Biology subjects

Cho, S.

Publications and source records attributed to Cho, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Exploring the Architectural Biases of the Canonical Cortical Microcircuit

The cortex plays a crucial role in various perceptual and cognitive functions, driven by its basic unit, the canonical cortical microcircuit. Yet, we remain short of a framework that definitively explains the structure-function relationships of this fundamental neuroanatomical motif. To better understand how physical substrates of cortical circuitry facilitate their neuronal dynamics, we employ a computational approach using recurrent neural networks and representational analyses. We examine the differences manifested by the inclusion and exclusion of biologically-motivated inter-areal laminar connections on the computational roles of different neuronal populations in the microcircuit of two hierarchically-related areas, throughout learning. Our findings show that the presence of feedback connections correlates with the functional modularization of cortical populations in different layers, and provides the microcircuit with a natural inductive bias to differentiate expected and unexpected inputs at initialization. Furthermore, when testing the effects of training the microcircuit and its variants with a predictive-coding inspired strategy, we find that doing so helps better encode noisy stimuli in areas of the cortex that receive feedback, all of which combine to suggest evidence for a predictive-coding mechanism serving as an intrinsic operative logic in the cortex.

neuroscience↗

bioRxiv2024

Comparison between EEG and MEG of static and dynamic resting-state networks

The characterisation of resting state networks (RSNs) using neuroimaging techniques has significantly contributed to our understanding of the organisation of brain activity. Prior work has demonstrated the electrophysiological basis of RSNs and their dynamic nature, revealing transient activations of brain networks with millisecond timescales. While previous research has confirmed the comparability of RSNs identified by electroencephalography (EEG) to those identified by magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), most studies have utilised static analysis techniques, ignoring the dynamic nature of brain activity. Often, these studies use high-density EEG systems, which limit their applicability in clinical settings. Addressing these gaps, our research studies RSNs using medium-density EEG systems (61 sensors), comparing both static and dynamic brain network features to those obtained from a high-density MEG system (306 sensors). We assess the qualitative and quantitative comparability of EEG-derived RSNs to those from MEG, including their ability to capture age-related effects, and explore the reproducibility of dynamic RSNs within and across the modalities. Our findings suggest that both MEG and EEG offer comparable static and dynamic network descriptions, albeit with MEG offering some increased sensitivity and reproducibility. Such RSNs and their comparability across the two modalities remained consistent qualitatively but not quantitatively when the data were reconstructed without subject-specific structural MRI images.

neuroscience↗

bioRxiv2024

rRNA Operon Improves Species-Level Classification of Bacteria and Microbial Community Analysis Compared to 16S rRNA

Precise identification of species is fundamental in microbial genomics, crucial for understanding the microbial communities. While the 16S rRNA gene, particularly its V3-V4 regions, has been extensively employed for microbial identification, however has limitations in achieving species-level resolution. Advancements in long-read sequencing technologies have highlighted the rRNA operon as a more accurate marker for microbial classification and analysis than the 16S rRNA gene. This study aims to compare the accuracy of species classification and microbial community analysis using the rRNA operon versus the 16S rRNA gene. We evaluated the species classification accuracy of the rRNA operon,16S rRNA gene, and 16S rRNA V3-V4 region using a BLAST based method and a k-mer matching based method with public data available from NCBI. We further preformed simulations to model microbial community analysis. We accessed the performance using each marker in community composition estimation and differential abundance analysis. Our findings demonstrate that the rRNA operon offers an advantage over the 16S rRNA gene and its V3-V4 region for species-level classification within genus. When applied to microbial community analysis, the rRNA operon enables a more accurate determination of composition. Using the rRNA operon yielded more reliable results in differential abundance analysis as well. IMPORTANCEWe quantitatively demonstrated that the rRNA operon outperformed the 16S rRNA and its V3-V4 regions in accuracy, for both individual species identification and species-level microbial community analysis. Our findings can provide guidelines for selecting appropriate markers in the field of microbial research.

microbiology↗

bioRxiv2024

Spatial Effects of Infiltrating T cells on Neighbouring Cancer Cells and Prognosis in Stage III CRC patients

Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks, as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5-fluorouracil-based chemotherapy. Images underwent segmentation for tumour, stroma and immune cells, and cancer cell state protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell - T cell interactions at single-cell level. In our discovery cohort (MSK), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (HV) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (Discovery cohort: p = 0.07, Validation cohort: p = 0.19). We next utilized our region-based nearest neighbourhood approach to determine the spatial relationships between cytotoxic T cells, helper T cells and cancer cell clusters. In the both cohorts, we found that lower distance between cytotoxic T cells, T helper cells and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered patients based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into low-risk and high-risk groups (Discovery cohort: p = 0.01, Validation cohort: p = 0.003).

cancer biology↗

bioRxiv2023

Pan-tissue scaling of stiffness versus fibrillar collagen reflects contractility-driven strain that inhibits fibril degradation

Polymer network properties such as stiffness often exhibit characteristic power laws in polymer density and other parameters. However, it remains unclear whether diverse animal tissues, composed of many distinct polymers, exhibit such scaling. Here, we examined many diverse tissues from adult mouse and embryonic chick to determine if stiffness (Etissue) follows a power law in relation to the most abundant animal protein, Collagen-I, even with molecular perturbations. We quantified fibrillar collagen in intact tissue by second harmonic generation (SHG) imaging and from tissue extracts by mass spectrometry (MS), and collagenase-mediated decreases were also tracked. Pan-tissue power laws for tissue stiffness versus Collagen-I levels measured by SHG or MS exhibit sub-linear scaling that aligns with results from cellularized gels of Collagen-I but not acellular gels. Inhibition of cellular myosin-II based contraction fits the scaling, and combination with inhibitors of matrix metalloproteinases (MMPs) show collagenase activity is strain - not stress- suppressed in tissues, consistent with past studies of gels and fibrils. Beating embryonic hearts and tendons, which differ in both collagen levels and stiffness by >1000-fold, similarly suppressed collagenases at physiological strains of [~]5%, with fiber-orientation regulating degradation. Scaling of Etissue based on use-it-or-lose-it kinetics provides insight into scaling of organ size, microgravity effects, and regeneration processes while suggesting contractility-driven therapeutics.

molecular biology↗

bioRxiv2023

PET imaging of fibroblast activation protein alpha (FAP) detects incipient cardiotoxicity due to anthracycline chemotherapy

BackgroundAnthracycline chemotherapy is associated with a risk of cardiotoxicity leading to heart disease, particularly in pediatric cancer patients. Gold standard methods of detecting cardiotoxicity are insufficiently sensitive to early damage and specific pathophysiologies driving disease. Positron emission tomography (PET) couples anatomical resolution with biochemical mechanistic selectivity and potentially addresses the current diagnostic limitations in cardio-oncology. We aimed to validate PET imaging biomarkers targeting fibroblast activation protein alpha (FAP), Translocator protein (TSPO), and norepinephrine receptor (NET) for detection of incipient anthracycline-induced cardiotoxicity. MethodsCardiotoxicity was established in male C57BL/6J mice by a cumulative dose of 24 mg/kg doxorubicin (DOX) over 2 weeks. DOX mice and their age-matched controls were imaged with echocardiography and PET, using [68Ga]Ga-FAPI-04, [18F]DPA-714, and [18F]MFBG, over 12 weeks. Fractional shortening (FS) was determined from the echocardiograms, and cardiac uptake of the radioligands was quantified from the PET images. Heart sections were collected and used for the analysis of bulk RNA-seq, RT-qPCR, Western blot, in situ hybridization (ISH), and histopathological analysis. ResultsDOX mice exhibited cardiotoxicity and cardiac atrophy. Cardiac [68Ga]Ga-FAPI-04 PET signal was significantly higher in DOX mice from 2 weeks through the study endpoint. By contrast, no cardiac dysfunction was evident by echocardiography until 10 weeks, at which point FS was significantly reduced in DOX mice. There were no differences in [18F]DPA-714 and [18F]MFBG signals. Transcription and translation of FAP, but not TSPO or NET, was detected in cardiomyocytes and were elevated in the DOX hearts, in agreement with the PET data. Genes related to cell adhesion and extracellular remodeling were significantly upregulated in the DOX mice relative to controls. ConclusionsFAP is a sensitive and selective imaging biomarker for incipient cardiotoxicity and FAPI PET is a promising non-invasive imaging tool for identifying patients at risk of cardiotoxicity during or after anthracycline chemotherapy. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/556130v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1d9e717org.highwire.dtl.DTLVardef@d2bde8org.highwire.dtl.DTLVardef@1b1f2c5org.highwire.dtl.DTLVardef@1b99bc6_HPS_FORMAT_FIGEXP M_FIG C_FIG NOVELTY AND SIGNIFICANCEO_ST_ABSWhat is Known?C_ST_ABSO_LIAnthracycline chemotherapy results in cardiotoxicity for a sizeable population of treated patients. Cardiotoxocity manifests as cardiac dysfunction, and may result in long-term cardiac disease and heart failure, particularly in survivors of pediatric cancer. C_LIO_LICardiotoxicity is typically defined in terms of left ventricular ejection fraction (LVEF) deficits, as measured by echocardiography. However, this metric is often poorly sensitive to early disease and agnostic to underlying pathophysiology. C_LIO_LIEarly treatment of cardiotoxicity improves recovery and long-term survival, emphasizing the need for accurate diagnostics in incipient disease. C_LI What New Information Does This Article Contain?O_LI[68Ga]Ga-FAPI-04 accumulates in the hearts of mice experiencing doxorubicin-induced cardiotoxicity as a function of fibroblast activation protein alpha (FAP) expression and activity. By contrast, cardiac uptake of radioligands targeting the translocator protein 18-kDa (TSPO) and the norepinephrine transporter (NET) do not differ between DOX animals and controls. C_LIO_LIPositron emission tomography (PET) imaging following administration of [68Ga]Ga-FAPI-04 detects abnormal cardiac remodeling significantly earlier than LVEF decrease is observed, indicating that it may be more sensitive to incipient disease. C_LI Our study identifies fibroblast activation protein alpha (FAP) as a promising diagnostic imaging biomarker in anthracycline-induced cardiotoxicity. We show that cardiac PET signal increases immediately after doxorubicin treatment, and the signal increase is sustained for at least 10 weeks. In addition, we demonstrate that FAP inhibitor (FAPI) PET correlates with expression of FAP protein and gene. Thus, we provide mechanistic insight into potentially-treatable pathophysiologies driving cardiac atrophy and toxicity, and have identified a translational PET tracer that can image the activation of these processes at an early stage.

cancer biology↗

bioRxiv2023

Sulfasalazine promotes myogenic differentiation via increasing of fast myosin heavy chain isoforms

Sarcopenia is a debilitating condition characterized by the progressive and generalized degeneration of skeletal muscle mass and function. As of now, there is no approved pharmacological treatment for sarcopenia. Previously, our research revealed that Yin Yang 1 (YY1) plays a crucial role in PHD finger protein 20 (PHF20)-mediated myogenic differentiation. A significant enhancement in YY1 transcription, mediated by PHF20, was observed in C2C12 myoblasts. Within skeletal muscle, YY1 is traditionally considered to inhibit myogenesis by directly repressing the synthesis of late-stage differentiation genes, such as skeletal muscle actin, muscle creatine kinase, and myosin heavy chain IIb. Through screening of a drug library using a PHF20/YY1 promoter reporter assay, sulfasalazine emerged as a promising candidate. Sulfasalazine is known for its anti-inflammatory and immunomodulatory properties and is commonly prescribed for autoimmune diseases. In this study, the treatment of C2C12 myoblasts with sulfasalazine accelerated the myogenic differentiation and bolstered the gene and protein expression of fast myosin heavy chain via a metabolic shift towards glycolysis. Additionally, oral administration of sulfasalazine demonstrated improvement in physical performance in aged mice, as well as in mice models with hindlimb disuse or damage. Moreover, sulfasalazine exhibited a remarkable ability to facilitate the recovery of muscle fibers damaged by Velcro immobilization. Collectively, our findings suggest that sulfasalazine could represent a novel therapeutic avenue for the amelioration of muscle weakness, including sarcopenia.

biochemistry↗

bioRxiv2023

Variable Gain DNA Nanostructure Charge Amplifiers for Biosensing

Electronic measurements of engineered nanostructures comprised solely of DNA (DNA nanostructures) enable new signal conditioning modalities in biosensing. Here, we demonstrate how DNA nanostructures that alter their conformation upon binding a nucleic acid analyte drastically, and reversibly, amplify the measured electrochemical signal. This amplification was controlled by the applied electrical field to achieve a response {approx} 2x104 times greater than that measured from DNA hybridization. Because the amplification is independent of the interaction between the analyte and the DNA nanostructure, our approach provides a platform for tuning the response of the system for high performance that is agnostic of the end application. These molecularly precise self-assembled DNA nanostructures when paired with scalable electronic readout can therefore lead the way to highly sensitive multiplexed biosensing.

bioengineering↗

bioRxiv2023

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Single-cell genetic and epigenetic analyses parse the brains billions of neurons into thousands of "cell-type" clusters, each residing in different brain structures. Many of these cell types mediate their unique functions by virtue of targeted long-distance axonal projections to allow interactions between specific cell types. Here we have used Epi-Retro-Seq to link single cell epigenomes and associated cell types to their long-distance projections for 33,034 neurons dissected from 32 different source regions projecting to 24 different targets (225 source [->]target combinations) across the whole mouse brain. We highlight uses of this large data set for interrogating both overarching principles relating projection cell types to their transcriptomic and epigenomic properties and for addressing and developing specific hypotheses about cell types and connections as they relate to genetics. We provide an overall synthesis of the data set with 926 statistical comparisons of the discriminability of neurons projecting to each target for every dissected source region. We integrate this dataset into the larger, annotated BICCN cell type atlas composed of millions of neurons to link projection cell types to consensus clusters. Integration with spatial transcriptomic data further assigns projection-enriched clusters to much smaller source regions than afforded by the original dissections. We exemplify these capabilities by presenting in-depth analyses of neurons with identified projections from the hypothalamus, thalamus, hindbrain, amygdala, and midbrain to provide new insights into the properties of those cell types, including differentially expressed genes, their associated cis-regulatory elements and transcription factor binding motifs, and neurotransmitter usage.

neuroscience↗

bioRxiv2023

Single-cell DNA Methylome and 3D Multi-omic Atlas of the Adult Mouse Brain

Cytosine DNA methylation is essential in brain development and has been implicated in various neurological disorders. A comprehensive understanding of DNA methylation diversity across the entire brain in the context of the brains 3D spatial organization is essential for building a complete molecular atlas of brain cell types and understanding their gene regulatory landscapes. To this end, we employed optimized single-nucleus methylome (snmC-seq3) and multi-omic (snm3C-seq1) sequencing technologies to generate 301,626 methylomes and 176,003 chromatin conformation/methylome joint profiles from 117 dissected regions throughout the adult mouse brain. Using iterative clustering and integrating with companion whole-brain transcriptome and chromatin accessibility datasets, we constructed a methylation-based cell type taxonomy that contains 4,673 cell groups and 261 cross-modality-annotated subclasses. We identified millions of differentially methylated regions (DMRs) across the genome, representing potential gene regulation elements. Notably, we observed spatial cytosine methylation patterns on both genes and regulatory elements in cell types within and across brain regions. Brain-wide multiplexed error-robust fluorescence in situ hybridization (MERFISH2) data validated the association of this spatial epigenetic diversity with transcription and allowed the mapping of the DNA methylation and topology information into anatomical structures more precisely than our dissections. Furthermore, multi-scale chromatin conformation diversities occur in important neuronal genes, highly associated with DNA methylation and transcription changes. Brain-wide cell type comparison allowed us to build a regulatory model for each gene, linking transcription factors, DMRs, chromatin contacts, and downstream genes to establish regulatory networks. Finally, intragenic DNA methylation and chromatin conformation patterns predicted alternative gene isoform expression observed in a companion whole-brain SMART-seq3 dataset. Our study establishes the first brain-wide, single-cell resolution DNA methylome and 3D multi-omic atlas, providing an unparalleled resource for comprehending the mouse brains cellular-spatial and regulatory genome diversity.

genomics↗

bioRxiv2023

Selective IL-27 production by intestinal regulatory T cells permits gut-specific regulation of Th17 immunity

Regulatory T (Treg) cells are instrumental in establishing immunological tolerance. However, the precise effector mechanisms by which Treg cells control a specific type of immune response in a given tissue remains unresolved. By simultaneously studying Treg cells from different tissue origins under systemic autoimmunity, here we show that IL-27 is specifically produced by intestinal Treg cells to regulate Th17 immunity. Selectively increased intestinal Th17 responses in mice with Treg cell-specific IL-27 ablation led to exacerbated intestinal inflammation and colitis-associated cancer, but also helped protect against enteric bacterial infection. Furthermore, single-cell transcriptomic analysis has identified a CD83+TCF1+ Treg cell subset that is distinct from previously characterized intestinal Treg cell populations as the main IL-27 producers. Collectively, our study uncovers a novel Treg cell suppression mechanism crucial for controlling a specific type of immune response in a particular tissue, and provides further mechanistic insights into tissue-specific Treg cell-mediated immune regulation.

immunology↗

bioRxiv2022

An international scholastic network to generate LexA enhancer-trap lines for Drosophila

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and eleven insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science.

genetics↗

bioRxiv2022

H3K36M provokes cellular plasticity to drive aberrant glandular formation and squamous carcinogenesis

Epigenetic dysregulation is pervasive in cancer, frequently impairing normal tissue development and differentiation1. Beyond alterations in histone modifying enzymes, "oncohistone" mutations have been described across a variety of cancers2-4, although the in vivo effects and underlying mechanisms behind these observations have not been well- studied and remain unclear. Here, by inducing the in vivo expression of histone H3.3 carrying a lysine to methionine (K to M) mutation at position 36 (H3K36M) in self- renewing stratifying epithelial tissues, we show that the H3K36M oncohistone dramatically disrupts normal epithelial differentiation, leading to extensive tissue dysplasia characterized by a significant increase in mitotic, proliferative basal stem cells. Furthermore, this differentiation blockade promotes increased cellular plasticity and enrichment of alternate cell fates, and in particular the aberrant generation of excessive glandular tissue including both hypertrophic salivary, sebaceous, and meibomian glands. Upon carcinogen stress, H3K36M mice display markedly enhanced squamous tumorigenesis. These aberrant phenotypic and gene expression manifestations are associated with global loss of H3K36me2 and concomitant gain of H3K27me3. Collectively, these results have revealed a previously unknown critical role for H3K36 methylation in both the in vivo maintenance of proper epithelial cell fate decisions and the prevention of squamous carcinogenesis. Additionally, they suggest that H3K36 methylation modulation may offer new avenues for the regulation of numerous common disorders driven by over- or under-active glandular function.

cancer biology↗

bioRxiv2022

Hydrogen and dark oxygen drive microbial productivity in diverse groundwater ecosystems

Groundwater ecosystems are globally wide-spread yet still poorly understood. We investigated the age, aqueous geochemistry, and microbiology of 138 groundwater samples from 87 monitoring wells (<250m depth) located in 14 aquifers in the Canadian Prairie. Geochemistry and microbial ecology were tightly linked revealing large-scale aerobic and anaerobic hydrogen, methane, nitrogen, and sulfur cycling carried out by diverse microbial communities. Older groundwaters contained on average more cells (up to 1.4x107/mL) than younger ground-waters. Organic carbon-rich strata featured some of the highest abundances, challenging current estimates of global groundwater population sizes. Substantial concentrations of dissolved oxygen (n=57; 0.52{+/-}0.12 mg/L [mean{+/-}SE]; 0.39 mg/L [median]) in older groundwaters could support aerobic lifestyles in subsurface ecosystems at an unprecedented scale. Metagenomics, oxygen isotope analyses and mixing models indicated that microbial "dark oxygen" contributed to the dissolved oxygen pool in subsurface ecosystems commonly assumed to be anoxic.

microbiology↗

bioRxiv2022

TMAO Destabilizes RNA Secondary Structurevia Direct Hydrogen Bond Interactions

Trimethylamine N-oxide (TMAO) is an osmolyte that accumulates in cells in response to osmotic stress. TMAO stabilizes proteins by the entropic stabilization mechanism, which pictures TMAO as a nano-crowder that predominantly destabilizes the unfolded state. However, the mechanism of action of TMAO on RNA is much less understood. Here, we use all atom molecular dynamics simulations to investigate how TMAO interacts with a 12-nt RNA hairpin with a high melting temperature, and an 8-nt RNA hairpin, which has a relatively fluid native basin in the absence of TMAO. The use of the two hairpins with different free energy of stabilization allows us to probe the origin of the destabilization effect of TMAO on RNA molecules without the possibility of forming tertiary interactions. We generated multiple trajectories using allatom molecular dynamics (MD) simulations in explicit water by employing AMBER and CHARMM force fields, both in the absence and presence of TMAO. We observed qualitatively similar RNA-TMAO interaction profiles from the simulations using the two force fields. TMAO hydrogen bond interactions are largely depleted around the paired RNA bases and ribose sugars. In contrast, we show that the oxygen atom in TMAO, the hydrogen bond acceptor, preferentially interacts with the hydrogen bond donors in the solvent exposed bases, such as those in the stem-loop, the destabilized base stacks in the unfolded state, especially in the marginally stable 8-nt RNA hairpin. The predicted destabilization mechanism through TMAO-RNA hydrogen bond interactions could be tested using two-dimensional IR spectroscopy. Since TMAO does not significantly interact with the hydroxyl group of the ribose sugars, we predict that similar results must also hold for DNA.

biophysics↗

bioRxiv2022

Jointly analyzing the association of human milk nutrients with cognition and temperament traits during the first 6 months of life

Early dietary exposure via human milk (HM) components offers a window of opportunity to support cognitive and temperamental development. While several studies have focused on associations of few pre-selected HM components with cognition and temperament, it is highly plausible that HM components synergistically and jointly support cognitive and behavioral development in early life. We aimed to discern the combined associations of a wide array of HM nutrients with cognition and temperament during the first six months of life and explore if there were persistent effects up to 18 months old, when HM is the primary source of an infants nutrition. The Mullen Scales of Early Learning and Infant Behavior Questionnaires-Revised were used to assess cognition and temperament, respectively, of fifty-four exclusively/predominantly breastfed infants in the first 6 months of life, whose follow-ups were conducted at 6-9, 9-12 and 12-18 months old. HM samples were obtained from the mothers of the participants at less than 6 months of life and analyzed for fatty acids (total monounsaturated fatty acids, polyunsaturated fatty acid, total saturated fatty acid (TSFA), arachidonic acid (ARA), docosahexaenoic acid (DHA), ARA/DHA, omega-6/omega-3 polyunsaturated fatty acids ratio (n-6/n-3)), phospholipids (phosphatidylcholine, phosphatidylethanolamine (PE), phosphatidylinositol (PI), sphingomyelin) and choline (free choline, phosphocholine (PCho), glycerophosphocholine). Feature selection was performed to select nutrients associated with cognition and temperament, respectively. The combined effects of selected nutrients were analyzed using multiple regression. A positive association between the arachidonic acid (ARA) and surgency was observed (p = 0.024). Significant effect of DHA, n-6/n-3, PE and TSFA concentrations on receptive language (R2 = 0.39, p = 0.025), and the elevated ARA, PCho, and PI with increased surgency (R2 = 0.43, p = 0.003) was identified, suggesting that DHA and ARA may have distinct roles for temperament and language functions. Furthermore, the exploratory association analyses suggest that the effects of HM nutrients on R.L. and surgency may persist beyond the first 6 months of life, particularly surgency at 12-18 months (p = 0.002). Our studies highlighted that various HM nutrients work together to support the development of cognition and temperament traits during early infancy.

developmental biology↗

bioRxiv2022

Human Digital Twin: Automated Cell Type Distance Computation and 3D Atlas Construction in Multiplexed Skin Biopsies

Mapping the human body at single cell resolution in three-dimensions (3D) is an important step toward a "digital twin" model that captures important structure and dynamics of cell-cell interactions. Current 3D imaging methods suffer from low resolution and are limited in their ability to distinguish cell types and their spatial relationships. We present a novel 3D workflow: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis) that generates a 3D map of cells from multiplexed images and calculates cell type distance from endothelial cells and other features of interest. We applied this workflow to multiplexed data from sequential skin sections from younger and older donors (n=10; 33-72 years) with biopsies from ten anatomical regions with different sun exposure effects (mild, moderate-marked). Up to 26 sequential sections from each sample underwent multiplexed imaging with 18 biomarkers covering 12 cell types (keratinocytes (granular, spinous, basal), epithelial and myoepithelial cells, fibroblasts, macrophages, T helpers, T killers, T regs, neurons and endothelial cells, markers of DNA damage and repair (p53, DDB2) and cell proliferation (Ki67). Following cell classification, the tissue and classified cells were reconstructed into 3D volumes. A significant inverse correlation between DDB2 positive cells and age was found (corr= -0.78, adj. p=0.047). This suggests reduced capacity for repair in non-cancer older sun-exposed individuals. While absolute immune cell count did not differ by age or sun exposure, the ratio of T Helper/T Killer cells was positively correlated with age (corr=0.82, adj. p=0.048) This is the first such 3D study in skin and paves the way for cataloging more cell types and spatial relationships in aging and disease in skin and other organs.

cell biology↗

bioRxiv2022

AIMP1-derived peptide secreted from hair follicle stem cells activates dermal papilla cells to promote hair growth

Hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) are crucial in the biogenesis and maintenance of hair follicles (HFs). In this study, a fragment derived from aminoacyl-tRNA synthetase-interacting multifunctional protein1 (AIMP1) was secreted from HFSCs to activate DPCs to maintain hair follicle homeostasis. A histological analysis revealed that AIMP1 levels in hair follicles decreased with hair loss. Hair regrowth in AIMP1-induced mice was faster than that in non-induced mice. Deletion mapping revealed 41 amino acids (TN41, aa 6-46) as the active region of AIMP1. The N-terminal peptide fragment of AIMP1 generated by MMP1 was secreted from Wnt-treated HFSCs to activate DPCs via FGFR2. TN41 activated Akt and ERK, increased {beta}-catenin, and enhanced DPCs activation. TN41 also promoted hair shaft elongation in cultured human hair follicles and improved the hair-inducing activity of cultured DPC spheroids. In summation, the AIMP1 fragment secreted from HFSCs appears to stimulate active hair regrowth through activating DPCs.

cell biology↗