Biology subjects

Lee, S.

Publications and source records attributed to Lee, S..

At least 559 records · Page 31Linked to original sources

bioRxiv2021

Defective flow-migration coupling causes arteriovenous malformations in hereditary hemorrhagic telangiectasia

BackgroundActivin receptor-like kinase 1 (ACVRL1, hereafter ALK1) is an endothelial transmembrane serine threonine kinase receptor for BMP family ligands that plays a critical role in cardiovascular development and pathology. Loss-of-function mutations in the ALK1 gene cause type 2 hereditary hemorrhagic telangiectasia (HHT), a devastating disorder that leads to arteriovenous malformations (AVMs). Here we show that ALK1 controls endothelial cell polarization against the direction of blood flow and flow-induced endothelial migration from veins through capillaries into arterioles. MethodsUsing Cre lines that recombine in different subsets of arterial, capillary-venous or endothelial tip cells, we showed that capillary-venous Alk1 deletion was sufficient to induce AVM formation in the postnatal retina. ResultsALK1 deletion impaired capillary-venous endothelial cell polarization against the direction of blood flow in vivo and in vitro. Mechanistically, ALK1 deficient cells exhibited increased integrin signaling interaction with VEGFR2, which enhanced downstream YAP/TAZ nuclear translocation. Pharmacological inhibition of integrin or YAP/TAZ signaling rescued flow migration coupling and prevented vascular malformations in Alk1 deficient mice. ConclusionsOur study reveals ALK1 as an essential driver of flow-induced endothelial cell migration and identifies loss of flow-migration coupling as a driver of AVM formation in HHT disease. Integrin-YAP/TAZ signaling blockers are new potential targets to prevent vascular malformations in HHT patients.

cell biology↗

bioRxiv2021

Protracted yet coordinated differentiation of long-lived SARS-CoV-2-specific CD8+ T cells during COVID-19 convalescence

CD8+ T cells are important antiviral effectors that can potentiate long-lived immunity against COVID-19, but a detailed characterization of these cells has been hampered by technical challenges. We screened 21 well-characterized, longitudinally-sampled convalescent donors that recovered from mild COVID-19 against a collection of SARS-CoV-2 tetramers, and identified one participant with an immunodominant response against Nuc322-331, a peptide that is conserved in all the SARS-CoV-2 variants-of-concern reported to date. We conducted 38- parameter CyTOF phenotyping on tetramer-identified Nuc322-331-specific CD8+ T cells, and on CD4+ and CD8+ T cells recognizing the entire nucleocapsid and spike proteins from SARS- CoV-2, and took 32 serological measurements on longitudinal specimens from this participant. We discovered a coordination of the Nuc322-331-specific CD8+ T response with both the CD4+ T cell and antibody pillars of adaptive immunity. Nuc322-331-specific CD8+ T cells were predominantly central memory T cells, but continually evolved over a [~]6-month period of convalescence. We observed a slow and progressive decrease in the activation state and polyfunctionality of the Nuc322-331-specific CD8+ T cells, accompanied by an increase in their lymph-node homing and homeostatic proliferation potential. These results suggest that following a typical case of mild COVID-19, SARS-CoV-2-specific CD8+ T cells not only persist but continuously differentiate in a coordinated fashion well into convalescence, into a state characteristic of long-lived, self-renewing memory.

immunology↗

bioRxiv2021

SARS-COV-2 induced Diarrhea is inflammatory, Ca2+ Dependent and involves activation of calcium activated Cl channels

Diarrhea occurs in 2-50% of cases of COVID-19 ([~]8% is average across series). The diarrhea does not appear to account for the disease mortality and its contribution to the morbidity has not been defined, even though it is a component of Long Covid or post-infectious aspects of the disease. Even less is known about the pathophysiologic mechanism of the diarrhea. To begin to understand the pathophysiology of COVID-19 diarrhea, we exposed human enteroid monolayers obtained from five healthy subjects and made from duodenum, jejunum, and proximal colon to live SARS-CoV-2 and virus like particles (VLPs) made from exosomes expressing SARS-CoV-2 structural proteins (Spike, Nucleocapsid, Membrane and Envelope). Results: 1) Live virus was exposed apically for 90 min, then washed out and studied 2 and 5 days later. SARS-Cov-2 was taken up by enteroids and live virus was present in lysates and in the apical>>basolateral media of polarized enteroids 48 h after exposure. This is the first demonstration of basolateral appearance of live virus after apical exposure. High vRNA concentration was detected in cell lysates and in the apical and basolateral media up to 5 days after exposure. 2) Two days after viral exposure, cytokine measurements of media showed significantly increased levels of IL-6, IL-8 and MCP-1. 3) Two days after viral exposure, mRNA levels of ACE2, NHE3 and DRA were reduced but there was no change in mRNA of CFTR. NHE3 protein was also decreased. 4) Live viral studies were mimicked by some studies with VLP exposure for 48 h. VLPs with Spike-D614G bound to the enteroid apical surface and was taken up; this resulted in decreased mRNA levels of ACE2, NHE3, DRA and CFTR. 4) VLP effects were determined on active anion secretion measured with the Ussing chamber/voltage clamp technique. S-D614G acutely exposed to apical surface of human ileal enteroids did not alter the short-circuit current (Isc). However, VLPS-D614G exposure to enteroids that were pretreated for [~]24 h with IL-6 plus IL-8 induced a concentration dependent increase in Isc indicating stimulated anion secretion, that was delayed in onset by [~]8 min. The anion secretion was inhibited by apical exposure to a specific calcium activated Cl channel (CaCC) inhibitor (AO1) but not by a specific CFTR inhibitor (BP027); was inhibited by basolateral exposure to the K channel inhibit clortimazole; and was prevented by pretreatment with the calcium buffer BAPTA-AM. 5) The calcium dependence of the VLP-induced increase in Isc was studied in Caco-2/BBe cells stably expressing the genetically encoded Ca2+ sensor GCaMP6s. 24 h pretreatment with IL-6/IL-8 did not alter intracellular Ca2+. However, in IL-6/IL-8 pretreated cells, VLP S-D614G caused appearance of Ca2+waves and an overall increase in intracellular Ca2+ with a delay of [~]10 min after VLP addition. We conclude that the diarrhea of COVID-19 appears to an example of a calcium dependent inflammatory diarrhea that involves both acutely stimulated Ca2+ dependent anion secretion (stimulated Isc) that involves CaCC and likely inhibition of neutral NaCl absorption (decreased NHE3 protein and mRNA and decreased DRA mRNA).

physiology↗

bioRxiv2021

The role of neural flexibility in cognitive aging

Studies assessing relationships between brain and cognitive changes in healthy aging have shown that a variety of aspects of brain structure and function explain a significant portion of the variability in cognitive outcomes throughout adulthood. Many studies assessing relationships between brain function and cognition have utilized time-averaged, or static functional connectivity methods to explore ways in which brain network organization may contribute to aspects of cognitive aging. However, recent studies in this field have suggested that time-varying, or dynamic measures of functional connectivity, which assess changes in functional connectivity throughout a scan session, may play a stronger role in explaining cognitive outcomes in healthy young adults. Further, both static and dynamic functional connectivity studies suggest that there may be differences in patterns of brain-cognition relationships as a function of whether or not the participant is performing a task during the scan. Thus, the goals of the present study were threefold: (1) assess whether dynamic connectivity (neural flexibility) during both resting as well as task-based scans is related to participant age and cognitive performance in a lifespan aging sample, (2) determine whether neural flexibility moderates relationships between age and cognitive performance, and (3) explore differences in neural flexibility between rest and task. Participants in the study were 423 healthy adults between the ages of 20-80 who provided resting state and/or task-based (Matrix Reasoning) functional magnetic resonance imaging (fMRI) scan data as part of their participation in two ongoing studies of cognitive aging. Neural flexibility measures from both resting and task-based scans reflected the number of times each node changed network assignment, and were averaged both across the whole brain (global neural flexibility) as well as within nine somatosensory/cognitive networks. Results showed that neural flexibility during the task was higher in older adults, and that neural flexibility in Default Mode and Visual networks was negatively related to performance on the Matrix Reasoning task. Resting state neural flexibility was not significantly related to either participant age or cognitive performance. Additionally, no neural flexibility measures that significantly moderated relationships between participant age and cognitive outcomes. Further, neural flexibility differed as a function of scan type, with resting state neural flexibility exhibiting significantly more variability than task-based neural flexibility. Thus, neural flexibility measures computed during a cognitive task may be more strongly related to cognitive performance across the adult lifespan, and are more sensitive to the effects of participant age on brain organization.

neuroscience↗

bioRxiv2021

Thalamocortical mechanisms regulating the relationship between transient beta events and human tactile perception

Transient neocortical events with high spectral power in the 15-29Hz beta band are among the most reliable predictors of sensory perception. Prestimulus beta event rates in primary somatosensory cortex correlate with sensory suppression, most effectively 100-300ms before stimulus onset. However, the neural mechanisms underlying this perceptual association are unknown. We combined human magnetoencephalography (MEG) measurements with biophysical neural modeling to test potential cellular and circuit mechanisms that underlie observed correlations between prestimulus beta events and tactile detection. Extending prior studies, we found that simulated bursts from higher-order, non-lemniscal thalamus were sufficient to drive beta event generation and to recruit slow supragranular inhibition acting on a 300ms time scale to suppress sensory information. Further analysis showed that the same beta generating mechanism can lead to facilitated perception for a brief period when beta events occur simultaneously with tactile stimulation before inhibition is recruited. These findings were supported by close agreement between model-derived predictions and empirical MEG data. The post-event suppressive mechanism explains an array of studies that associate beta with decreased processing, while the during-event faciliatory mechanism may demand a reinterpretation of the role of beta events in the context of coincident timing.

neuroscience↗

bioRxiv2021

Visualization of reactive astrocytes in living brain of Alzheimer's disease patient

An early appearance of reactive astrocytes is a hallmark of Alzheimers disease (AD)1,2, providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

neuroscience↗

bioRxiv2021

Visualizing reactive astrogliosis extends survival in glioblastoma patients

Glioblastoma multiforme (GBM) is a devastating brain tumor with dismal prognosis of only 15-month survival regardless of surgical resection. Here, we report an advanced neuroimaging technique combining 11C-acetate PET and MRI (AcePET), visualizing the boundary beyond the MRI-defined tumor. Targeted biopsy of the regions with increased 11C-acetate uptake revealed the presence of reactive astrocytes with enhanced acetate-transporter MCT1, along with cancer stem cells. Reactive astrogliosis and MCT1-dependent 11C-acetate-uptake were recapitulated in U87MG-orthotopic models. Mechanistically, glycolytic tumor cells release excessive acetate causing reactive astrogliosis, leading to the release of aberrant astrocytic GABA and H2O2, which further down-regulate the neuronal glucose uptake through GLUT3. Clincally, AcePET-guided surgery allows complete tumor resection of infiltrating cancer stem cells and extends the overall survival of patients by 5.25 months compared to conventional MRI-guided surgery. We established a new concept of the metabolic interactions between GBM cells and neighboring neurons through reactive astrocytes and developed AcePET-guided surgery to fight against GBM.

cancer biology↗

bioRxiv2021

Subthalamic-Cortical Network Reorganization during Parkinson's Tremor

Tremor, a common and often primary symptom of Parkinsons disease, has been modeled with distinct onset and maintenance dynamics. To identify the neurophysiologic correlates of each state, we acquired intraoperative cortical and subthalamic nucleus recordings from ten patients performing a naturalistic visual-motor task. From this task we isolated short epochs of tremor onset and sustained tremor. Comparing these epochs, we found that the subthalamic nucleus was central to tremor onset, as it drove both motor cortical activity and tremor output. Once tremor became sustained, control of tremor shifted to cortex. At the same time, changes in directed functional connectivity across sensorimotor cortex further distinguished the sustained tremor state. SIGNIFICANCE STATEMENTTremor is a common symptom of Parkinsons disease (PD). While tremor pathophysiology is thought to involve both basal ganglia and cerebello-thalamic-cortical circuits, it is unknown how these structures functionally interact to produce tremor. In this manuscript, we analyzed intracranial recordings from the subthalamic nucleus and sensorimotor cortex in patients with PD undergoing deep brain stimulation (DBS) surgery. Using an intraoperative task, we examined tremor in two separate dynamic contexts: when tremor first emerged, and when tremor was sustained. We believe that these findings reconcile several models of Parkinsons tremor, while describing the short-timescale dynamics of subcortical-cortical interactions during tremor for the first time. These findings may describe a framework for developing proactive and responsive neurostimulation models for specifically treating tremor.

neuroscience↗

bioRxiv2021

Astrocytes render memory flexible

Cognitive flexibility is an essential ability to adapt to changing environment and circumstances. NMDAR has long been implicated in cognitive flexibility, but the precise molecular and cellular mechanism is not well understood. Here, we report that astrocytes regulate NMDAR tone through Best1-mediated glutamate and D-serine release, which is critical for cognitive flexibility. Co-release of D-serine and glutamate is required for not only homosynaptic LTD but also heterosynaptic LTD, which is induced at unstimulated synapses upon release of norepinephrine and activation of astrocytic 1-AR during homosynaptic LTP. Remarkably, heterosynaptic LTD at unstimulated synapses during memory acquisition is required for later repotentiation LTP during reversal learning, laying a foundation for flexible memory and cognitive flexibility. Our study sheds light on the pivotal role of astrocytes in orchestrating multiple synapses during memory formation and determining the fate of consolidated memory to be retained as a flexible memory. HighlightsO_LIAstrocytes regulate NMDAR tone via Best1-mediated glutamate and D-serine release C_LIO_LIActivation of astrocytic 1-AR induces heterosynaptic LTD via NMDAR tone C_LIO_LIHeterosynaptic LTD is required for repotentiation LTP and spatial reversal learning C_LIO_LIAstrocytic regulation of NMDAR tone is critical for metaplasticity and flexible memory C_LI

neuroscience↗

bioRxiv2021

CHRONIC INFLAMMATION IN ULCERATIVE COLITIS CAUSES LONG TERM CHANGES IN GOBLETCELL FUNCTION

ObjectiveOne of the features of ulcerative colitis (UC) is a defect in the protective mucus layer. This has been attributed to a reduced number of goblet cells (GC). However, it is not known whether abnormal GC mucus secretion also contributes to the reduced mucus layer. Our aims were to test the hypothesis that GC secretion was abnormal in UC with the changes persistent in colonoids even in the absence of immune cells. DesignColonoids were established from intestinal stem cells of healthy subjects (HS) and from patients with UC (inactive and active sites). Colonoids were maintained as undifferentiated (UD) or induced to differentiate (DF) and studied as 3D or monolayers on Transwell filters. Total RNA was extracted for quantitative real-time PCR analysis. Carbachol and PGE2 mediated stimulation followed by examination of mucus layer by MUC2 IF/confocal microscopy and TEM were performed. ResultsColonoids derived from patients with UC can be propagated over many passages; however, they exhibit a reduced rate of growth and TEER compared with colonoids from HS. Differentiated UC colonoid monolayers form a thin and non-continuous mucus layer. UC colonoids have increased expression of secretory lineage markers: ATOH1 and SPDEF, including MUC2 positive GCs and ChgA positive enteroendocrine cells but failed to secrete mucin when exposed to the cholinergic agonist carbachol and PGE2, which caused increased secretion in HS. Exposure to TNF- (5days), reduced the number of GC with a greater percentage decrease in UC colonoids compared to HS. ConclusionsAbnormal mucus layer in UC is due to long term changes in epithelial cells that lead to abnormal mucus secretion as well as effects of the inflammatory environment to reduce the number of GC. This continued defect in GC mucus secretion may be involved in UC recurrence.

physiology↗

bioRxiv2021

An fMRI-based brain marker predicts individual differences in delay discounting

Individual differences in impatience--how much we discount future compared to immediate rewards--are associated with general life outcomes and related to substance use, psychiatric diseases, and obesity. Here, we use machine-learning on fMRI activity during an intertemporal choice task to develop a brain marker of individual differences in delay discounting. Study 1 (N=110) was used as a training and cross-validation set, resulting in significant prediction accuracy (r = 0.49) and suggesting an interplay between brain regions associated with affect, value, and cognitive control. The validity of the brain marker was replicated in an independent data set (Study 2, N=145, r = 0.45). In both studies, responses of the marker significantly differed between overweight and lean individuals. This pattern is a first step towards a generalizable neuromarker of delay discounting and a potentially transdiagnostic phenotype, which can be used as a brain-based target measure in future studies.

neuroscience↗

bioRxiv2021

Open Data Commons for Preclinical Traumatic Brain Injury Research: Empowering Data Sharing and Big Data Analytics

Traumatic brain injury (TBI) is a major unsolved public health problem worldwide with considerable preclinical research dedicated to recapitulating clinical TBI, deciphering the underlying pathophysiology, and developing therapeutics. However, the heterogeneity of clinical TBI and correspondingly in preclinical studies have made translation from bench to bedside difficult. Here, we present the potential of data sharing, data aggregation, and multivariate analytics to integrate heterogeneity and empower researchers. We introduce the Open Data Commons for Traumatic Brain Injury (ODC-TBI.org) as a user-centered web platform and cloudbased repository focused on preclinical TBI research that enables data citation with persistent identifiers, promotes data element harmonization, and follows FAIR data sharing principles. Importantly, the ODC-TBI implements data sharing at the level of individual subjects, thus enabling data reuse for granular big data analytics and data-hungry machine learning approaches. We provide use cases applying descriptive analytics and unsupervised machine learning on pooled ODC-TBI data. Descriptive statistics included subject-level data for 11 published papers (N = 1250 subjects) representing six distinct TBI models across mice and rats (implementing controlled cortical impact, closed head injury, fluid percussion injury, and CHIMERA TBI modalities). We performed principal component analysis (PCA) on cohorts of animals combined through the ODC-TBI to identify persistent inflammatory patterns across different experimental designs. Our workflow ultimately improved the sensitivity of our analyses in uncovering patterns of pro- vs anti-inflammation and oxidative stress without the multiple testing problems of univariate analyses. As the practice of open data becomes increasingly required by the scientific community, ODC-TBI provides a foundation that creates new scientific opportunities for researchers and their work, facilitates multi-dataset and multidimensional analytics, and drives collaboration across molecular and computational biologists to bridge preclinical research to the clinic.

neuroscience↗

bioRxiv2021

Altered cortico-subcortical network after adolescent alcohol exposure mediates behavioral deficits in flexible decision-making

Behavioral flexibility, the ability to modify behavior according to changing conditions, is essential to optimize decision-making. Deficits in behavioral flexibility that persist into adulthood are one consequence of adolescent alcohol exposure, and another is decreased functional connectivity in brain structures involved in decision-making; however, a link between these two outcomes has not been established. We assessed effects of adolescent alcohol and sex on both Pavlovian and instrumental behaviors and functional connectivity in adult animals to determine associations between behavioral flexibility and resting-state functional connectivity. Alcohol exposure impaired attentional set reversals and decreased functional connectivity among cortical and subcortical regions-of-interest that underlie flexible behavior. Moreover, mediation analyses indicated that adolescent alcohol-induced reductions in functional connectivity within a subnetwork of affected brain regions mediated errors committed during reversal learning. These results provide a novel link between persistent reductions in brain functional connectivity and deficits in behavioral flexibility resulting from adolescent alcohol exposure.

neuroscience↗

bioRxiv2021

Phodopus roborovskii SH101 as a systemic infection model of SARS-CoV-2

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is currently causing a worldwide threat with its unusually high transmission rates and rapid evolution into diverse strains. Unlike typical respiratory viruses, SARS-CoV-2 frequently causes systemic infection by breaking the boundaries of the respiratory systems. The development of animal models recapitulating the clinical manifestations of COVID-19 is of utmost importance not only for the development of vaccines and antivirals but also for understanding the pathogenesis. However, there has not been developed an animal model for systemic infection of SARS-CoV-2 representing most aspects of the clinical manifestations of COVID-19 with systemic symptoms. Here we report that a hamster strain of Phodopus roborovskii SH101, a laboratory inbred hamster strain of P. roborovskii, displayed most symptoms of systemic infection upon SARS-CoV-2 infection as in the case of the human counterpart, unlike current COVID-19 animal models. P. roborovskii SH101 post-infection of SARS-CoV-2 represented most clinical symptoms of COVID-19 such as snuffling, dyspnea, cough, labored breathing, hunched posture, progressive weight loss, and ruffled fur, in addition to high fever following shaking chills. Histological examinations also revealed a serious right-predominated pneumonia as well as slight organ damages in the brain and liver, manifesting systemic COVID-19 cases. Considering the merit of a small animal as well as its clinical manifestations of SARS-CoV-2 infection in human, this hamster model seems to provide an ideal tool to investigate COVID-19. Author summaryAlthough the current animal models supported SARS-CoV-2 replication and displayed varying degrees of illness after SARS-CoV-2 infection, the infections of SARS-CoV-2 were mainly limited to the respiratory systems of these animals, including hACE2 transgenic mice, hamsters, ferrets, fruit bats, guinea pigs, African green monkey, Rhesus macaques, and Cynomolgus macaques. While these animal models can be a modest model for the respiratory infection, there is a clear limit for use them in the study of COVID-19 that also displays multiple systemic symptoms. Therefore, the development of an animal model recapitulating COVID-19-specific symptoms such as the right-predominated pneumonia would be the utmost need to overcome the imminent threat posed by COVID-19. We identified a very interesting hamster strain, Phodopus roborovskii SH101, which mimics almost all aspects of the clinical manifestations of COVID-19 upon SARS-CoV-2 infection. Unlike the current animal models, SARS-CoV-2-infected P. roborovskii SH101 not only displayed the symptoms of respiratory infection but also clinical manifestations specific to human COVID-19 such as high fever following shaking chills, serious right-predominated pneumonia, and minor organ damages in the brain and liver.

microbiology↗

bioRxiv2021

Antiviral effect of a nucleic acid hydrolyzing scFv against oseltamivir resistant influenza A virus

Influenza viral genome is frequently mutated due to antigenic shift and drift, and therefore the existing antiviral drugs have been suffered from low efficacy against the viruses. Here we report an innovative strategy for treating influenza Type A (IAV) infection by 3D8 single chain variable fragment (scFv) showing intrinsic viral RNA hydrolyzing activity, cell penetration activity and the epidermal cell penetration ability. In this study, we first analyzed antiviral activity directed by 3D8 scFv to three different strains, two oseltamivir-sensitive (A/PuertoRico/8/1934, A/X-31) and oseltamivir-resistant (A/Korea/2785/2009pdm) using cell culture models, suggesting that 3D8 scFv reduces viral genomic RNA. Moreover, we further addressed antiviral effect to analyze clinical outcomes in in vivo mice model. Intranasal administered 3D8 scFv rescued the mice challenged by oseltamivir resistant H1N1. Consistent results are observed through IHC pathology and molecular virological analysis. Taken together, these results demonstrate that 3D8 scFv has antiviral potential against a wide range of IAV.

microbiology↗

bioRxiv2021

Automated assignment of cell identity from single-cell multiplexed imaging and proteomic data

The creation of scalable single-cell and highly-multiplexed imaging technologies that profile the protein expression and phosphorylation status of heterogeneous cellular populations has led to multiple insights into disease processes including cancer initiation and progression. A major analytical challenge in interpreting the resulting data is the assignment of cells to a priori known cell types in a robust and interpretable manner. Existing approaches typically solve this by clustering cells followed by manual annotation of individual clusters or by strategies that gate protein expression at predefined thresholds. However, these often require several subjective analysis choices such as selecting the number of clusters and do not automatically assign cell types in line with prior biological knowledge. They further lack the ability to explicitly assign cells to an unknown or uncharacterized type, which exist in most highly multiplexed imaging experiments due to the limited number of markers quantified. To address these issues we present Astir, a probabilistic model to assign cells to cell types by integrating prior knowledge of marker proteins. Astir uses deep recognition neural networks for fast Bayesian inference, allowing for cell type annotations at the million-cell scale and in the absence of previously annotated reference data across multiple experimental modalities and antibody panels. We demonstrate that Astir outperforms existing approaches in terms of accuracy and robustness by applying it to over 2.1 million single cells from several suspension and imaging mass cytometry and microscopy datasets in multiple tissue contexts. We further showcase that Astir can be used for the fast analysis of the spatial architecture of the tumour microenvironment, automatically quantifying the immune influx and spatial heterogeneity of patient samples. Astir is freely available as an open source Python package at https://www.github.com/camlab-bioml/astir.

bioinformatics↗

bioRxiv2021

An integral genomic signature approach for tailored cancer targeted therapy using genome-wide sequencing data

With the advent of low-cost sequencing, transcriptome and genome sequencing is expected to become clinical routine and transform precision oncology within next decade. However, viable genome-wide modeling methods that can facilitate rational selection of patients for tailored intervention while tolerating sequencing biases are far lacking. Here we propose an integral genomic signature (iGenSig) analysis as a new class of transparent, interpretable, and resilient methods for precision oncology based on multiple types of genome-wide sequencing data. We postulate that the redundant high-dimensional genomic features, which are typically eliminated during multi-omics modeling, may help overcome the sequencing biases. We thus conceive a novel method that models the therapeutic response using the high-dimensional transcriptional and mutational features predictive of tumor response, which we termed as an integral genomic signature (iGenSig), and then algorithmically resolve the feature redundancy tailored for each patient subject. Using genomic dataset of chemical perturbations, we developed the iGenSig models for predicting targeted therapy responses, and applied selected models to independent datasets for cancer cell lines, patient-derived xenografts, and patient subjects. iGenSig models exhibit outstanding cross-dataset performance compared to artificial intelligence methods, with exceptional resilience against simulated errors in genomic features. In particular, the iGenSig model for the EGFR inhibitor Erlotinib significantly predicted the responses of patient-derived xenografts and patients from a clinical trial, biological interpretation of which led to new insights into the predictive signature pathways with clinical relevance. Together, iGenSig will provide a computational infrastructure to empower tailored cancer intervention based on genome-wide sequencing data.

bioinformatics↗

bioRxiv2021

Dynamic Representation of the Subjective Value of Information

To improve future decisions, people should seek information based on the value of information (VOI), which depends on the current evidence and the reward structure of the upcoming decision. When additional evidence is supplied, people should update VOI to adjust subsequent information seeking, but the neurocognitive mechanisms of this updating process remain unknown. We used a modified beads task to examine how the VOI is represented and updated in the human brain. We theoretically derived, and empirically verified, a normative prediction that the VOI depends on decision evidence and is biased by reward asymmetry. Using fMRI, we found that the subjective VOI is represented in right dorsolateral prefrontal cortex (DLPFC). Critically, this VOI representation was updated when additional evidence was supplied, showing that DLPFC dynamically tracks the up-to-date VOI over time. These results provide new insights into how humans adaptively seek information in the service of decision making.

neuroscience↗