The Microglial Sensome Revealed by Direct RNA Sequencing

Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluorescent dual in-situ hybridization, unbiased proteomic analysis and quantitative PCR. We report here that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we term the “sensome”. With aging, sensome transcripts for endogenous ligand recognition are downregulated, whereas those involved in microbe recognition and host defense are upregulated. In addition, aging is associated with an overall increase in expression of microglial genes involved in neuroprotection

Evolution of fNL to the adiabatic limit

We study inflationary perturbations in multiple-field models, for which zeta typically evolves until all isocurvature modes decay--the "adiabatic limit". We use numerical methods to explore the sensitivity of the nonlinear parameter fNL to the process by which this limit is achieved, finding an appreciable dependence on model-specific data such as the time at which slow-roll breaks down or the timescale of reheating. In models with a sum-separable potential where the isocurvature modes decay before the end of the slow-roll phase we give an analytic criterion for the asymptotic value of fNL to be large. Other examples can be constructed using a waterfall field to terminate inflation while fNL is transiently large, caused by descent from a ridge or convergence into a valley. We show that these two types of evolution are distinguished by the sign of the bispectrum, and give approximate expressions for the peak fNL.Comment: v1: 25 pages, plus Appendix and bibliography, 6 figures. v2: minor edits to match published version in JCA

Scara1 deficiency impairs clearance of soluble Amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression

In Alzheimer’s disease soluble amyloid beta (sAβ) causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of sAβ are not known. Here we use shRNA screening and identify the scavenger receptor Scara1 as a receptor for sAβ expressed on myeloid cells. To determine the role of Scara1 in clearance of sAβ in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer’s disease and generate PS1-APP- Scara1-deficient mice. Scara1 deficiency markedly accelerates Aβ accumulation leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aβ clearance. This approach is a potential treatment strategy for Alzheimer’s disease

Scara1 deficiency impairs clearance of soluble Amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression

In Alzheimer’s disease soluble amyloid beta (sAβ) causes synaptic dysfunction and neuronal loss. Receptors involved in clearance of sAβ are not known. Here we use shRNA screening and identify the scavenger receptor Scara1 as a receptor for sAβ expressed on myeloid cells. To determine the role of Scara1 in clearance of sAβ in vivo, we cross Scara1 null mice with PS1-APP mice, a mouse model of Alzheimer’s disease and generate PS1-APP- Scara1-deficient mice. Scara1 deficiency markedly accelerates Aβ accumulation leading to increased mortality. In contrast, pharmacological upregulation of Scara1 expression on mononuclear phagocytes increases Aβ clearance. This approach is a potential treatment strategy for Alzheimer’s disease

Artificial Intelligence and Digital Microscopy Applications in Diagnostic Hematopathology

Digital Pathology is the process of converting histology glass slides to digital images using sophisticated computerized technology to facilitate acquisition, evaluation, storage, and portability of histologic information. By its nature, digitization of analog histology data renders it amenable to analysis using deep learning/artificial intelligence (DL/AI) techniques. The application of DL/AI to digital pathology data holds promise, even if the scope of use cases and regulatory framework for deploying such applications in the clinical environment remains in the early stages. Recent studies using whole-slide images and DL/AI to detect histologic abnormalities in general and cancer in particular have shown encouraging results. In this review, we focus on these emerging technologies intended for use in diagnostic hematology and the evaluation of lymphoproliferative diseases

The scavenger receptor SCARF1 mediates apoptotic cell clearance and prevents autoimmunity

Clearance of apoptotic cells is critical for control of tissue homeostasis however the full range of receptor(s) on phagocytes responsible for recognition of apoptotic cells remains to be identified. Here we show that dendritic cells (DCs), macrophages and endothelial cells use scavenger receptor type F family member 1 (SCARF1) to recognize and engulf apoptotic cells via C1q. Loss of SCARF1 impairs uptake of apoptotic cells. Consequently, in SCARF1-deficient mice, dying cells accumulate in tissues leading to a lupus-like disease with the spontaneous generation of autoantibodies to DNA-containing antigens, immune cell activation, dermatitis and nephritis. The discovery of SCARF1 interactions with C1q and apoptotic cells provides insights into molecular mechanisms involved in maintenance of tolerance and prevention of autoimmune disease

CD123 as a Biomarker in Hematolymphoid Malignancies: Principles of Detection and Targeted Therapies

CD123, the α chain of the interleukin 3 receptor, is a cytokine receptor that is overexpressed in multiple hematolymphoid neoplasms, including acute myeloid leukemia, blastic plasmacytoid dendritic cell neoplasm, acute lymphoblastic leukemia, hairy cell leukemia, and systemic mastocytosis. Importantly, CD123 expression is upregulated in leukemic stem cells relative to non-neoplastic hematopoietic stem cells, which makes it a useful diagnostic and therapeutic biomarker in hematologic malignancies. Varying levels of evidence have shown that CD123-targeted therapy represents a promising therapeutic approach in several cancers. Tagraxofusp, an anti-CD123 antibody conjugated to a diphtheria toxin, has been approved for use in patients with blastic plasmacytoid dendritic cell neoplasm. Multiple clinical trials are investigating the use of various CD123-targeting agents, including chimeric antigen receptor-modified T cells (expressing CD123, monoclonal antibodies, combined CD3-CD123 dual-affinity retargeting antibody therapy, recombinant fusion proteins, and CD123-engager T cells. In this review, we provide an overview of laboratory techniques used to evaluate and monitor CD123 expression, describe the strengths and limitations of detecting this biomarker in guiding therapy decisions, and provide an overview of the pharmacologic principles and strategies used in CD123-targeted therapies

Clinical features of De Novo acute myeloid leukemia with concurrent DNMT3A, FLT3 and NPM1 mutations

BACKGROUND: De novo acute myeloid leukemia (AML) with concurrent DNMT3A, FLT3 and NPM1 mutations (AML(DNMT3A/FLT3/NPM1)) has been suggested to represent a unique AML subset on the basis of integrative genomic analysis, but the clinical features of such patients have not been characterized systematically. METHODS: We assessed the features of patients (n = 178) harboring mutations in DNMT3A, FLT3 and/or NPM1, including an index group of AML(DNMT3A/FLT3/NPM1) patients. RESULTS: Patients with AML(DNMT3A/FLT3/NPM1) (n = 35) were significantly younger (median, 56.0 vs. 62.0 years; p = 0.025), mostly women (65.7% vs. 46.9%; p = 0.045), and presented with a higher percentage of bone marrow blasts (p < 0.001) and normal cytogenetics (p = 0.024) in comparison to patients within other mutation groups in this study. Among patients <60 years old, those with AML(DNMT3A/FLT3/NPM1) had a shorter event-free survival (EFS) (p = 0.047). DNMT3A mutations and not FLT3 or NPM1 mutations were independently associated with overall survival (OS) (p = 0.026). Within mutation subgroups, patients with AML(DNMT3A/NPM1) had a significantly shorter OS compared to those with AML(FLT3-ITD/NPM1) (p = 0.047) suggesting that the adverse impact of DNMT3A mutations is more pronounced than that of FLT3-ITD among patients with NPM1 mutation. CONCLUSIONS: DNMT3A has a significant dominant effect on the clinical features and outcomes of de novo AML patients with concurrent DNMT3A, FLT3 and NPM1 mutations. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-014-0074-4) contains supplementary material, which is available to authorized users

Experimental Diabetes Mellitus Exacerbates Tau Pathology in a Transgenic Mouse Model of Alzheimer's Disease

Diabetes mellitus (DM) is characterized by hyperglycemia caused by a lack of insulin, insulin resistance, or both. There is increasing evidence that insulin also plays a role in Alzheimer's disease (AD) as it is involved in the metabolism of β-amyloid (Aβ) and tau, two proteins that form Aβ plaques and neurofibrillary tangles (NFTs), respectively, the hallmark lesions in AD. Here, we examined the effects of experimental DM on a pre-existing tau pathology in the pR5 transgenic mouse strain that is characterized by NFTs. pR5 mice express P301L mutant human tau that is associated with dementia. Experimental DM was induced by administration of streptozotocin (STZ), which causes insulin deficiency. We determined phosphorylation of tau, using immunohistochemistry and Western blotting. Solubility of tau was determined upon extraction with sarkosyl and formic acid, and Gallyas silver staining was employed to reveal NFTs. Insulin depletion by STZ administration in six months-old non-transgenic mice causes increased tau phosphorylation, without its deposition or NFT formation. In contrast, in pR5 mice this results in massive deposition of hyperphosphorylated, insoluble tau. Furthermore, they develop a pronounced tau-histopathology, including NFTs at this early age, while the pathology in sham-treated pR5 mice is moderate. Whereas experimental DM did not result in deposition of hyperphosphorylated tau in non-transgenic mice, a predisposition to develop a tau pathology in young pR5 mice was both sufficient and necessary to exacerbate tau deposition and NFT formation. Hence, DM can accelerate onset and increase severity of disease in individuals with a predisposition to developing tau pathology

A Consensus Definitive Classification of Scavenger Receptors and Their Roles in Health and Disease

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by theUnited StatesNational Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and a standardized nomenclature based on that definition. Fifteen experts in the scavenger receptor field attended the workshop and, after extensive discussion, reached a consensus regarding the definition of scavenger receptors and a proposed scavenger receptor nomenclature. Scavenger receptors were defined as cell surface receptors that typically bind multiple ligands and promote the removal of nonself or altered-self targets. They often function by mechanisms that include endocytosis, phagocytosis, adhesion, and signaling that ultimately lead to the elimination of degraded or harmful substances. Based on this definition, nomenclature and classification of these receptors into 10 classes were proposed. This classification was discussed at three national meetings and input from participants at these meetings was requested. The following manuscript is a consensus statement that combines the recommendations of the initial workshop and incorporates the input received from the participants at the three national meetings