Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic ...reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.Type 3 innate lymphoid cells (ILC3s) are key regulators of intestinal homeostasis and epithelial barrier integrity. In this issue of the JCI, Cao and colleagues found that a sensor of endoplasmic reticulum (ER) stress, the inositol-requiring kinase 1α/X-box-binding protein 1 (IRE1α/XBP1) pathway, fine-tuned the functions of ILC3s. Activation of IRE1α and XBP1 in ILC3s limited intestinal inflammation in mice and correlated with the efficacy of ustekinumab, an IL-12/IL-23 blocker, in patients with Crohn's disease. These results advance our understanding in the use of ILCs as biomarkers not only to predict disease outcomes but also to indicate the response to biologicals in patients with inflammatory bowel disease.
The new European Directive RED-II on the promotion of the use of renewable energy sources has introduced the concept of the Renewable Energy Community. This new entity has the potential to change the ...relations among end-users and the latter and the other actors of the energy sector. In particular, the electrical sector appears the most influenced by the implementation of this paradigm. Indeed, the need for self-consumption and for exploiting the full potential of renewable energy in a Renewable Energy Community influences how the end-users exchange energy with the power grid, the rules for their connection to the grid, the implementation of Demand Response and other energy management programs. For this reason, after a review of the existing legal framework, this paper investigates various aspects concerning the interaction of Renewable Energy Communities with the power system, highlighting what issues must still be addressed for a complete implementation of Renewable Energy Communities and their integration in the power system, with a focus on the Italian context.
•Renewable Energy Communities and jointly acting renewables self-consumers appear as new actors in the electricity sector.•Regulation on self-consumption is presented and the international implementation experience are discussed.•Self-consumption schemes have the potential to impact in a significant way on the electric power system.•The evaluation of the shared electricity in various scenarios is discussed.•The application of the Blockchain technology to the REC model is debated.
Existing continuum multiphase tumor growth models typically do not include microvasculature, or if present, this is modeled as a non-deformable network of vessels. Vasculature behavior and blood flow ...are usually non-coupled with the underlying tumor phenomenology from the mechanical viewpoint; hence, phenomena like vessel compression/occlusion modifying microcirculation and oxygen supply cannot be taken into account. Here, the tumor tissue is modeled as a reactive bi-compartment porous medium: the extracellular matrix constitutes the solid scaffold; blood flows in the vascular porosity, whereas the extravascular porous compartment is saturated by two cell phases and interstitial fluid (mixture of water and nutrient species). The pressure difference between blood and the extravascular overall pressure is sustained by vessel walls and drives shrinkage or dilatation of the vascular porosity. Model closure is achieved thanks to a consistent non-conventional definition of the Biot’s effective stress tensor. Angiogenesis is modeled by introducing a vascularization state variable and accounting for tumor angiogenic factors and endothelial cells. Closure relationships and mass exchange terms related to vessel formation are detailed in a numerical example reproducing the principal features of angiogenesis. This example is preceded by a first pedagogical numerical study on one-dimensional bio-consolidation. Results demonstrate that the bi-compartment poromechanical model is fully coupled (the external loads impact fluid flow in both porous compartments) and that it can serve as a basis for further applications like modeling of drug delivery and tissue ulceration.
Innate lymphoid cells (ILCs) patrol environmental interfaces to defend against infection and protect barrier integrity. Using a genetic tuning model, we demonstrate that the signal-dependent ...transcription factor (TF) STAT5 is critical for accumulation of all known ILC subsets in mice and reveal a hierarchy of STAT5 dependency for populating lymphoid and nonlymphoid tissues. We apply transcriptome and genomic distribution analyses to define a STAT5 gene signature in natural killer (NK) cells, the prototypical ILC subset, and provide a systems-based molecular rationale for its key functions downstream of IL-15. We also uncover surprising features of STAT5 behavior, most notably the wholesale redistribution that occurs when NK cells shift from tonic signaling to acute cytokine-driven signaling, and genome-wide coordination with T-bet, another key TF in ILC biology. Collectively, our data position STAT5 as a central node in the TF network that instructs ILC development, homeostasis, and function and provide mechanistic insights on how it works at cellular and molecular levels.
Today, the blockchain is synonymous of technological innovation, being recognized among the 10 top strategy technologies in 2018 by the consulting company Gartner, it is more and more adopted in ...different sectors. However, the initial enthusiasm around this technology is going beyond the peak of inflated expectations, towards more stable applications in money transactions, cryptocurrencies and Digital Commodity Exchanges. Essentially, misguided efforts, the overuse of blockchain, and the Bitcoin's price drop have been the main reasons for this decay in expectations. Nevertheless, the exploitation of the blockchain technology in the power systems area appears largely underexplored, furthermore, the relation to the physical asset makes the blockchain application more complex but also more reliable and related to measurable benefits. The most common applications in the power systems area relate to the energy market. When the blockchain technology is indeed applied to the energy field, the term energy blockchain is used. This article aims to propose a wide perspective about the application of the blockchain technology in the power systems area, clarifying some technical aspects concerning this promising technology, the features and applications developed so far, while focusing on the future of innovative applications in the electrical energy sector.
•Blockchain technology applications for power systems are presented and discussed.•The paper discusses pros and cons of the use of blockchain technology in power systems applications.•For each class of applications the most suitable blockchain technology is identified.•The paper proposes a way for identifying when blockchain can be really useful for power systems applications.
Objective
Dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated premature vascular damage. No drug to date ...targets both systemic inflammatory disease and the cardiovascular complications of SLE. Tofacitinib is a JAK inhibitor that blocks signaling downstream of multiple cytokines implicated in lupus pathogenesis. While clinical trials have shown that tofacitinib exhibits significant clinical efficacy in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized.
Methods
MRL/lpr lupus‐prone mice were administered tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm). Nephritis, skin inflammation, serum levels of autoantibodies and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium‐dependent vasorelaxation, and endothelial differentiation were compared in treated and untreated mice.
Results
Treatment with tofacitinib led to significant improvement in measures of disease activity, including nephritis, skin inflammation, and autoantibody production. In addition, tofacitinib treatment reduced serum levels of proinflammatory cytokines and interferon responses in splenocytes and kidney tissue. Tofacitinib also modulated the formation of NETs and significantly increased endothelium‐dependent vasorelaxation and endothelial differentiation. The drug was effective in both preventive and therapeutic strategies.
Conclusion
Tofacitinib modulates the innate and adaptive immune responses, ameliorates murine lupus, and improves vascular function. These results indicate that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.
Summary
Immunity to pathogens is ensured through integration of early responses mediated by innate cells and late effector functions taking place after terminal differentiation of adaptive ...lymphocytes. In this context, innate lymphoid cells (ILCs) and adaptive T cells represent a clear example of how prototypical effector functions, including polarized expression of cytokines and/or cytotoxic activity, can occur with overlapping modalities but different timing. The ability of ILCs to provide early protection relies on their poised epigenetic state, which determines their propensity to quickly respond to cytokines and to activate specific patterns of signal‐dependent transcription factors. Cytokines activating the Janus kinases (JAKs) and members of the signal transducer and activator of transcription (STAT) pathway are key regulators of lymphoid development and sustain the processes underlying T‐cell activation and differentiation. The role of the JAK/STAT pathway has been recently extended to several aspects of ILC biology. Here, we discuss how JAK/STAT signals affect ILC development and effector functions in the context of immune responses, highlighting the molecular mechanisms involved in regulation of gene expression as well as the potential of targeting the JAK/STAT pathway in inflammatory pathologies.
NK cell maturation is a continuous process, which initiates in the bone marrow and proceeds in peripheral tissues, where NK cells follow distinct differentiation routes. Drastic phenotypic changes ...are observed during progression from precursors to mature NK cells, including changes of expression and functionalities of several chemoattractant receptors. Upon differentiation, mature NK cells migrate outside the bone marrow; as well, peculiar subsets of NK cells can also home back to or localize in this anatomic compartment to play specific functions. In humans, NK cells with a tissue resident phenotype have been identified in bone marrow, sharing similarities with tissue resident memory CD8
T cells; while in mouse, long-lived NK cells undergo homeostatic proliferation in this site during viral infections. The mechanisms underlying NK cell subset localization in the bone marrow have only recently started to be investigated, especially in pathological settings such as tumors or infections. In this review, we discuss the phenotype and function of NK cells as well as their requirements for bone marrow maintenance and/or homing.
Natural killer (NK) cells are key innate immune effectors against multiple myeloma, their activity declining in multiple myeloma patients with disease progression. To identify the mechanisms ...underlying NK cell functional impairment, we characterized the distribution of functionally distinct NK cell subsets in the bone marrow of multiple myeloma-bearing mice. Herein we report that the number of KLRG1(-) NK cells endowed with potent effector function rapidly and selectively decreases in bone marrow during multiple myeloma growth, this correlating with decreased bone marrow NK cell degranulation in vivo. Altered NK cell subset distribution was dependent on skewed chemokine/chemokine receptor axes in the multiple myeloma microenvironment, with rapid downmodulation of the chemokine receptor CXCR3 on NK cells, increased CXCL9 and CXCL10, and decreased CXCL12 expression in bone marrow. Similar alterations in chemokine receptor/chemokine axes were observed in patients with multiple myeloma. Adoptive transfer experiments demonstrated that KLRG1(-) NK cell migration to the bone marrow was more efficient in healthy than multiple myeloma-bearing mice. Furthermore, bone marrow localization of transferred CXCR3-deficient NK cells with respect to wild type was enhanced in healthy and multiple myeloma-bearing mice, suggesting that CXCR3 restrains bone marrow NK cell trafficking. Our results indicate that multiple myeloma-promoted CXCR3 ligand upregulation together with CXCL12 downmodulation act as exit signals driving effector NK cells outside the bone marrow, thus weakening the antitumor immune response at the primary site of tumor growth.
PDF
