Charles R. Vanderburg

Broad Institute of MIT and Harvard · Stanley Center for Psychiatric Research

The function of the mammalian brain relies upon the specification and spatial positioning of diversely specialized cell types. Yet, the molecular identities of the cell types and their positions within individual anatomical structures remain incompletely known. To construct a comprehensive atlas of cell types in each brain structure, we paired high...

Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed1–6. However, missing from these measurements is the ability to routinely and easily spatially localize these profiled cells. We d...

Recent technological innovations have enabled the high-throughput quantification of gene expression and epigenetic regulation within individual cells, transforming our understanding of how complex tissues are constructed. Missing from these measurements, however, is the ability to routinely and easily spatially localise these profiled cells. We dev...

Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known to participate in immune responses and play significant functions during infections, the role of MKs within the immune system remains largely unexplored. Histological studies of sepsis patients identifie...

Chordoma is a rare malignant tumor demonstrating notochordal differentiation. It is dependent on Brachyury (TBXT), a hallmark notochordal gene and transcription factor, and shares histological features and the same anatomical location as the notochord. In this study, we perform a molecular comparison of chordoma and notochord to identify dysregulat...

Background Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor ( MC1R ) and risk of Parkinson’s disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neuro...

Charting an organs’ biological atlas requires us to spatially resolve the entire single-cell transcriptome, and to relate such cellular features to the anatomical scale. Single-cell and single-nucleus RNA-seq (sc/snRNA-seq) can profile cells comprehensively, but lose spatial information. Spatial transcriptomics allows for spatial measurements, but...

The cerebellar cortex is a well-studied brain structure with diverse roles in motor learning, coordination, cognition and autonomic regulation. However, a complete inventory of cerebellar cell types is currently lacking. Here, using recent advances in high-throughput transcriptional profiling1–3, we molecularly define cell types across individual l...

Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain1–3. With the proliferation of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of cell-type organization. Here we generated transcriptomes and epigen...

Here we report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcripto...

53 MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene 54 regulation that have a major impact on many diseases and provides an exciting avenue towards 55 antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, 56 miR-2392, that is directly involved with SARS-CoV-2 machinery du...

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we determined a circulating miRNA, miR-2392, is directly involved with SARS-CoV-2 machinery during host infection. S...

Midbrain dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) project widely throughout the central nervous system, playing critical roles in voluntary movements, reward processing, and working memory. Many of these neurons are highly sensitive to neurodegeneration in Parkinson's Disease (PD), and their loss correlates strongly with t...

MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene regulation that have a major impact on many diseases and provides an exciting avenue towards antiviral therapeutics. From patient transcriptomic data, we have discovered a circulating miRNA, miR-2392, that is directly involved with SARS-CoV-2 machinery during host in...

Background: Epidemiological studies suggest a link between the melanoma-related pigmentation gene melanocortin 1 receptor ( MC1R ) and risk of Parkinson disease (PD). We previously showed that MC1R signaling can facilitate nigrostriatal dopaminergic neuron survival. The present study investigates the neuroprotective potential of MC1R against neurot...

A key aspect of nearly all single cell experiments is the necessity to dissociate intact tissues into single cell suspensions for processing. While many protocols have been optimized for optimal cell yield, they have often overlooked the effects that dissociation can have on ex vivo gene expression changes during this process. Microglia, the brain’...

Graphical Abstract Highlights d Spaceflight miRNA signature validated in multiple organism models d Components of miRNA signature related to space radiation and microgravity d Downstream targets and circulating dependence of miRNAs in NASA Twins Study d Inhibition of key microvasculature miRNAs mitigates space radiation impact (C.E.M.), afshin.behe...

Charting a biological atlas of an organ, such as the brain, requires us to spatially-resolve whole transcriptomes of single cells, and to relate such cellular features to the histological and anatomical scales. Single-cell and single-nucleus RNA-Seq (sc/snRNA-seq) can map cells comprehensively, but relating those to their histological and anatomica...

Histones are typically located within the intracellular compartment, and more specifically, within the nucleus. When histones are located within the extracellular compartment, they change roles and become damage-associated molecular patterns (DAMPs), promoting inflammation and coagulation. Patients with sepsis have increased levels of extracellular...

The cerebellum is a well-studied brain structure with diverse roles in motor learning, coordination, cognition, and autonomic regulation. Nonetheless, a complete inventory of cerebellar cell types is presently lacking. We used high-throughput transcriptional profiling to molecularly define cell types across individual lobules of the adult mouse cer...

Single cell transcriptomics has transformed the characterization of brain cell identity by providing quantitative molecular signatures for large, unbiased samples of brain cell populations. With the proliferation of taxonomies based on individual datasets, a major challenge is to integrate and validate results toward defining biologically meaningfu...

Single cell transcriptomics has transformed the characterization of brain cell identity by providing quantitative molecular signatures for large, unbiased samples of brain cell populations. With the proliferation of taxonomies based on individual datasets, a major challenge is to integrate and validate results toward defining biologically meaningfu...

Protocol for extraction of nuclei from frozen tissue in preparation for single-nuclei sequencing (droplet-based/10X). This protocol is based strongly on a similar extraction protocol from the McCarroll lab.

There remains a need to identify new sensitive diagnostic and predictive blood-based platforms in lymphoma. We previously discovered a novel circulating microRNA (miRNA) signature in a Smurf2-deficient mouse model that spontaneously develops diffuse large B-cell lymphoma (DLBCL). Herein, we investigated this 10-miRNA signature (miR-15a, let-7c, let...

Megakaryocytes (MKs) are precursors to platelets, the second most abundant cells in the peripheral circulation. However, while platelets are known participate in immune responses and play significant roles during infections, the role of MKs within the immune system has not been explored. Here we utilize in vitro techniques to show that both cord bl...

Determining whether a patient has taken a direct oral anticoagulant (DOAC) is critical during the periprocedural and preoperative period in the emergency department. However, the inaccessibility of complete medical records, along with the generally inconsistent sensitivity of conventional coagulation tests to these drugs, complicates clinical decis...

Defining cell types requires integrating diverse single-cell measurements from multiple experiments and biological contexts. To flexibly model single-cell datasets, we developed LIGER, an algorithm that delineates shared and dataset-specific features of cell identity. We applied it to four diverse and challenging analyses of human and mouse brain c...

Gene expression at fine scale Mapping gene expression at the single-cell level within tissues remains a technical challenge. Rodriques et al. developed a method called Slide-seq, whereby RNA was spatially resolved from tissue sections by transfer onto a surface covered with DNA-barcoded beads. Applying Slide-seq to regions of a mouse brain revealed...

Alzheimer's disease (AD) is an age-related progressive form of dementia that features neuronal loss, intracellular tau, and extracellular amyloid-β (Aβ) protein deposition. Neurodegeneration is accompanied by neuroinflammation mainly involving microglia, the resident innate immune cell population of the brain. During AD progression, microglia shift...

The spatial organization of cells in tissue has a profound influence on their function, yet a high-throughput, genome-wide readout of gene expression with cellular resolution is lacking. Here, we introduce Slide-seq, a highly scalable method that enables facile generation of large volumes of unbiased spatial transcriptomes with 10 µm spatial resolu...

Background: MiRNAs are small non-coding RNAs that regulate post-transcriptional gene expression, contribute to various facets of cancer pathogenesis, and may serve as a sensitive diagnostic platform as well as potential novel therapeutic targets. We recently identified a 9 miRNA (miR-15a, let-7c, let-7b, miR-27a, miR10b, miR-18a, miR130a, miR24, an...

Defining cell types requires integrating diverse measurements from multiple experiments and biological contexts. Recent technological developments in single-cell analysis have enabled high-throughput profiling of gene expression, epigenetic regulation, and spatial relationships amongst cells in complex tissues, but computational approaches that del...

Although the amyloid β-protein (Aβ) is believed to play an initiating role in Alzheimer's disease (AD), the molecular characteristics of the key pathogenic Aβ forms are not well understood. As a result, it has proved difficult to identify optimal agents that target disease-relevant forms of Aβ. Here, we combined the use of Aβ-rich aqueous extracts...

Synaptic dysfunction and loss are core pathological features in Alzheimer disease (AD). In the vicinity of amyloid‐β plaques in animal models, synaptic toxicity occurs and is associated with chronic activation of the phosphatase calcineurin (CN). Indeed, pharmacological inhibition of CN blocks amyloid‐β synaptotoxicity. We therefore hypothesized th...

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The transition between soluble intrinsically disordered tau protein and aggregated tau in neurofibrillary tangles in Alzheimer's disease is unknown. Here, we propose that soluble tau species can undergo liquid-liquid phase separation (LLPS) under cellular conditions and that phase-separated tau droplets can serve as an intermediate toward tau aggre...

[F-18]-AV-1451 is a novel positron emission tomography (PET) tracer with high affinity to neurofibrillary tau pathology in Alzheimer’s disease (AD). PET studies have shown increased tracer retention in patients clinically diagnosed with dementia of AD type and mild cognitive impairment in regions that are known to contain tau lesions. In vivo uptak...

Metallosis is the accumulation of metallic debris in soft tissues resulting from wear following total joint replacement. A dog was evaluated for lameness 4 years after total hip arthroplasty using a titanium alloy and cobalt chromium total hip system. Radiographs revealed severe acetabular component wear, implant-bone interface deterioration, and p...

Metal alloys are frequently used as implant materials in veterinary medicine. Recent studies suggest that many alloys induce both local and systemic inflammatory responses. In this study, 37 rhesus macaques with long-term skull-anchored percutaneous titanium alloy implants (duration, 0 to 14 y) were evaluated for changes in their hematology, coagul...

Bipolar disorder (BD) is a common, recurring psychiatric illness with unknown pathogenesis. Recent studies suggest that microRNA (miRNA) levels in brains of BD patients are significantly altered, and these changes may offer insight into BD pathology or etiology. Previously, we observed significant alterations of miR-29c levels in extracellular vesi...

Extensive epidemiological data have demonstrated an exponential rise in the incidence of non-Hodgkin lymphoma (NHL) that is associated with increasing age. The molecular etiology of this remains largely unknown, which impacts the effectiveness of treatment for patients. We proposed that age-dependent circulating microRNA (miRNA) signatures in the h...

The mean miRNA expression values and p-values from spleen tissue from two month old Smurf2-/- and wild-type mice. (DOCX)

The mean miRNA expression values and p-values from bone marrow tissue from two month old Smurf2-/- and wild-type mice. (DOCX)

Objective: Individuals with Parkinson's disease are more likely to develop melanoma, and melanoma patients are reciprocally at higher risk of developing Parkinson's disease. Melanoma is strongly tied to red hair/fair skin, a phenotype of loss-of-function polymorphisms in the MC1R (melanocortin 1 receptor) gene. Loss-of-function variants of MC1R hav...

Background: Extensive epidemiological data have demonstrated an exponential rise in the incidence of NHL associated with increasing age. The molecular etiology of this remains largely unknown. Additionally, recent data have suggested that older females with diffuse large B cell lymphoma (DLBCL) have improved survival when treated with rituximab-bas...

Rhesus macaques (Macaca mulatta) are a common model for the study of human biology and disease. To manage coagulopathies in these animals and to study their clotting changes, the ability to measure coagulation biomarkers is necessary. Currently, few options for coagulation testing in NHP are commercially available. In this study, assays for 4 coagu...

Introduction: AV-1451 is a PET tracer tailored to allow in vivo detection of paired helical filament-(PHF)-tau- containing lesions. There is great need to better understand the regional and substrate specific binding patterns of this tracer not only in AD brains but also in non-AD tauopathies. Objective: To carefully examine the correlation of in v...

Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcripti...

Supplementary Table 1. Number of patients from the TCGA dataset used for each grouping. Supplementary Table 2. Complete list of Gene Set Enrichment Analysis (GSEA) for Reactome gene sets for old DLBCL patients (>58 years old) compared to young DLBCL patients (<58 years old) with gender independent and gender specific analysis and Female vs Male DLB...

Objective To examine region- and substrate-specific autoradiographic and in vitro binding patterns of positron emission tomography tracer [F-18]-AV-1451 (previously known as T807), tailored to allow in vivo detection of paired helical filament-tau-containing lesions, and to determine whether there is off-target binding to other amyloid/non-amyloid...

Living bone is a complex, three-dimensional composite material consisting of numerous cell types spatially organized within a mineralized extracellular matrix. To date, mechanistic investigation of the complex cellular level cross-talk involved between the major bone-forming cells involved in the response of bone to mechanical and biochemical stimu...

Alzheimer's disease (AD) is a multifactorial and fatal neurodegenerative disorder for which the mechanisms leading to profound neuronal loss are incompletely recognized. MicroRNAs (miRNAs) are recently discovered small regulatory RNA molecules that repress gene expression and are increasingly acknowledged as prime regulators involved in human brain...