Atherosclerosis is the primary cause of heart disease and stroke and is thus the underlying pathology of the leading causes of death in the western world. Although risk can be reduced by lowering ...lipid levels, the equally important contribution of inflammation to the development of cardiovascular disease is not adequately addressed by existing therapies. Here, we summarize the evidence supporting a role for inflammation in the pathogenesis of atherosclerosis, discuss agents that are currently in the clinic and provide a perspective on the challenges faced in the development of drugs that target vascular inflammation.
Advantages in several fields of research and industry are expected with the rise of quantum computers. However, the computational cost to load classical data in quantum computers can impose ...restrictions on possible quantum speedups. Known algorithms to create arbitrary quantum states require quantum circuits with depth O(N) to load an N-dimensional vector. Here, we show that it is possible to load an N-dimensional vector with exponential time advantage using a quantum circuit with polylogarithmic depth and entangled information in ancillary qubits. Results show that we can efficiently load data in quantum devices using a divide-and-conquer strategy to exchange computational time for space. We demonstrate a proof of concept on a real quantum device and present two applications for quantum machine learning. We expect that this new loading strategy allows the quantum speedup of tasks that require to load a significant volume of information to quantum devices.
Dendritic cells (DCs) in tissues and lymphoid organs comprise distinct functional subsets that differentiate in situ from circulating progenitors. Tissue-specific signals that regulate DC subset ...differentiation are poorly understood. We report that DC-specific deletion of the Notch2 receptor caused a reduction of DC populations in the spleen. Within the splenic CD11b
+ DC subset, Notch signaling blockade ablated a distinct population marked by high expression of the adhesion molecule Esam. The Notch-dependent Esam
hi DC subset required lymphotoxin beta receptor signaling, proliferated in situ, and facilitated CD4
+ T cell priming. The Notch-independent Esam
lo DCs expressed monocyte-related genes and showed superior cytokine responses. In addition, Notch2 deletion led to the loss of CD11b
+CD103
+ DCs in the intestinal lamina propria and to a corresponding decrease of IL-17-producing CD4
+ T cells in the intestine. Thus, Notch2 is a common differentiation signal for T cell-priming CD11b
+ DC subsets in the spleen and intestine.
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► Notch2 controls differentiation of splenic classical DCs ► Notch2 dependence defines a distinct Esam
hi population of splenic CD11b
+ DCs ► The Esam
hi CD11b
+ DCs are required for CD4
+ T cell priming in the spleen ► Notch2 controls differentiation of CD11b
+CD103
+ DCs in the intestinal lamina propria
Monocyte subpopulations distinguished by differential expression of chemokine receptors CCR2 and CX3CR1 are difficult to track in vivo, partly due to lack of CCR2 reagents.
We created CCR2-red ...fluorescent protein (RFP) knock-in mice and crossed them with CX3CR1-GFP mice to investigate monocyte subset trafficking. In mice with experimental autoimmune encephalomyelitis, CCR2 was critical for efficient intrathecal accumulation and localization of Ly6C(hi)/CCR2(hi) monocytes. Surprisingly, neutrophils, not Ly6C(lo) monocytes, largely replaced Ly6C(hi) cells in the central nervous system of these mice. CCR2-RFP expression allowed the first unequivocal distinction between infiltrating monocytes/macrophages from resident microglia.
These results refine the concept of monocyte subsets, provide mechanistic insight about monocyte entry into the central nervous system, and present a novel model for imaging and quantifying inflammatory myeloid populations.
Immunotherapy directed at the PD-L1/PD-1 axis has produced treatment advances in various human cancers. Unfortunately, progress has not extended to glioblastoma (GBM), with phase III clinical trials ...assessing anti-PD-1 monotherapy failing to show efficacy in newly diagnosed and recurrent tumors. Myeloid-derived suppressor cells (MDSCs), a subset of immunosuppressive myeloid derived cells, are known to infiltrate the tumor microenvironment of GBM. Growing evidence suggests the CCL2–CCR2 axis is important for this process. This study evaluated the combination of PD-1 blockade and CCR2 inhibition in anti-PD-1–resistant gliomas. CCR2 deficiency unmasked an anti-PD-1 survival benefit in KR158 glioma-bearing mice. CD11b⁺/Ly6Chi/PD-L1⁺ MDSCs within established gliomas decreased with a concomitant increase in overall CCR2⁺ cells and MDSCs within bone marrow of CCR2-deficient mice. The CCR2 antagonist CCX872 increased median survival as a monotherapy in KR158 glioma-bearing animals and further increased median and overall survival when combined with anti-PD-1. Additionally, combination of CCX872 and anti-PD-1 prolonged median survival time in 005 GSC GBM-bearing mice. In both models, CCX872 decreased tumor associated MDSCs and increased these cells within the bone marrow. Examination of tumor-infiltrating lymphocytes revealed an elevated population, increased IFNγ expression, indicating enhanced cytolytic activity, as well as decreased expression of exhaustion markers in CD4⁺ and CD8⁺ T cells following combination treatment. These data establish that combining CCR2 and PD-1 blockade extends survival in clinically relevant murine glioma models and provides the basis on which to advance this combinatorial treatment toward early-phase human trials.
Monocytes are recruited from the blood to sites of inflammation, where they contribute to wound healing and tissue repair. There are at least two subsets of monocytes: classical or proinflammatory ...(CCR2(hi)CX3CR1(low)) and nonclassical, patrolling, or alternative (CCR2(low)CX3CR1(hi)) monocytes. Using spinning-disk confocal intravital microscopy and mice with fluorescent reporters for each of these subsets, we were able to track the dynamic spectrum of monocytes that enter a site of sterile hepatic injury in vivo. We observed that the CCR2(hi)CX3CR1(low) monocytes were recruited early and persisted for at least 48 h, forming a ringlike structure around the injured area. These monocytes transitioned, in situ, from CCR2(hi)Cx3CR1(low) to CX3CR1(hi)CCR2(low) within the ringlike structure and then entered the injury site. This phenotypic conversion was essential for optimal repair. These results demonstrate a local, cytokine driven reprogramming of classic, proinflammatory monocytes into nonclassical or alternative monocytes to facilitate proper wound-healing.
Aims. The nuclei of active galaxies harbor massive young stars, an accreting central black hole, or both. In order to determine the physical conditions that pertain to molecular gas close to the ...sources of radiation, numerical models are constructed. Methods. These models iteratively determine the thermal and chemical balance of molecular gas that is exposed to X-rays (1-100 keV) and far-ultraviolet radiation (6-13.6 eV), as a function of depth. Results. We present a grid of XDR and PDR models that span ranges in density ( 10 super(2)-10 super(6.5) cm super(-3)), irradiation ( 10 super(0.5)-10 super(5) G sub(0) and F_{\rm X}=1.6\times 10-}160 erg cm super(-2) s super(-1)) and column density ( 3\times 10-}1\times 10cm super(-2)). Predictions are made for the most important atomic fine-structure lines, e.g., CII, OI, CI, SiII, and for molecular species like HCO super(+), HCN, HNC, CS and SiO up to J =4, CO and super(13) CO up to J =16, and column densities for CN, CH, CH super(+), HCO, HOC super(+), NO and N sub(2) H super(+). We find that surface temperatures are higher (lower) in PDRs compared to XDRs for densities >10 super(4) (<10 super(4)) cm super(-3). For the atomic lines, we find that, largely due to the different XDR ionization balance, the fine- structure line ratios of SiII 35 \mum/CII 158 \mum, OI 63 \mum/CII 158 \mum, FeII 26 \mum/CII 158 \mum and CI 369 \mum/CI 609 \mum are larger in XDRs than in PDRs, for a given density, column and irradiation strength. Similarly, for the molecular lines, we find that the line ratios HCN/HCO super(+) and HNC/HCN, as well as the column density ratio CN/HCN, discriminate between PDRs and XDRs. In particular, the HCN/HCO super(+) 1-0 ratio is <1 (>1) for XDRs (PDRs) if the density exceeds 10 super(5) cm super(-3) and if the column density is larger than 10 super(23) cm super(-2). For columns less than 10 super(22.5) cm super(-2) the XDR HCN/HCO super(+) 1-0 ratio becomes larger than one, although the individual HCN 1-0 and HCO super(+) 1-0 line intensities are weaker. For modest densities, n =10 super(4)-10 super(5) cm super(-3), and strong radiation fields (>100 erg s super(-1) cm super(-2)), HCN/HCO super(+) ratios can become larger in XDRs than PDRs as well. Also, the HCN/CO 1- 0 ratio is typically smaller in XDRs, and the HCN emission in XDRs is boosted with respect to CO only for high (column) density gas, with columns in excess of 10 super(23) cm super(-2) and densities larger than 10 super(4) cm super(-3). Furthermore, CO is typically warmer in XDRs than in PDRs, for the same total energy input. This leads to higher CO J = N +1- N /CO 1-0, N\ge 1, line ratios in XDRs. In particular, lines with N\ge 10, like CO(16-15) and CO(10-9) observable with HIFI/Herschel, discriminate very well between XDRs and PDRs. This is crucial since the XDR/AGN contribution will typically be of a much smaller (possibly beam diluted) angular scale and a 10-25% PDR contribution can already suppress XDR distinguishing features involving HCN/HCO+ and HNC/HCN. For possible future observations, column density ratios indicate that CH, CH super(+), NO, HOC super(+) and HCO are good PDR/XDR discriminators.
AngII (angiotensin II) induces atherosclerosis and AAAs (abdominal aortic aneurysms) through multiple proposed mechanisms, including chemotaxis. Therefore, we determined the effects of whole-body ...deficiency of the chemokine receptor CCR2 (CC chemokine receptor 2) on these diseases. To meet this objective, apoE (apolipoprotein E)-/- mice that were either CCR2+/+ or CCR2-/-, were infused with either saline or AngII (1000 ng.kg-1 of body weight.min-1) for 28 days via mini-osmotic pumps. Deficiency of CCR2 markedly attenuated both atherosclerosis and AAAs, unrelated to systolic blood pressure or plasma cholesterol concentrations. During the course of the present study, we also observed that AngII infusion led to large dilatations that were restricted to the ascending aortic region of apoE-/- mice. The aortic media in most of the dilated area was thickened. In regions of medial thickening, distinct elastin layers were discernable. There was an expansion of the distance between elastin layers in a gradient from the intimal to the adventitial aspect of the media. This pathology differed in a circumscribed area of the anterior region of ascending aortas in which elastin breaks were focal and almost transmural. All regions of the ascending aorta of AngII-infused mice had diffuse medial macrophage accumulation. Deficiency of CCR2 greatly attenuated the AngII-induced lumen dilatation in the ascending aorta. This new model of ascending aortic aneurysms has pathology that differs markedly from AngII-induced atherosclerosis or AAAs, but all vascular pathologies were attenuated by CCR2 deficiency.
In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue ...damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
Objective:
Cognitive decline accompanies acute illness and surgery, especially in the elderly. Surgery engages the innate immune system that launches a systemic inflammatory response that, if ...unchecked, can cause multiple organ dysfunction. We sought to understand the mechanisms whereby the brain is targeted by the inflammatory response and how this can be resolved.
Methods:
C57BL/6J, Ccr2RFP/+Cx3cr1GFP/+, IkkF/F mice and LysM‐Cre/IkkF/F mice underwent stabilized tibial fracture operation under analgesia and general anesthesia. Separate cohorts of mice were tested for systemic and hippocampal inflammation, integrity of the blood–brain barrier (BBB), and cognition. The putative resolving effects of the cholinergic pathway on these postoperative responses were also studied.
Results:
Peripheral surgery disrupts the BBB via release of tumor necrosis factor‐alpha (TNFα), which facilitates the migration of macrophages into the hippocampus. Macrophage‐specific deletion of Ikappa B kinase (IKK)β, a central coordinator of TNFα signaling through activation of nuclear factor (NF) κB, prevents BBB disruption and macrophage infiltration in the hippocampus following surgery. Activation of the α7 subtype of nicotinic acetylcholine receptors, an endogenous inflammation‐resolving pathway, prevents TNFα‐induced NF‐κB activation, macrophage migration into the hippocampus, and cognitive decline following surgery.
Interpretation:
These data reveal the mechanisms for bidirectional communication between the brain and immune system following aseptic trauma. Pivotal molecular mechanisms can be targeted to prevent and/or resolve postoperative neuroinflammation and cognitive decline. ANN NEUROL 2011;70:986–995
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