ABSTRACT
Over the last decade, biology has begun utilizing 'big data' approaches, resulting in large, comprehensive atlases in modalities ranging from transcriptomics to neural connectomics. However, these approaches must be complemented and integrated with 'small data' approaches to efficiently utilize data from individual labs. Integration of smaller datasets with major reference atlases is critical to provide context to individual experiments, and approaches toward integration of large and small data have been a major focus in many fields in recent years. Here we discuss progress in integration of small data with consortium-sized atlases across multiple modalities, and its potential applications. We then examine promising future directions for utilizing the power of small data to maximize the information garnered from small-scale experiments. We envision that, in the near future, international consortia comprising many laboratories will work together to collaboratively build reference atlases and foundation models using small data methods.
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The R47H missense mutation of the TREM2 gene is a known risk factor for development of Alzheimer's Disease. In this study, we analyze the impact of the Trem2R47H mutation on specific cell types in multiple cortical and subcortical brain regions in the context of wild-type and 5xFAD mouse background. We profile 19 mouse brain sections consisting of wild-type, Trem2R47H, 5xFAD and Trem2R47H; 5xFAD genotypes using MERFISH spatial transcriptomics, a technique that enables subcellular profiling of spatial gene expression. Spatial transcriptomics and neuropathology data are analyzed using our custom pipeline to identify plaque and Trem2R47H-induced transcriptomic dysregulation. We initially analyze cell type-specific transcriptomic alterations induced by plaque proximity. Next, we analyze spatial distributions of disease associated microglia and astrocytes, and how they vary between 5xFAD and Trem2R47H; 5xFAD mouse models. Finally, we analyze the impact of the Trem2R47H mutation on neuronal transcriptomes. The Trem2R47H mutation induces consistent upregulation of Bdnf and Ntrk2 across many cortical excitatory neuron types, independent of amyloid pathology. Spatial investigation of genotype enriched subclusters identified spatially localized neuronal subpopulations reduced in 5xFAD and Trem2R47H; 5xFAD mice. Overall, our MERFISH spatial transcriptomics analysis identifies glial and neuronal transcriptomic alterations induced independently by 5xFAD and Trem2R47H mutations, impacting inflammatory responses in microglia and astrocytes, and activity and BDNF signaling in neurons.
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OBJECTIVES: The purpose of this study was to assess the effects of family resilience, caregiver needs, and caregiver readiness on benefit finding for family caregivers of patients with stroke and to examine the mediating role of caregiver needs and caregiver readiness between family resilience and benefit finding. METHODS: In this cross-sectional study, convenience sampling was designed and used to recruit participants from three general hospitals in Jinan, Shandong Province, China, from February to September 2022, in which 340 participants completed the General Information Questionnaire, Chinese version of the Family Resilience Assessment Scale (C-FRAS), Caregiver Needs Assessment Scale (CNAS) Chinese version of the Caregiver Preparedness Scale (C-CPS), and Caregiver Benefit Finding Scale (CBFS). Model 6 in process version 4.0 was used to test the chain mediation model between family resilience and benefit finding for caregiver needs and caregiver readiness. RESULTS: Correlation analysis showed that benefit finding in family caregivers was positively associated with family resilience and caregiver readiness and negatively associated with caregiver needs; mediation model tests showed that the total indirect effect of family resilience on benefit finding was 0.163, with the specific mediating effects of caregiver needs and caregiver readiness accounting for 33.74% and 59.51%, and the chain mediating effect of both accounting for 6.75%. CONCLUSIONS: Family resilience not only directly influences benefit finding for family caregivers but also indirectly affects benefit finding through caregiver needs and caregiver readiness. Caregiver needs and caregiver readiness have a mediating role between family resilience and benefit finding in family caregivers.
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Molecular and genomic technological advancements have greatly enhanced our understanding of biological processes by allowing us to quantify key biological variables such as gene expression, protein levels, and microbiome compositions. These breakthroughs have enabled us to achieve increasingly higher levels of resolution in our measurements, exemplified by our ability to comprehensively profile biological information at the single-cell level. However, the analysis of such data faces several critical challenges: limited number of individuals, non-normality, potential dropouts, outliers, and repeated measurements from the same individual. In this article, we propose a novel method, which we call U-statistic based latent variable (ULV). Our proposed method takes advantage of the robustness of rank-based statistics and exploits the statistical efficiency of parametric methods for small sample sizes. It is a computationally feasible framework that addresses all the issues mentioned above simultaneously. We show that our method controls false positives at desired significance levels. An additional advantage of ULV is its flexibility in modeling various types of single-cell data, including both RNA and protein abundance. The usefulness of our method is demonstrated in two studies: a single-cell proteomics study of acute myelogenous leukemia (AML) and a single-cell RNA study of COVID-19 symptoms. In the AML study, ULV successfully identified differentially expressed proteins that would have been missed by the pseudobulk version of the Wilcoxon rank-sum test. In the COVID-19 study, ULV identified genes associated with covariates such as age and gender, and genes that would be missed without adjusting for covariates. The differentially expressed genes identified by our method are less biased toward genes with high expression levels. Furthermore, ULV identified additional gene pathways likely contributing to the mechanisms of COVID-19 severity.
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In the realm of neuroscience, mapping the three-dimensional (3D) neural circuitry and architecture of the brain is important for advancing our understanding of neural circuit organization and function. This study presents a novel pipeline that transforms mouse brain samples into detailed 3D brain models using a collaborative data analytics platform called "Texera." The user-friendly Texera platform allows for effective interdisciplinary collaboration between team members in neuroscience, computer vision, and data processing. Our pipeline utilizes the tile images from a serial two-photon tomography/TissueCyte system, then stitches tile images into brain section images, and constructs 3D whole-brain image datasets. The resulting 3D data supports downstream analyses, including 3D whole-brain registration, atlas-based segmentation, cell counting, and high-resolution volumetric visualization. Using this platform, we implemented specialized optimization methods and obtained significant performance enhancement in workflow operations. We expect the neuroscience community can adopt our approach for large-scale image-based data processing and analysis.
Subject(s)
Brain , Workflow , Animals , Brain/diagnostic imaging , Brain/physiology , Mice , Imaging, Three-Dimensional/methods , Image Processing, Computer-Assisted/methods , SoftwareABSTRACT
Low-rankness plays an important role in traditional machine learning but is not so popular in deep learning. Most previous low-rank network compression methods compress networks by approximating pretrained models and retraining. However, the optimal solution in the Euclidean space may be quite different from the one with low-rank constraint. A well-pretrained model is not a good initialization for the model with low-rank constraints. Thus, the performance of a low-rank compressed network degrades significantly. Compared with other network compression methods such as pruning, low-rank methods attract less attention in recent years. In this article, we devise a new training method, low-rank projection with energy transfer (LRPET), that trains low-rank compressed networks from scratch and achieves competitive performance. We propose to alternately perform stochastic gradient descent training and projection of each weight matrix onto the corresponding low-rank manifold. Compared to retraining on the compact model, this enables full utilization of model capacity since solution space is relaxed back to Euclidean space after projection. The matrix energy (the sum of squares of singular values) reduction caused by projection is compensated by energy transfer. We uniformly transfer the energy of the pruned singular values to the remaining ones. We theoretically show that energy transfer eases the trend of gradient vanishing caused by projection. In modern networks, a batch normalization (BN) layer can be merged into the previous convolution layer for inference, thereby influencing the optimal low-rank approximation (LRA) of the previous layer. We propose BN rectification to cut off its effect on the optimal LRA, which further improves the performance. Comprehensive experiments on CIFAR-10 and ImageNet have justified that our method is superior to other low-rank compression methods and also outperforms recent state-of-the-art pruning methods. For object detection and semantic segmentation, our method still achieves good compression results. In addition, we combine LRPET with quantization and hashing methods and achieve even better compression than the original single method. We further apply it in Transformer-based models to demonstrate its transferability. Our code is available at https://github.com/BZQLin/LRPET.
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Novel brain clearing methods revolutionize imaging by increasing visualization throughout the brain at high resolution. However, combining the standard tool of immunostaining targets of interest with clearing methods has lagged behind. We integrate whole-mount immunostaining with PEGASOS tissue clearing, referred to as iPEGASOS (immunostaining-compatible PEGASOS), to address the challenge of signal quenching during clearing processes. iPEGASOS effectively enhances molecular-genetically targeted fluorescent signals that are otherwise compromised during conventional clearing procedures. Additionally, we demonstrate the utility of iPEGASOS for visualizing neurochemical markers or viral labels to augment visualization that transgenic mouse lines cannot provide. Our study encompasses three distinct applications, each showcasing the versatility and efficacy of this approach. We employ whole-mount immunostaining to enhance molecular signals in transgenic reporter mouse lines to visualize the whole-brain spatial distribution of specific cellular populations. We also significantly improve the visualization of neural circuit connections by enhancing signals from viral tracers injected into the brain. Last, we show immunostaining without genetic markers to selectively label beta-amyloid deposits in a mouse model of Alzheimer's disease, facilitating the comprehensive whole-brain study of pathological features.
Subject(s)
Alzheimer Disease , Brain , Mice, Transgenic , Animals , Brain/metabolism , Brain/diagnostic imaging , Mice , Alzheimer Disease/pathology , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/metabolism , Immunohistochemistry , Neuroimaging/methods , Amyloid beta-Peptides/metabolism , Mice, Inbred C57BLABSTRACT
Autism spectrum disorder has been emerging as a growing public health threat. Early diagnosis of autism spectrum disorder is crucial for timely, effective intervention and treatment. However, conventional diagnosis methods based on communications and behavioral patterns are unreliable for children younger than 2 years of age. Given evidences of neurodevelopmental abnormalities in autism spectrum disorder infants, we resort to a novel deep learning-based method to extract key features from the inherently scarce, class-imbalanced, and heterogeneous structural MR images for early autism diagnosis. Specifically, we propose a Siamese verification framework to extend the scarce data, and an unsupervised compressor to alleviate data imbalance by extracting key features. We also proposed weight constraints to cope with sample heterogeneity by giving different samples different voting weights during validation, and used Path Signature to unravel meaningful developmental features from the two-time point data longitudinally. We further extracted machine learning focused brain regions for autism diagnosis. Extensive experiments have shown that our method performed well under practical scenarios, transcending existing machine learning methods and providing anatomical insights for autism early diagnosis.
Subject(s)
Autism Spectrum Disorder , Brain , Deep Learning , Early Diagnosis , Humans , Autism Spectrum Disorder/diagnostic imaging , Autism Spectrum Disorder/diagnosis , Infant , Brain/diagnostic imaging , Brain/pathology , Magnetic Resonance Imaging/methods , Child, Preschool , Male , Female , Autistic Disorder/diagnosis , Autistic Disorder/diagnostic imaging , Autistic Disorder/pathology , Unsupervised Machine LearningABSTRACT
This scoping review paper redefines the Artificial Intelligence-based Internet of Things (AIoT) driven Human Activity Recognition (HAR) field by systematically extrapolating from various application domains to deduce potential techniques and algorithms. We distill a general model with adaptive learning and optimization mechanisms by conducting a detailed analysis of human activity types and utilizing contact or non-contact devices. It presents various system integration mathematical paradigms driven by multimodal data fusion, covering predictions of complex behaviors and redefining valuable methods, devices, and systems for HAR. Additionally, this paper establishes benchmarks for behavior recognition across different application requirements, from simple localized actions to group activities. It summarizes open research directions, including data diversity and volume, computational limitations, interoperability, real-time recognition, data security, and privacy concerns. Finally, we aim to serve as a comprehensive and foundational resource for researchers delving into the complex and burgeoning realm of AIoT-enhanced HAR, providing insights and guidance for future innovations and developments.
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Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal derepression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use multiplexed error-robust fluorescent in situ hybridization (MERFISH) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated myotubes and unfused mononuclear cells (MNCs) of control, isogenic D4Z4 contraction mutant and FSHD patient samples, as well as the individual nuclei within them. We find myocyte nuclei segregate into two clusters defined by the expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, whereas MNCs cluster based on developmental states. Patient/mutant myotubes are found in "FSHD-hi" and "FSHD-lo" states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target-expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared with the control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.
Subject(s)
Muscle Fibers, Skeletal , Muscular Dystrophy, Facioscapulohumeral , Myoblasts , Single-Cell Analysis , Transcriptome , Muscular Dystrophy, Facioscapulohumeral/genetics , Muscular Dystrophy, Facioscapulohumeral/pathology , Muscular Dystrophy, Facioscapulohumeral/metabolism , Humans , Myoblasts/metabolism , Single-Cell Analysis/methods , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Cell Differentiation/genetics , In Situ Hybridization, Fluorescence , Gene Expression Profiling/methodsABSTRACT
Leveraging AAVs' versatile tropism and labeling capacity, we expanded the scale of in vivo CRISPR screening with single-cell transcriptomic phenotyping across embryonic to adult brains and peripheral nervous systems. Through extensive tests of 86 vectors across AAV serotypes combined with a transposon system, we substantially amplified labeling efficacy and accelerated in vivo gene delivery from weeks to days. Our proof-of-principle in utero screen identified the pleiotropic effects of Foxg1, highlighting its tight regulation of distinct networks essential for cell fate specification of Layer 6 corticothalamic neurons. Notably, our platform can label >6% of cerebral cells, surpassing the current state-of-the-art efficacy at <0.1% by lentivirus, to achieve analysis of over 30,000 cells in one experiment and enable massively parallel in vivo Perturb-seq. Compatible with various phenotypic measurements (single-cell or spatial multi-omics), it presents a flexible approach to interrogate gene function across cell types in vivo, translating gene variants to their causal function.
Subject(s)
Gene Regulatory Networks , Single-Cell Analysis , Animals , Female , Humans , Mice , Cerebral Cortex/metabolism , Cerebral Cortex/cytology , CRISPR-Cas Systems/genetics , Dependovirus/genetics , Forkhead Transcription Factors/metabolism , Forkhead Transcription Factors/genetics , Genetic Vectors/metabolism , Mice, Inbred C57BL , Nerve Tissue Proteins/metabolism , Nerve Tissue Proteins/genetics , Neurons/metabolism , Neurons/cytology , Single-Cell Analysis/methods , Transcriptome/genetics , Cell Line , Transcription, GeneticABSTRACT
Exploiting consistent structure from multiple graphs is vital for multi-view graph clustering. To achieve this goal, we propose an Efficient Balanced Multi-view Graph Clustering via Good Neighbor Fusion (EBMGC-GNF) model which comprehensively extracts credible consistent neighbor information from multiple views by designing a Cross-view Good Neighbors Voting module. Moreover, a novel balanced regularization term based on p-power function is introduced to adjust the balance property of clusters, which helps the model adapt to data with different distributions. To solve the optimization problem of EBMGC-GNF, we transform EBMGC-GNF into an efficient form with graph coarsening method and optimize it based on accelareted coordinate descent algorithm. In experiments, extensive results demonstrate that, in the majority of scenarios, our proposals outperform state-of-the-art methods in terms of both effectiveness and efficiency.
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The employment of flexible piezoresistive sensors has sparked growing interest within the realm of wearable electronic devices, specifically in the fields of health detection and e-skin. Nevertheless, the advancement of piezoresistive sensors has been impeded by their limited sensitivity and restricted operating ranges. Consequently, it is imperative to fabricate sensors with heightened sensitivity and expanded operating ranges through the utilization of the appropriate methodologies. In this paper, piezoresistive sensors were fabricated utilizing electrospun polyvinylidene fluoride/polyacrylonitrile/polyethylene-polypropylene glycol multilayer fibrous membranes anchored with polypyrrole granules as the sensing layer, while electrospun thermoplastic polyurethane (TPU) fibers were employed as the flexible substrate. The sensitivity of the sensor is investigated by varying the fiber diameter of the sensing layer. The experimental findings reveal that a concentration of 14 wt % in the spinning solution exhibits high sensitivity (996.7 kPa-1) within a wide working range (0-10 kPa). This is attributed to the favorable diameter of the fibers prepared at this concentration, which facilitates the uniform in situ growth of pyrrole. The highly deformable TPU flexible fibers and multilayer sensing layer structure enable different linear responses across a broad pressure range (0-1 MPa). Furthermore, the sensor demonstrates good cyclic stability and can detect human movements under different pressures. These results suggest that the piezoresistive sensor with a wide operating range and high sensitivity has significant potential for future health monitoring and artificial intelligence applications.
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Maturation of the forebrain involves transitions from higher to lower levels of synaptic plasticity. The timecourse of these changes likely differs between regions, with the stabilization of some networks scaffolding the development of others. To gain better insight into neuroplasticity changes associated with maturation to adulthood, we examined the distribution of two molecular markers for developmental plasticity. We conducted the examination on male and female degus (Octodon degus), a rodent species with a relatively long developmental timecourse that offers a promising model for studying both development and age-related neuropathology. Immunofluorescent staining was used to measure perineuronal nets (PNNs), an extracellular matrix structure that emerges during the closure of critical plasticity periods, as well as microglia, resident immune cells that play a crucial role in synapse remodeling during development. PNNs (putatively restricting plasticity) were found to be higher in non-juvenile (>3 month) degus, while levels of microglia (putatively mediating plasticity) decreased across ages more gradually, and with varying timecourses between regions. Degus also showed notable variation in PNN levels between cortical layers and hippocampal subdivisions that have not been previously reported in other species. These results offer a glimpse into neuroplasticity changes occurring during degu maturation and highlight adolescence as a unique phase of neuroplasticity, in which PNNs have been established but microglia remain relatively high.
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The subiculum (SUB), a hippocampal formation structure, is among the earliest brain regions impacted in Alzheimer's disease (AD). Toward a better understanding of AD circuit-based mechanisms, we mapped synaptic circuit inputs to dorsal SUB using monosynaptic rabies tracing in the 5xFAD mouse model by quantitatively comparing the circuit connectivity of SUB excitatory neurons in age-matched controls and 5xFAD mice at different ages for both sexes. Input-mapped brain regions include the hippocampal subregions (CA1, CA2, CA3), medial septum and diagonal band, retrosplenial cortex, SUB, postsubiculum (postSUB), visual cortex, auditory cortex, somatosensory cortex, entorhinal cortex, thalamus, perirhinal cortex (Prh), ectorhinal cortex, and temporal association cortex. We find sex- and age-dependent changes in connectivity strengths and patterns of SUB presynaptic inputs from hippocampal subregions and other brain regions in 5xFAD mice compared with control mice. Significant sex differences for SUB inputs are found in 5xFAD mice for CA1, CA2, CA3, postSUB, Prh, lateral entorhinal cortex, and medial entorhinal cortex: all of these areas are critical for learning and memory. Notably, we find significant changes at different ages for visual cortical inputs to SUB. While the visual function is not ordinarily considered defective in AD, these specific connectivity changes reflect that altered visual circuitry contributes to learning and memory deficits. Our work provides new insights into SUB-directed neural circuit mechanisms during AD progression and supports the idea that neural circuit disruptions are a prominent feature of AD.
Subject(s)
Alzheimer Disease , Rabies , Mice , Female , Male , Animals , Hippocampus , Entorhinal Cortex/physiology , Neurons/physiologyABSTRACT
Animals in the natural world constantly encounter geometrically complex landscapes. Successful navigation requires that they understand geometric features of these landscapes, including boundaries, landmarks, corners and curved areas, all of which collectively define the geometry of the environment1-12. Crucial to the reconstruction of the geometric layout of natural environments are concave and convex features, such as corners and protrusions. However, the neural substrates that could underlie the perception of concavity and convexity in the environment remain elusive. Here we show that the dorsal subiculum contains neurons that encode corners across environmental geometries in an allocentric reference frame. Using longitudinal calcium imaging in freely behaving mice, we find that corner cells tune their activity to reflect the geometric properties of corners, including corner angles, wall height and the degree of wall intersection. A separate population of subicular neurons encode convex corners of both larger environments and discrete objects. Both corner cells are non-overlapping with the population of subicular neurons that encode environmental boundaries. Furthermore, corner cells that encode concave or convex corners generalize their activity such that they respond, respectively, to concave or convex curvatures within an environment. Together, our findings suggest that the subiculum contains the geometric information needed to reconstruct the shape and layout of naturalistic spatial environments.
Subject(s)
Environment , Form Perception , Hippocampus , Neurons , Animals , Female , Male , Mice , Calcium/analysis , Calcium/metabolism , Form Perception/physiology , Hippocampus/cytology , Hippocampus/physiology , Neurons/metabolism , Neurons/physiology , Surface PropertiesABSTRACT
Brain extraction and image quality assessment are two fundamental steps in fetal brain magnetic resonance imaging (MRI) 3D reconstruction and quantification. However, the randomness of fetal position and orientation, the variability of fetal brain morphology, maternal organs around the fetus, and the scarcity of data samples, all add excessive noise and impose a great challenge to automated brain extraction and quality assessment of fetal MRI slices. Conventionally, brain extraction and quality assessment are typically performed independently. However, both of them focus on the brain image representation, so they can be jointly optimized to ensure the network learns more effective features and avoid overfitting. To this end, we propose a novel two-stage dual-task deep learning framework with a brain localization stage and a dual-task stage for joint brain extraction and quality assessment of fetal MRI slices. Specifically, the dual-task module compactly contains a feature extraction module, a quality assessment head and a segmentation head with feature fusion for simultaneous brain extraction and quality assessment. Besides, a transformer architecture is introduced into the feature extraction module and the segmentation head. We utilize a multi-step training strategy to guarantee a stable and successful training of all modules. Finally, we validate our method by a 5-fold cross-validation and ablation study on a dataset with fetal brain MRI slices in different qualities, and perform a cross-dataset validation in addition. Experiments show that the proposed framework achieves very promising performance.
Subject(s)
Image Processing, Computer-Assisted , Magnetic Resonance Imaging , Humans , Pregnancy , Female , Image Processing, Computer-Assisted/methods , Magnetic Resonance Imaging/methods , Brain/diagnostic imaging , Head , Fetus/diagnostic imagingABSTRACT
Regeneration in the injured spinal cord is limited by physical and chemical barriers. Acute implantation of a multichannel poly(lactide-co-glycolide) (PLG) bridge mechanically stabilizes the injury, modulates inflammation, and provides a permissive environment for rapid cellularization and robust axonal regrowth through this otherwise inhibitory milieu. However, without additional intervention, regenerated axons remain largely unmyelinated (<10%), limiting functional repair. While transplanted human neural stem cells (hNSC) myelinate axons after spinal cord injury (SCI), hNSC fate is highly influenced by the SCI inflammatory microenvironment, also limiting functional repair. Accordingly, we investigated the combination of PLG scaffold bridges with hNSC to improve histological and functional outcome after SCI. In vitro, hNSC culture on a PLG scaffold increased oligodendroglial lineage selection after inflammatory challenge. In vivo, acute PLG bridge implantation followed by chronic hNSC transplantation demonstrated a robust capacity of donor human cells to migrate into PLG bridge channels along regenerating axons and integrate into the host spinal cord as myelinating oligodendrocytes and synaptically integrated neurons. Axons that regenerated through the PLG bridge formed synaptic circuits that connected the ipsilateral forelimb muscle to contralateral motor cortex. hNSC transplantation significantly enhanced the total number of regenerating and myelinated axons identified within the PLG bridge. Finally, the combination of acute bridge implantation and hNSC transplantation exhibited robust improvement in locomotor recovery. These data identify a successful strategy to enhance neurorepair through a temporally layered approach using acute bridge implantation and chronic cell transplantation to spare tissue, promote regeneration, and maximize the function of new axonal connections.
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The first International Conference on Unconventional Animal Models of Alzheimer's Disease and Aging (UAMAA) took place on December 13-16, 2023, in Santiago, Chile. The Alzheimer's disease (AD) research field is currently in search for new and unconventional models that could hold greater translational potential than transgenic mouse models. Thus this UAMAA conference is timely and significant. The event consisted of 6 sessions with talks from 28 world-class scientists from all over the world. These animal models of interest include the degu (Octodon degu), the dog (Canis familiaris), and certain species of nonhuman primates that may better recapitulate neuropathology and cognitive impairments in human AD. Our conference has provided a formal forum to discuss and highlight new research directions, alternative animal models, and innovative approaches for the AD and aging research field.
Subject(s)
Alzheimer Disease , Octodon , Humans , Mice , Animals , Dogs , Alzheimer Disease/pathology , Aging/pathology , Mice, Transgenic , Disease Models, AnimalABSTRACT
Fetal-to-adult hemoglobin switching is controlled by programmed silencing of γ-globin while the re-activation of fetal hemoglobin (HbF) is an effective strategy for ameliorating the clinical severity of ß-thalassemia and sickle cell disease. The identification of enhancer RNAs (eRNAs) related to the fetal (α2γ2) to adult hemoglobin (α2ß2) switching remains incomplete. In this study, the transcriptomes of GYPA+ cells from six ß-thalassemia patients with extreme HbF levels were sequenced to identify differences in patterns of noncoding RNA expression. It is interesting that an enhancer upstream of CHD4, an HbF-related core subunit of the NuRD complex, was differentially transcribed. We found a significantly positive correlation of eRNA-CHD4 enhancer-gene interaction using the public database of FANTOM5. Specifically, the eRNA-CHD4 expression was found to be significantly higher in both CD34+ HSPCs and HUDEP-2 than those in K562 cells which commonly expressed high level of HbF, suggesting a correlation between eRNA and HbF expression. Furthermore, prediction of transcription binding sites of cis-eQTLs and the CHD4 genomic region revealed a putative interaction site between rs73264846 and ZNF410, a known transcription factor regulating HbF expression. Moreover, in-vitro validation showed that the inhibition of eRNA could reduce the expression of HBG expression in HUDEP-2 cells. Taken together, the findings of this study demonstrate that a distal enhancer contributes to stage-specific silencing of γ-globin genes through direct modulation of CHD4 expression and provide insights into the epigenetic mechanisms of NuRD-mediated hemoglobin switching.