taking sequential glimpses of objects.

animal behavior and cognition↗

bioRxiv2022

Gallbladder adenocarcinomas undergo subclonal diversification and selection from precancerous lesions to metastatic tumors

We aimed to elucidate the evolutionary trajectories of gallbladder adenocarcinoma (GBAC) using multi-regional and longitudinal tumor samples. Using whole-exome sequencing data, we constructed phylogenetic trees in each patient, and analyzed mutational signatures. A total of 11 patients including 2 rapid autopsy cases were enrolled. The most frequently altered gene in primary tumors was ERBB2 (54.5%), followed by TP53 (45.5%), and FBXW7 (27.3%). Most mutations in frequently altered genes in primary tumors were detectable in concurrent precancerous lesions (biliary intraepithelial neoplasia, BilIN), but some of them were subclonal. Subclonal diversity was common in BilIN (n=4). However, among subclones in BilIN, a certain subclone commonly shrank in concurrent primary tumors. In addition, selected subclones underwent linear and branching evolution, maintaining subclonal diversity. In combined analysis with metastatic tumors (n=11), branching evolution was identified in 9 (81.8%) patients. Of these, 8 patients (88.9%) had a total of 11 subclones expanded at least 7-fold during metastasis. These subclones harbored putative metastasis-driving mutations in tumor suppressor genes such as SMAD4, ROBO1, and DICER1. In mutational signature analysis, 6 mutational signatures were identified: 1, 3, 7, 13, 22, and 24 (cosine similarity >0.9). Signatures 1 (age) and 13 (APOBEC) decreased during metastasis while signatures 22 (aristolochic acid) and 24 (aflatoxin) were relatively highlighted. Subclonal diversity arose early in precancerous lesions and the clonal selection was a common event during malignant transformation in GBAC. However, selected cancer clones continued to evolve and thus maintained subclonal diversity in metastatic tumors.

genetics↗

bioRxiv2021

Hematopoietic stem and progenitor cells integrate Bacteroides-derived innate immune signals to promote gut tissue repair

Bone marrow (BM)-resident hematopoietic stem and progenitor cells (HSPCs) are often activated by bacterial insults to replenish the host hemato-immune system, but how they integrate the associated tissue damage signals to initiate distal tissue repair is largely unknown. Here, we showed that acute gut inflammation expands HSPCs in the BM through GM-CSFR activation, and directs them to inflamed mesenteric lymph nodes for further differentiation into myeloid cells specialized in gut tissue repair. We also identified that this process is exclusively mediated by Bacteroides, a commensal gram-negative bacteria, that activates innate immune signaling. In contrast, chronic gut inflammation reduces HSC potential for hematopoietic reconstitution and immune response against infection. Similarly, microbial signals contribute to aging-associated HSPC expansion. These findings establish a cross-organ communication that promotes tissue regeneration, but if sustained, impairs tissue homeostasis that may be relevant to aging and chronic disorders. SummaryThe infiltrating microbiota Bacteroides upon acute colitis directed MPP migration from the BM to the MLN for their subsequent expansion and differentiation into tissue-repairing Ly6C+/G+ cells, whereas chronic colitis impairs HSC functionality similarly as aging.

pathology↗

bioRxiv2021

Intravital imaging of cerebral microinfarct reveals an astrocyte reaction led to glial scar

Cerebral microinfarct increases the risk of dementia. But how microscopic cerebrovascular disruption affects the brain tissue in cellular-level are mostly unknown. Herein, with a longitudinal intravital imaging, we serially visualized in vivo dynamic cellular-level changes in astrocyte, pericyte and neuron as well as microvascular integrity after the induction of cerebral microinfarction for 1 month in mice. At day 2-3, it revealed a localized edema with acute astrocyte loss, neuronal death, impaired pericyte-vessel coverage and extravascular leakage indicating blood-brain barrier (BBB) dysfunction. At day 5, edema disappeared with recovery of pericyte-vessel coverage and BBB integrity. But brain tissue continued to shrink with persisted loss of astrocyte and neuron in microinfarct until 30 days, resulting in a collagen-rich fibrous scar surrounding the microinfarct. Notably, reactive astrocytes appeared at the peri-infarct area early at day 2 and thereafter accumulated in the peri-infarct. Oral administration of a reversible monoamine oxidase B inhibitor significantly decreased the astrocyte reactivity and fibrous scar formation. Our result suggests that astrocyte reactivity may be a key target to alleviate the impact of microinfarction.

neuroscience↗

bioRxiv2021

The C. elegans DAF-19M module: a shift from general ciliogenesis to ciliary and behavioral specialization

In animals, cilia are important for the interaction with environments and the proper function of tissues and organs. Understanding the distinctive identities of each type of ciliated cell is essential for therapeutic solutions for ciliopathies, complex disorders with impairments of various organs caused by defective cilia development and function. Here, we report a regulatory module consisting of a cascade of transcription factors and their target genes that confer the cell type-specific ciliary identities on the IL2 ciliated neurons in C. elegans. We found that DAF-19M, isoform of the sole C. elegans RFX transcription factor DAF-19, through X-box promoter motif variants, heads a regulatory module in IL2 neurons, comprising the core target genes klp-6 (kinesin), osm-9 (TRP channel), and cwp-4 (novel); under the overall control of terminal selector proteins UNC-86 and CFI-1. Considering the conservation of this DAF-19M module in IL2 neurons for nictation, a dauer larva-specific behavior, and in male-specific neurons for mating behavior, we propose the existence of an evolutionarily adaptable, hard-wired genetic module for distinct behaviors that share the feature "recognizing the environment."

molecular biology↗

bioRxiv2020

COCO-Search18: A Dataset for Predicting Goal-directed Attention Control

Attention control is a basic behavioral process that has been studied for decades. The currently best models of attention control are deep networks trained on free-viewing behavior to predict bottom-up attention control--saliency. We introduce COCO-Search18, the first dataset of laboratory-quality goal-directed behavior large enough to train deep-network models. We collected eye-movement behavior from 10 people searching for each of 18 target-object categories in 6202 natural-scene images, yielding[~] 300,000 search fixations. We thoroughly characterize COCO-Search18, and benchmark it using three machine-learning methods: a ResNet50 object detector, a ResNet50 trained on fixation-density maps, and an inverse-reinforcement-learning model trained on behavioral search scanpaths. Models were also trained/tested on images transformed to approximate a foveated retina, a fundamental biological constraint. These models, each having a different reliance on behavioral training, collectively comprise the new state-of-the-art in predicting goal-directed search fixations. Our expectation is that future work using COCO-Search18 will far surpass these initial efforts, finding applications in domains ranging from human-computer interactive systems that can anticipate a persons intent and render assistance to the potentially early identification of attention-related clinical disorders (ADHD, PTSD, phobia) based on deviation from neurotypical fixation behavior.

animal behavior and cognition↗

bioRxiv2020

Progesterone modulates theta oscillations in the frontal-parietal network

The neuroactive metabolites of the steroid hormones progesterone (P4) and testosterone (T) are GABAergic modulators that influence cognitive control, yet the specific effect of P4 and T on brain network activity remains poorly understood. Here, we investigated if a fundamental oscillatory network activity pattern related to cognitive control, frontal midline theta (FMT) oscillations, are modulated by steroids hormones, P4 and T. We measured the concentration P4 and T using salivary enzyme immunoassay and FMT oscillations using high-density electroencephalography (EEG) during the eyes-open resting state in fifty-five healthy female and male participants. Electrical brain activity was analyzed using Morlet wavelet convolution, beamformer source localization, background noise spectral fitting, and phase amplitude coupling analysis. Steroid hormone concentrations and biological sex were used as predictors for scalp and source-estimated theta oscillations and for top-down theta-gamma phase amplitude coupling. Elevated concentrations of P4 predicted increased FMT oscillatory amplitude across both sexes, and no relationship was found with T. The positive correlation with P4 was specific to the frontal-midline electrodes and survived correction for the background noise of the brain. Using source localization, FMT oscillations were localized to the frontal-parietal network. Additionally, theta amplitude within the frontal-parietal network, but not the default mode network, positively correlated with P4 concentration. Finally, P4 concentration correlated with increased coupling between FMT phase and posterior gamma amplitude. Our results suggest that P4 concentration modulates brain activity via upregulation of theta oscillations in the frontal-parietal network and increased top-down control over posterior cortical sites. Significance StatementThe neuroactive metabolites of the steroid hormones progesterone (P4) and testosterone (T) are GABAergic modulators that influence cognitive control, yet the specific effect of P4 and T on brain network activity remains poorly understood. Here, we investigated if a fundamental oscillatory network activity pattern related to cognitive control, frontal midline theta (FMT) oscillations, are modulated by steroids hormones, P4 and T. Our results suggest that P4 concentration modulates brain activity via upregulation of theta oscillations in the frontal-parietal network and increased top-down control over posterior cortical sites.

neuroscience↗

bioRxiv2019

Pinging the Brain with Transcranial Magnetic Stimulation Reveals Cortical Reactivity in Time and Space

Single-pulse transcranial magnetic stimulation (TMS) elicits an evoked electroencephalography (EEG) potential (TMS-evoked potential, TEP), which is interpreted as direct evidence of cortical reactivity to TMS. Thus, combining TMS with EEG may enable the mechanistic investigation of how TMS treatment paradigms engage network targets in the brain. However, there remains a central controversy about whether the TEP is a genuine marker of cortical reactivity to TMS or the TEP is contaminated by responses to peripheral somatosensory and auditory inputs. Resolving this controversy is of great significance for the field and will validate TMS as a tool to probe networks of interest in cognitive and clinical neuroscience. Here, we delineated the TEPs cortical origins by localizing successive TEP components in time and space and modulating them subsequently with transcranial direct current stimulation (tDCS). We collected both motor evoked potentials (MEPs) and TEPs elicited by suprathreshold single-pulse TMS to the left primary motor cortex (M1). We found that the earliest TEP component (P25) was localized on the TMS target location (left M1) and the following TEP components (N45 and P60) largely were localized on the primary somatosensory cortex, which may reflect afferent input by hand-muscle twitches. The later TEP components (N100, P180, and N280) largely were localized to the auditory cortex. To casually test that these components reflect cortical and corticospinal excitability, we applied tDCS to the left M1. As hypothesized, we found that tDCS modulated cortical and corticospinal excitability selectively by modulating the pre-stimulus mu-rhythm oscillatory power. Together, our findings provide causal evidence that the early TEP components reflect cortical reactivity to TMS.

neuroscience↗

bioRxiv2019

Dysregulation of temporal dynamics of synchronous neural activity in adolescents on autism spectrum

Autism spectrum disorder is increasingly understood to be based on atypical signal transfer among multiple interconnected networks in the brain. Relative temporal patterns of neural activity have been shown to underlie both the altered neurophysiology and the altered behaviors in a variety of neurogenic disorders. We assessed brain network dynamics variability in Autism Spectrum Disorders (ASD) using measures of synchronization (phase-locking) strength, and timing of synchronization and desynchronization of neural activity (desynchronization ratio) across frequency bands of resting state EEG. Our analysis indicated that fronto-parietal synchronization is higher in ASD, but with more short periods of desynchronization. It also indicates that the relationship between the properties of neural synchronization and behavior is different in ASD and typically developing populations. Recent theoretical studies suggest that neural networks with high desynchronization ratio have increased sensitivity to inputs. Our results point to the potential significance of this phenomenon to autistic brain. This sensitivity may disrupt production of an appropriate neural and behavioral responses to external stimuli. Cognitive processes dependent on integration of activity from multiple networks may be, as a result, particularly vulnerable to disruption.\n\nLay SummaryParts of the brain can work together by synchronizing activity of the neurons. We recorded electrical activity of the brain in adolescents with autism spectrum disorder, and then compared the recording to that of their peers without the diagnosis. We found that in participants with autism, there were a lot of very short time periods of non-synchronized activity between frontal and parietal parts of the brain. Mathematical models show that the brain system with this kind of activity is very sensitive to external events.

neuroscience↗

bioRxiv2019

Exploring the Relationship between Geomagnetic Activity and Human Heart Rate Variability

Both geomagnetic and solar activity fluctuate over time and have been proposed to affect human physiology. One physiological measurement that has been previously investigated in this context, heart rate variability (HRV), has substantial health implications regarding the ability to adapt to stressors and has been shown to be altered in many cardiovascular and neurological disorders. Intriguingly, previous work found significant, strong correlations between HRV and geomagnetic/solar activity. In an attempt to replicate these findings, we simultaneously measured HRV from 20 healthy participants during a thirty-day period. In agreement with previous work, we found several significant correlations between HRV and geophysical time-series. However, after correction for autocorrelation, which is inherent in time-series, the only significant results were an increase in very low frequency during higher local geomagnetic activity and a geomagnetic anticipatory decrease in heart rate a day before higher global geomagnetic activity. Both correlations were very low. The loss of most significant effects after this correction suggests that previous findings may be a result of autocorrelation. A further note of caution is required since our and the previous studies in the field do not correct for multiple comparisons given the exploratory analysis strategy. We thus conclude that the effects of geomagnetic and solar activity are (if present) most likely of very small effect size and question the validity of the previous studies given the methodological concerns we have uncovered in our work.

physiology↗

bioRxiv2019

Targeting the Autonomic Nervous System Balance in Patients with Chronic Low Back Pain using Transcranial Alternating Current Stimulation: A Randomized, Crossover, Double-Blind, Placebo-Controlled Pilot Study

BackgroundChronic low back pain (CLBP) is characterized by an alteration in pain processing by the central nervous system that may affect autonomic nervous system (ANS) balance. Heart rate variability (HRV) reflects the balance of parasympathetic and sympathetic ANS activation. In particular, respiratory sinus arrhythmia (RSA) solely reflects parasympathetic input and is reduced in CLBP patients. Yet, it remains unknown if non-invasive brain stimulation can alter ANS balance in CLBP patients. ObjectiveTo evaluate if non-invasive brain stimulation modulates the ANS, we analyzed HRV metrics collected in a previously published study of transcranial alternating current stimulation (tACS) for the modulation of CLBP through enhancing alpha oscillations. We hypothesized that tACS would increase RSA. MethodsA randomized, crossover, double-blind, sham-controlled pilot study was conducted to investigate the effects of 10Hz-tACS on metrics of ANS balance calculated from electrocardiogram (ECG). ECG data were collected for 2 minutes before and after 40 minutes of 10Hz-tACS or sham stimulation. ResultsThere were no significant changes in RSA or other frequency-domain HRV components from 10Hz-tACS. However, exploratory time-domain HRV analysis revealed a significant increase in the standard deviation of normal RR intervals (SDNN) for 10Hz-tACS relative to sham. Conclusion(s)Although tACS did not significantly increase RSA, we found in an exploratory analysis that tACS modulated an integrated HRV measure of both ANS branches. These findings support the further study of how the ANS and alpha oscillations interact and are modulated by tACS.

clinical trials↗

bioRxiv2019

Neurophysiological Substrates of Configural Face Perception in Schizotypy

Face perception is a highly developed function of the human visual system. Previous studies of event-related potentials (ERPs) have identified a face-selective ERP component (negative peak at about 170 milliseconds after stimulation onset, N170) in healthy participants. In contrast, patients with schizophrenia exhibit reduced amplitude of the N170, which may represent a pathological deficit in the neurophysiology of face perception. Interestingly, healthy humans with schizophrenia-like experiences (schizotypy) also exhibit abnormal processing of face perception. Yet, it has remained unknown how schizotypy in healthy humans is associated with the neurophysiological substrate of face perception. Here, we recruited 35 participants and assessed their schizotypy by the magical ideation rating scale. We used high-density electroencephalography to obtain ERPs elicited by a set of Mooney faces (face and non-face conditions). We divided the participants into two groups (high and low schizotypy) by a median split of schizotypy scores. We investigated mean reaction times and the N170 component in response to the stimuli. We found significant slowed reaction times and reduced amplitude of the N170 component in response to the face stimuli in the high-schizotypy group. In addition, across the full data set, we found that the schizotypy scores were significantly correlated with both the reaction times and the N170 amplitude. Our results thus support the model of schizotypy as a manifestation of a continuum between healthy individuals and patients with schizophrenia, where the N170 impairment serves as a biomarker for the degree of pathology along this continuum.

neuroscience↗

bioRxiv2018

A normalized template matching method for improving spike detection in extracellular voltage recordings

Spike sorting is the process of detecting and clustering action potential waveforms from extracellular voltage recordings to identify spikes of putative single neurons. Typically, spike detection is done using a fixed voltage threshold and shadow period, but this approach can lead to missed spikes during high firing rate epochs or noisy conditions. We developed a novel spike detection method utilizing a computationally simple form of template matching that efficiently detects spikes from candidate single units and is tolerant of high firing rates and electrical noise without a whitening filter. Template matching was based on a sliding cosine similarity between mean spike waveforms of candidate single units and the extracellular voltage signal. Performance was tested in whisker somatosensory cortex (S1) of anesthetized mice in vivo. The method consistently detected whisker-evoked spikes that were missed by a standard fixed voltage threshold. Detection was most improved for spikes evoked by strong stimuli (40-70% increase), less improved for weaker stimuli, and unchanged for spontaneous spiking. This reflected the failure of standard detection during spatiotemporally dense spiking. Template-based detection revealed higher signal-to-noise ratio for sensory responses and sharper sensory tuning. Thus, this template matching method (and other model-based spike detection methods) critically improve the quantification of single-unit spiking activity.

neuroscience↗

bioRxiv2017

Shallow whole genome sequencing for robust copy number profiling of formalin-fixed paraffin-embedded breast cancers

Pathology archives with linked clinical data are an invaluable resource for translational research, with the limitation that most cancer samples are formalin-fixed paraffin-embedded (FFPE) tissues. Therefore, FFPE tissues are an important resource for genomic profiling studies but are under-utilised due to the low amount and quality of extracted nucleic acids. We profiled the copy number landscape of 356 breast cancer patients using DNA extracted FFPE tissues by shallow whole genome sequencing. We generated a total of 491 sequencing libraries from 2 kits and obtained data from 98.4% of libraries with 86.4% being of good quality. We generated libraries from as low as 3.8ng of input DNA and found that the success was independent of input DNA amount and quality, processing site and age of the fixed tissues. Since copy number alterations (CNA) play a major role in breast cancer, it is imperative that we are able to use FFPE archives and we have shown in this study that sWGS is a robust method to do such profiling.

genomics↗

bioRxiv2017

aBayesQR: A Bayesian method for reconstruction of viral populations characterized by low diversity

RNA viruses replicate with high mutation rates, creating closely related viral populations. The heterogeneous virus populations, referred to as viral quasispecies, rapidly adapt to environmental changes thus adversely affecting efficiency of antiviral drugs and vaccines. Therefore, studying the underlying genetic heterogeneity of viral populations plays a significant role in the development of effective therapeutic treatments. Recent high-throughput sequencing technologies have provided invaluable opportunity for uncovering the structure of quasispecies populations (i.e., reconstruction of viral sequences and discovery of their relative frequencies). However, accurate reconstruction of viral quasispecies remains difficult due to limited read-lengths and presence of sequencing errors. The problem is particularly challenging when the strains in a population are highly similar, i.e., the sequences are characterized by low mutual genetic distances, and further exacerbated if some of those strains are relatively rare; this is the setting where state-of-the-art methods struggle. In this paper, we present a novel viral quasispecies reconstruction algorithm, aBayesQR, that employs a maximum-likelihood framework to infer individual sequences in a mixture from high-throughput sequencing data. The search for the most likely quasispecies is conducted on long contigs that our method constructs from the set of short reads via agglomerative hierarchical clustering; operating on contigs rather than short reads enables identification of close strains in a population and provides computational tractability of the Bayesian method. Results on both simulated and real HIV-1 data demonstrate that the proposed algorithm generally outperforms state-of-the-art methods; aBayesQR particularly stands out when reconstructing a set of closely related viral strains (e.g., quasispecies characterized by low diversity).

bioinformatics↗