A
bstract
Clarifying the locality properties of higher-spin gravity is a pressing task, but notoriously difficult due to the absence of a weakly-coupled flat regime. The simplest non-trivial case ...where this question can be addressed is the quartic self-interaction of the AdS scalar field present in the higher-spin multiplet. We investigate this issue in the context of the holographic duality between the minimal bosonic higher-spin theory on AdS
4
and the free
O
(
N
) vector model in three dimensions. In particular, we determine the exact explicit form of the derivative expansion of the bulk scalar quartic vertex. The quartic vertex is obtained from the field theory four-point function of the operator dual to the bulk scalar, by making use of our previous results for the Witten diagrams of higher-spin exchanges. This is facilitated by establishing the conformal block expansions of both the boundary four-point function and the dual bulk Witten diagram amplitudes. We show that the vertex we find satisfies a generalised notion of locality.
Monocytic cells exhibit a high level of heterogeneity and have two distinct modes of their activation: 1) classical M1 path associated with inflammation and tissue damage, and 2) alternative M2 path. ...Although it has been demonstrated that M2 macrophages play an important role in the regulation of the allergic immune responses, tissue maintenance and repair, little is known about the mechanisms that determine the M2 phenotype. We have previously shown that miR-124 is expressed in microglia that exhibit the M2 phenotype and overexpression of miR-124 in macrophages resulted in downregulation of a number of M1 markers (MHC class II, CD86) and up-regulation of several M2 markers (Fizz1, Arg1). We further investigated whether the polarization of macrophages towards the M2 phenotype induced miR-124 expression. We found that exposure of cells to IL-4 and IL-13 resulted in the upregulation of miR-124 in macrophages. We also demonstrated that IL-4 induced expression of three miR-124 precursor transcripts with predominant expression of pri-miR-124.3, suggesting regulation of miR-124 expression by IL-4 on a transcriptional level. Expression of miR-124 in microglia did not depend on IL-4 and/or IL-13, whereas expression of miR-124 in lung resident macrophages was IL-4 and IL-13-dependent and was upregulated by systemic administration of IL-4 or during allergic inflammation. Upregulation of several M2 markers (CD206, Ym1) and downregulation of the M1 markers (CD86, iNOS, TNF) in M2-polarized macrophages was abrogated by a miR-124 inhibitor, suggesting that this microRNA contributed to the M2 phenotype development and maintenance. Finally we showed that human CD14(+)CD16(+) intermediate monocytes, which are found in increased numbers in patients with allergies and bronchial asthma, expressed high levels of miR-124 and exhibited other properties of M2-like cells. Thus, our study suggests that miR-124 serves as a regulator of the M2 polarization in various subsets of monocytic cells both in vitro and in vivo.
Recent studies suggest that in addition to their common function in the regulation of thrombosis and hemostasis, platelets also contribute to tissue inflammation affecting adaptive immunity. ...Platelets have a number of pro-inflammatory and regulatory mediators stored in their α-granules and dense granules, which are promptly released at sites of inflammation or tissue injury. Platelet-derived mediators include cytokines (IL-1α, IL-1β, and TGFβ1), chemokines (CXCL4 and CCL3), immunomodulatory neurotransmitters (serotonin, dopamine, epinephrine, histamine, and GABA), and other low-molecular-weight mediators. In addition, activated platelets synthesize a number of lipid pro-inflammatory mediators such as platelet-activating factor and prostaglandins/thromboxanes. Notably, platelets express multiple toll-like receptors and MHC class I on their surface and store IgG in their α-granules. Platelet-derived factors are highly effective in directly or indirectly modulating the priming and effector function of various subsets of T cells. Besides secreting soluble factors, activated platelets upregulate a number of integrins, adhesion molecules, and lectins, leading to the formation of platelet-T cells aggregates. Activated platelets are able to instantly release neurotransmitters acting similar to neuronal presynaptic terminals, affecting CD4 T cells and other cells in close contact with them. The formation of platelet-T cell aggregates modulates the functions of T cells
direct cell-cell contact interactions and the local release of soluble factors including neurotransmitters. New data suggest an important role for platelets as neuronal and innate-like cells that directly recognize damage- or pathogen- associated molecular patterns and instantly communicate with T cells.
The central nervous system (CNS) is highly vascularized where neuronal cells are located in proximity to endothelial cells, astroglial limitans, and neuronal processes constituting integrated ...neurovascular units. In contrast to many other organs, the CNS has a blood-brain barrier (BBB), which becomes compromised due to infection, neuroinflammation, neurodegeneration, traumatic brain injury, and other reasons. BBB disruption is presumably involved in neuronal injury during epilepsy and psychiatric disorders. Therefore, many types of neuropsychological disorders are accompanied by an increase in BBB permeability leading to direct contact of circulating blood cells in the capillaries with neuronal cells in the CNS. The second most abundant type of blood cells are platelets, which come after erythrocytes and outnumber ~100-fold circulating leukocytes. When BBB becomes compromised, platelets swiftly respond to the vascular injury and become engaged in thrombosis and hemostasis. However, more recent studies demonstrated that platelets could also enter CNS parenchyma and directly interact with neuronal cells. Within CNS, platelets become activated by recognizing major brain gangliosides on the surface of astrocytes and neurons and releasing a milieu of pro-inflammatory mediators, neurotrophic factors, and neurotransmitters. Platelet-derived factors directly stimulate neuronal electric and synaptic activity and promote the formation of new synapses and axonal regrowth near the site of damage. Despite such active involvement in response to CNS damage, the role of platelets in neurological disorders was not extensively studied, which will be the focus of this review.
A
bstract
Within holography, we calculate the contribution of an arbitrary spin-
s
gauge boson exchange in AdS
d
+1
to the four-point function with scalar operators on the boundary. As an important ...ingredient, we first compute the complete bulk-to-bulk propagators for massless bosonic higher-spin fields in the metric-like formulation, in any dimension and in various gauges. The split representation of the bulk-to-bulk propagators in terms of bulk-to-boundary propagators allows to present the higher-spin exchange diagram in the form of a conformal partial wave expansion. Our results provide a step towards the larger goal of the holographic reconstruction of bulk interactions, and of clarifying bulk locality.
Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in neurodegenerative diseases such as multiple sclerosis (MS). We investigated the role of ...interleukin-4 (IL-4) in regulating CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis (EAE). We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells. We also found that CNS-resident microglial cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated macrophages (aaMphis), in an IL-4-dependent manner. This aaMphi phenotype extended to the lack of nitric oxide (NO) production by activated microglial cells, which is a marker of classically activated macrophages. We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, macrophages that migrate into the CNS exhibit a dual phenotype. These data indicate that IL-4 production in the CNS is essential for controlling autoimmune inflammation by inducing a microglial cell aaMphi phenotype. Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for microglial cells in the regulation of inflammation in the CNS.
DANSS is a highly segmented 1 m3 plastic scintillator detector. Its 2500 one meter long scintillator strips have a Gd-loaded reflective cover. The DANSS detector is placed under an industrial 3.1 ...GWth reactor of the Kalinin Nuclear Power Plant 350 km NW from Moscow. The distance to the core is varied on-line from 10.7 m to 12.7 m. The reactor building provides about 50 m water-equivalent shielding against the cosmic background. DANSS detects almost 5000 ν˜e per day at the closest position with the cosmic background less than 3%. The inverse beta decay process is used to detect ν˜e. Sterile neutrinos are searched for assuming the 4ν model (3 active and 1 sterile ν). The exclusion area in the Δm142,sin22θ14 plane is obtained using a ratio of positron energy spectra collected at different distances. Therefore results do not depend on the shape and normalization of the reactor ν˜e spectrum, as well as on the detector efficiency. Results are based on 966 thousand antineutrino events collected at three different distances from the reactor core. The excluded area covers a wide range of the sterile neutrino parameters up to sin22θ14<0.01 in the most sensitive region.
The process of macrophage polarization is involved in many pathologies such as anti-cancer immunity and autoimmune diseases. Polarized macrophages exhibit various levels of plasticity when M2/M(IL-4) ...macrophages are reprogrammed into an M1-like phenotype following treatment with IFNγ and/or LPS. At the same time, M1 macrophages are resistant to reprogramming in the presence of M2-like stimuli. The molecular mechanisms responsible for the macrophages polarization, plasticity of M2 macrophages, and lack of plasticity in M1 macrophages remain unknown. Here, we explored the role of Egr2 in the induction and maintenance of macrophage M1 and M2 polarization in the mouse
and
models of inflammation. Egr2 knockdown with siRNA treatment fail to upregulate either M1 or M2 markers upon stimulation, and the overexpression of Egr2 potentiated M1 or M2 marker expression following polarization. Polarisation with M2-like stimuli (IL-4 or IL-13) results in increased Egr2 expression, but macrophages stimulated with M1-like stimuli (IFNγ, LPS, IL-6, or TNF) exhibit a decrease in Egr2 expression. Egr2 was critical for the expression of transcription factors CEBPβ and PPARγ in M2 macrophages, and CEBPβ was highly expressed in M1-polarized macrophages. In siRNA knockdown studies the transcription factor CEBPβ was found to negatively regulate Egr2 expression and is likely to be responsible for the maintenance of the M1-like phenotype and lack plasticity. During thioglycolate-induced peritonitis, adoptively transferred macrophages with Egr2 knockdown failed to become activated as determined by upregulation of MHC class II and CD86. Thus, our study indicates that Egr2 expression is associated with the ability of unstimulated or M2 macrophages to respond to stimulation with inflammatory stimuli, while low levels of Egr2 expression is associated with non-responsiveness of macrophages to their activation.
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