Over the past decades the notion of ＇inflammation＇ has been extended beyond the original hallmarks of rubor （redness）, calor （heat）, tumor （swelling） and dolor （pain） described by Celsus. We have ...gained a more detailed understanding of the cellular players and molecular mediators of inflammation which is now being applied and extended to areas of biomedical research such as cancer, obesity, heart disease, metabolism, auto-inflammatory disorders, autoimmunity and infectious diseases. Innate cytokines are often central components of inflammatory responses. Here, we discuss how the type I interferon and interleukin-1 cytokine pathways represent distinct and specialized categories of inflammatory responses and how these key mediators of inflammation counter-regulate each other.
A new realization of the International Celestial Reference Frame (ICRF) is presented based on the work achieved by a working group of the International Astronomical Union (IAU) mandated for this ...purpose. This new realization follows the initial realization of the ICRF completed in 1997 and its successor, ICRF2, adopted as a replacement in 2009. The new frame, referred to as ICRF3, is based on nearly 40 years of data acquired by very long baseline interferometry at the standard geodetic and astrometric radio frequencies (8.4 and 2.3 GHz), supplemented with data collected at higher radio frequencies (24 GHz and dual-frequency 32 and 8.4 GHz) over the past 15 years. State-of-the-art astronomical and geophysical modeling has been used to analyze these data and derive source positions. The modeling integrates, for the first time, the effect of the galactocentric acceleration of the solar system (directly estimated from the data) which, if not considered, induces significant deformation of the frame due to the data span. The new frame includes positions at 8.4 GHz for 4536 extragalactic sources. Of these, 303 sources, uniformly distributed on the sky, are identified as “defining sources” and as such serve to define the axes of the frame. Positions at 8.4 GHz are supplemented with positions at 24 GHz for 824 sources and at 32 GHz for 678 sources. In all, ICRF3 comprises 4588 sources, with three-frequency positions available for 600 of these. Source positions have been determined independently at each of the frequencies in order to preserve the underlying astrophysical content behind such positions. They are reported for epoch 2015.0 and must be propagated for observations at other epochs for the most accurate needs, accounting for the acceleration toward the Galactic center, which results in a dipolar proper motion field of amplitude 0.0058 milliarcsecond yr −1 (mas yr −1 ). The frame is aligned onto the International Celestial Reference System to within the accuracy of ICRF2 and shows a median positional uncertainty of about 0.1 mas in right ascension and 0.2 mas in declination, with a noise floor of 0.03 mas in the individual source coordinates. A subset of 500 sources is found to have extremely accurate positions, in the range of 0.03–0.06 mas, at the traditional 8.4 GHz frequency. Comparing ICRF3 with the recently released Gaia Celestial Reference Frame 2 in the optical domain, there is no evidence for deformations larger than 0.03 mas between the two frames, in agreement with the ICRF3 noise level. Significant positional offsets between the three ICRF3 frequencies are detected for about 5% of the sources. Moreover, a notable fraction (22%) of the sources shows optical and radio positions that are significantly offset. There are indications that these positional offsets may be the manifestation of extended source structures. This third realization of the ICRF was adopted by the IAU at its 30th General Assembly in August 2018 and replaced the previous realization, ICRF2, on January 1, 2019.
There is emerging evidence that diet has a major modulatory influence on brain-gut-microbiome (BGM) interactions with important implications for brain health, and for several brain disorders. The BGM ...system is made up of neuroendocrine, neural, and immune communication channels which establish a network of bidirectional interactions between the brain, the gut and its microbiome. Diet not only plays a crucial role in shaping the gut microbiome, but it can modulate structure and function of the brain through these communication channels. In this review, we summarize the evidence available from preclinical and clinical studies on the influence of dietary habits and interventions on a selected group of psychiatric and neurologic disorders including depression, cognitive decline, Parkinson's disease, autism spectrum disorder and epilepsy. We will particularly address the role of diet-induced microbiome changes which have been implicated in these effects, and some of which are shared between different brain disorders. While the majority of these findings have been demonstrated in preclinical and in cross-sectional, epidemiological studies, to date there is insufficient evidence from mechanistic human studies to make conclusions about causality between a specific diet and microbially mediated brain function. Many of the dietary benefits on microbiome and brain health have been attributed to anti-inflammatory effects mediated by the microbial metabolites of dietary fiber and polyphenols. The new attention given to dietary factors in brain disorders has the potential to improve treatment outcomes with currently available pharmacological and non-pharmacological therapies.
Emotional intelligence (EI) involves the ability to carry out accurate reasoning about emotions and the ability to use emotions and emotional knowledge to enhance thought. We discuss the origins of ...the EI concept, define EI, and describe the scope of the field today. We review three approaches taken to date from both a theoretical and methodological perspective. We find that Specific-Ability and Integrative-Model approaches adequately conceptualize and measure EI. Pivotal in this review are those studies that address the relation between EI measures and meaningful criteria including social outcomes, performance, and psychological and physical well-being. The Discussion section is followed by a list of summary points and recommended issues for future research.
Necrotic cell death during
(Mtb) infection is considered host detrimental since it facilitates mycobacterial spread. Ferroptosis is a type of regulated necrosis induced by accumulation of free iron ...and toxic lipid peroxides. We observed that Mtb-induced macrophage necrosis is associated with reduced levels of glutathione and glutathione peroxidase-4 (Gpx4), along with increased free iron, mitochondrial superoxide, and lipid peroxidation, all of which are important hallmarks of ferroptosis. Moreover, necrotic cell death in Mtb-infected macrophage cultures was suppressed by ferrostatin-1 (Fer-1), a well-characterized ferroptosis inhibitor, as well as by iron chelation. Additional experiments in vivo revealed that pulmonary necrosis in acutely infected mice is associated with reduced Gpx4 expression as well as increased lipid peroxidation and is likewise suppressed by Fer-1 treatment. Importantly, Fer-1-treated infected animals also exhibited marked reductions in bacterial load. Together, these findings implicate ferroptosis as a major mechanism of necrosis in Mtb infection and as a target for host-directed therapy of tuberculosis.
Mitochondrial DNA (mtDNA) copy number is a critical component of overall mitochondrial health. In this chapter, we describe methods for isolation of both mtDNA and nuclear DNA (nucDNA) and ...measurement of their respective copy numbers using quantitative PCR. Methods differ depending on the species and cell type of the starting material and availability of specific PCR reagents.
Interleukin-1 (IL-1) receptor signaling is necessary for control of
Mycobacterium tuberculosis (
Mtb) infection, yet the role of its two ligands, IL-1α and IL-1β, and their regulation in vivo are ...poorly understood. Here, we showed that both IL-1α and IL-1β are critically required for host resistance and identified two multifunctional inflammatory monocyte-macrophage and DC populations that coexpressed both IL-1 species at the single-cell level in lungs of
Mtb-infected mice. Moreover, we demonstrated that interferons (IFNs) played important roles in regulating IL-1 production by these cells in vivo. Type I interferons inhibited IL-1 production by both subsets whereas CD4
+ T cell-derived IFN-γ selectively suppressed monocyte-macrophages. These data provide a cellular basis for both the anti-inflammatory effects of IFNs and probacterial functions of type I IFNs during
Mtb infection and reveal differential regulation of IL-1 production by distinct cell populations as an additional layer of complexity in the activity of IL-1 in vivo.
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► Besides IL-1β, IL-1α is also required for IL-1R1-mediated host resistance to Mtb ► Both IL-1 species are coproduced by two subsets of inflammatory myeloid cells ► Type I IFN suppresses IL-1α and IL-1β production by inflammatory monocytes and DCs ► CD4 T cell-derived IFN-γ inhibits IL-1α and IL-1β production by inflammatory monocytes
Mycobacterium tuberculosis (Mtb) has evolved to evade host innate immunity by interfering with macrophage functions. Interleukin-1β (IL-1β) is secreted by macrophages after the activation of the ...inflammasome complex and is crucial for host defense against Mtb infections. We have previously shown that Mtb is able to inhibit activation of the AIM2 inflammasome and subsequent pyroptosis. Here we show that Mtb is also able to inhibit host cell NLRP3 inflammasome activation and pyroptosis. We identified the serine/threonine kinase PknF as one protein of Mtb involved in the NLRP3 inflammasome inhibition, since the pknF deletion mutant of Mtb induces increased production of IL-1β in bone marrow-derived macrophages (BMDMs). The increased production of IL-1β was dependent on NLRP3, the adaptor protein ASC and the protease caspase-1, as revealed by studies performed in gene-deficient BMDMs. Additionally, infection of BMDMs with the pknF deletion mutant resulted in increased pyroptosis, while the IL-6 production remained unchanged compared to Mtb-infected cells, suggesting that the mutant did not affect the priming step of inflammasome activation. In contrast, the activation step was affected since potassium efflux, chloride efflux and the generation of reactive oxygen species played a significant role in inflammasome activation and subsequent pyroptosis mediated by the Mtb pknF mutant strain. In conclusion, we reveal here that the serine/threonine kinase PknF of Mtb plays an important role in innate immune evasion through inhibition of the NLRP3 inflammasome.
Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified ...because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.
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