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"Fisher, Daniel"
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IMC-Denoise: a content aware denoising pipeline to enhance Imaging Mass Cytometry
Imaging Mass Cytometry (IMC) is an emerging multiplexed imaging technology for analyzing complex microenvironments using more than 40 molecularly-specific channels. However, this modality has unique data processing requirements, particularly for patient tissue specimens where signal-to-noise ratios for markers can be low, despite optimization, and pixel intensity artifacts can deteriorate image quality and downstream analysis. Here we demonstrate an automated content-aware pipeline, IMC-Denoise, to restore IMC images deploying a differential intensity map-based restoration (DIMR) algorithm for removing hot pixels and a self-supervised deep learning algorithm for shot noise image filtering (DeepSNiF). IMC-Denoise outperforms existing methods for adaptive hot pixel and background noise removal, with significant image quality improvement in modeled data and datasets from multiple pathologies. This includes in technically challenging human bone marrow; we achieve noise level reduction of 87% for a 5.6-fold higher contrast-to-noise ratio, and more accurate background noise removal with approximately 2 × improved F1 score. Our approach enhances manual gating and automated phenotyping with cell-scale downstream analyses. Verified by manual annotations, spatial and density analysis for targeted cell groups reveal subtle but significant differences of cell populations in diseased bone marrow. We anticipate that IMC-Denoise will provide similar benefits across mass cytometric applications to more deeply characterize complex tissue microenvironments.
Multiplexed imaging technologies can reveal the complex cellular and molecular profiles of tissue. Here, the authors develop and implement a denoising pipeline to significantly enhance imaging mass cytometry quality and improve single-cell analyses.
Journal Article
Fever and the thermal regulation of immunity: the immune system feels the heat
Key Points
The hallmark fever response during infection and disease has been maintained throughout hundreds of millions of years in endothermic (warm-blooded) and ectothermic (cold-blooded) species.
Febrile temperatures boost the probability of an effective immune response by stimulating both the innate and the adaptive arms of the immune system.
The pyrogenic cytokine interleukin-6 (IL-6) contributes to two phases of the febrile response: it elevates the core body temperature via thermoregulatory autonomic mechanisms, and it also serves as a thermally sensitive effector molecule that amplifies lymphocyte trafficking into lymphoid organs.
There is emerging evidence that adrenergic signalling pathways associated with thermogenesis can greatly influence immune cell function.
Thus, the thermal element of fever serves as a systemic alert system that broadly promotes immune surveillance in the setting of infection and disease.
This Review considers the impact of host temperature on the immune system. In particular, the authors focus on how the thermal element of the fever response can shape both innate and adaptive immune responses.
Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.
Journal Article
ماوراء المنطق : استخدام العواطف عندما تتفاوض
يقدم كتاب ما وراء المنطق ل روجر فيشر ودانيال شابيرو طريقة للتعامل مع استراتيجية تمكنك من خلق انفعالات إيجابية ومن التعامل مع الانفعالات السلبية ولن تكون بعد الآن خاضعا لانفعالاتك أو انفعالات الآخرين وستكون مفاوضاتك أكثر أريحية وكفاءة وهذه الاستراتيجية فعالة بما يكفى لاستخدامها سواء أكانت مع زميل متصلب الرأي أو مقايض صعب الإرضاء أو مع شريك حياتك كذلك والكتاب يتناول الانفعالات لذا أضاف المؤلفين بعدا شخصيا فقد أوردا عددا من الأمثلة المستمدة من حياتهم الشخصية وكذلك من عملهم سنوات طويلة فى مجال المفاوضات.
Book
Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms
Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F-knockin mice with α-KG supplementation significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte, and platelet counts. Finally, α-KG treatment significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling that contributes to platelet hyperreactivity in MPN patients.
Journal Article
Cytokine production in myelofibrosis exhibits differential responsiveness to JAK-STAT, MAP kinase, and NFκB signaling
The distinct clinical features of myelofibrosis (MF) have been attributed in part to dysregulated inflammatory cytokine production. Circulating cytokine levels are elevated in MF patients; a subset of which have been shown to be poor prognostic indicators. In this study, cytokine overproduction was examined in MF patient plasma and in MF blood cells ex vivo using mass cytometry. Plasma cytokines measured following treatment with ruxolitinib remained markedly abnormal, indicating that aberrant cytokine production persists despite therapeutic JAK2 inhibition. In MF patient samples, 14/15 cytokines measured by mass cytometry were found to be constitutively overproduced, with the principal cellular source for most cytokines being monocytes, implicating a non-cell-autonomous role for monocyte-derived cytokines impacting disease-propagating stem/progenitor cells in MF. The majority of cytokines elevated in MF exhibited ex vivo hypersensitivity to thrombopoietin (TPO), toll-like receptor (TLR) ligands, and/or tumor necrosis factor (TNF). A subset of this group (including TNF, IL-6, IL-8, IL-10) was minimally sensitive to ruxolitinib. All TPO/TLR/TNF-sensitive cytokines, however, were sensitive to pharmacologic inhibition of NFκB and/or MAP kinase signaling. These results indicate that NFκB and MAP kinase signaling maintain cytokine overproduction in MF, and that inhibition of these pathways may provide optimal control of inflammatory pathophysiology in MF.
Journal Article
Now you see me 2 : the closer you look, the less you'll see
The Four Horsemen are on a new mission to steal a chip that can decrypt any electronic device in the world.
DVD
Stabilization of extensive fine-scale diversity by ecologically driven spatiotemporal chaos
It has recently become apparent that the diversity of microbial life extends far below the species level to the finest scales of genetic differences. Remarkably, extensive fine-scale diversity can coexist spatially. How is this diversity stable on long timescales, despite selective or ecological differences and other evolutionary processes? Most work has focused on stable coexistence or assumed ecological neutrality. We present an alternative: extensive diversity maintained by ecologically driven spatiotemporal chaos, with no assumptions about niches or other specialist differences between strains. We study generalized Lotka–Volterra models with antisymmetric correlations in the interactions inspired by multiple pathogen strains infecting multiple host strains. Generally, these exhibit chaos with increasingly wild population fluctuations driving extinctions. But the simplest spatial structure, many identical islands with migration between them, stabilizes a diverse chaotic state. Some strains (subspecies) go globally extinct, but many persist for times exponentially long in the number of islands. All persistent strains have episodic local blooms to high abundance, crucial for their persistence as, for many, their average population growth rate is negative. Snapshots of the abundance distribution show a power law at intermediate abundances that is essentially indistinguishable from the neutral theory of ecology. But the dynamics of the large populations are much faster than birth–death fluctuations. We argue that this spatiotemporally chaotic “phase” should exist in a wide range of models, and that even in rapidly mixed systems, longer-lived spores could similarly stabilize a diverse chaotic phase.
Journal Article