Purinergic and Calcium Signaling in Macrophage Function and Plasticity

In addition to a fundamental role in cellular bioenergetics, the purine nucleotide adenosine triphosphate (ATP) plays a crucial role in the extracellular space as a signaling molecule. ATP and its metabolites serve as ligands for a family of receptors that are collectively referred to as purinergic receptors. These receptors were first described and characterized in the nervous system but it soon became evident that they are expressed ubiquitously. In the immune system, purinergic signals regulate the migration and activation of immune cells and they may also orchestrate the resolution of inflammation (1, 2). The intracellular signal transduction initiated by purinergic receptors is strongly coupled to Ca2+-signaling and coordination of these pathways plays a critical role in innate immunity. In this review, we provide an overview of purinergic and Ca2+-signaling in the context of macrophage phenotypic polarization and discuss the implications on macrophage function in physiological and pathological conditions

Statistical properties of eigenstate amplitudes in complex quantum systems

We study the eigenstates of quantum systems with large Hilbert spaces, via their distribution of wavefunction amplitudes in a real-space basis. For single-particle 'quantum billiards', these real-space amplitudes are known to have Gaussian distribution for chaotic systems. In this work, we formulate and address the corresponding question for many-body lattice quantum systems. For integrable many-body systems, we examine the deviation from Gaussianity and provide evidence that the distribution generically tends toward power-law behavior in the limit of large sizes. We relate the deviation from Gaussianity to the entanglement content of many-body eigenstates. For integrable billiards, we find several cases where the distribution has power-law tails.Comment: revised version, with appendices; 15 pages, 10 figure

Caspase-11 Controls Interleukin-1 beta Release through Degradation of TRPC1

Caspase-11 is a highly inducible caspase that controls both inflammatory responses and cell death. Caspase-11 controls interleukin 1 beta (IL-1 beta) secretion by potentiating caspase-1 activation and induces caspase-1-independent pyroptosis downstream of noncanonical NLRP3 inflammasome activators such as lipopolysaccharide (LPS) and Gram-negative bacteria. However, we still know very little about the downstream mechanism of caspase-11 in regulating inflammation because the known substrates of caspase-11 are only other caspases. Here, we identify the cationic channel subunit transient receptor potential channel 1 (TRPC1) as a substrate of caspase-11. TRPC1 deficiency increases the secretion of IL-1 beta without modulating caspase-1 cleavage or cell death in cultured macrophages. Consistently, trpc1(-/-) mice show higher IL-1 beta secretion in the sepsis model of intraperitoneal LPS injection. Altogether, our data suggest that caspase-11 modulates the cationic channel composition of the cell and thus regulates the unconventional secretion pathway in a manner independent of caspase-1

Neuronal hyperexcitability is a DLK-dependent trigger of Herpes Simplex Virus reactivation that can be induced by IL-1

Herpes simplex virus-1 (HSV-1) establishes a latent infection in neurons and periodically reactivates to cause disease. The stimuli that trigger HSV-1 reactivation have not been fully elucidated. We demonstrate HSV-1 reactivation from latently infected mouse neurons induced by forskolin requires neuronal excitation. Stimuli that directly induce neurons to become hyperexcitable also induced HSV-1 reactivation. Forskolin-induced reactivation was dependent on the neuronal pathway of DLK/JNK activation and included an initial wave of viral gene expression that was independent of histone demethylase activity and linked to histone phosphorylation. IL-1β is released under conditions of stress, fever and UV exposure of the epidermis; all known triggers of clinical HSV reactivation. We found that IL-1β induced histone phosphorylation and increased the excitation in sympathetic neurons. Importantly, IL-1β triggered HSV-1 reactivation, which was dependent on DLK and neuronal excitability. Thus, HSV-1 co-opts an innate immune pathway resulting from IL-1 stimulation of neurons to induce reactivation

Revaluation of magnetic properties of Magneto

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A high-conductance chemo-optogenetic system based on the vertebrate channel Trpa1b

Optogenetics is a powerful research approach that allows localized optical modulation of selected cells within an animal via the expression of genetically encoded photo-excitable ion channels. Commonly used optogenetic techniques rely on the expression of microbial opsin variants, which have many excellent features but suffer from various degrees of blue spectral overlap and limited channel conductance. Here, we expand the optogenetics toolbox in the form of a tunable, high-conductance vertebrate cation channel, zTrpa1b, coupled with photo-activated channel ligands, such as optovin and 4g6. Our results demonstrate that zTrpa1b/ligand pairing offers high light sensitivity, millisecond-scale response latency in vivo, as well as adjustable channel off latency. Exogenous in vivo expression of zTrpa1b in sensory neurons allowed subcellular photo-activation, enabling light-dependent motor control. zTrpa1b/ligand was also suitable for cardiomyocyte pacing, as shown in experiments performed on zebrafish hearts in vivo as well as in human stem cell-derived cardiomyocytes in vitro. Therefore, zTrpa1b/optovin represents a novel tool for flexible, high-conductance optogenetics