Yangmcgee5837

Macrophage polarization is a dynamic and integral process in tissue inflammation and remodeling. In this study, we describe that lipoprotein-associated phospholipase A2 (Lp-PLA2) plays an important role in controlling inflammatory macrophage (M1) polarization in rodent experimental autoimmune encephalomyelitis (EAE) and in monocytes from multiple sclerosis (MS) patients. Specific inhibition of Lp-PLA2 led to an ameliorated EAE via markedly decreased inflammatory and demyelinating property of M1. The effects of Lp-PLA2 on M1 function were mediated by lysophosphatidylcholine, a bioactive product of oxidized lipids hydrolyzed by Lp-PLA2 through JAK2-independent activation of STAT5 and upregulation of IRF5. This process was directed by the G2A receptor, which was only found in differentiated M1 or monocytes from MS patients. M1 polarization could be inhibited by a G2A neutralizing Ab, which led to an inhibited disease in rat EAE. In addition, G2A-deficient rats showed an ameliorated EAE and an inhibited autoimmune response. This study has revealed a mechanism by which lipid metabolites control macrophage activation and function, modification of which could lead to a new therapeutic approach for MS and other inflammatory disorders.The activation and degranulation of mast cells is critical in the pathogenesis of allergic inflammation and modulation of inflammation. Recently, we demonstrated that the unconventional long-tailed myosin, MYO1F, localizes with cortical F-actin and mediates adhesion and migration of mast cells. In this study, we show that knockdown of MYO1F by short hairpin RNA reduces human mast cell degranulation induced by both IgE crosslinking and by stimulation of the Mas-related G protein-coupled receptor X2 (MRGPRX2), which has been associated with allergic and pseudoallergic drug reactions, respectively. Defective degranulation was accompanied by a reduced reassembly of the cortical actin ring after activation but reversed by inhibition of actin polymerization. Our data show that MYO1F is required for full Cdc42 GTPase activation, a critical step in exocytosis. Furthermore, MYO1F knockdown resulted in less granule localization in the cell membrane and fewer fissioned mitochondria along with deficient mitochondria translocation to exocytic sites. Consistent with that, AKT and DRP1 phosphorylation are diminished in MYO1F knockdown cells. Altogether, our data point to MYO1F as an important regulator of mast cell degranulation by contributing to the dynamics of the cortical actin ring and the distribution of both the secretory granules and mitochondria.Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor β (ERβ) reporter mice was induced by 4-vinylcyclohexene diepoxide in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ERβ agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not in age-matched male mice. It was also found that ERβ agonist administration in peri-AOF females, but not males, suppressed the heightened NMDAR signaling and reactive oxygen production in ERβ neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ERβ in the PVN of gonadally intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ERβ signaling in the PVN plays an important role in blood pressure regulation in female mice and contributes to hypertension susceptibility in females at an early stage of ovarian failure comparable to human perimenopause.We examined the signaling route for fever during localized inflammation in male and female mice, elicited by casein injection into a preformed air pouch. The localized inflammation gave rise to high concentrations of prostaglandins of the E species (PGE2) and cytokines in the air pouch and elevated levels of these inflammatory mediators in plasma. this website There were also elevated levels of PGE2 in the cerebrospinal fluid, although there was little evidence for PGE2 synthesis in the brain. Global deletion of the PGE2 prostaglandin E receptor 3 (EP3) abolished the febrile response as did deletion of the EP3 receptor in neural cells, whereas its deletion on peripheral nerves had no effect, implying that PGE2 action on this receptor in the CNS elicited the fever. Global deletion of the interleukin-1 receptor type 1 (IL-1R1) also abolished the febrile response, whereas its deletion on neural cells or peripheral nerves had no effect. However, deletion of the IL-1R1 on brain endothelial cells, as well as deletion of the interleukin-6 receptor α on these cells, attenuated the febrile response. In contrast, deletion of the PGE2 synthesizing enzymes cyclooxygenase-2 and microsomal prostaglandin synthase-1 in brain endothelial cells, known to attenuate fever evoked by systemic inflammation, had no effect. We conclude that fever during localized inflammation is not mediated by neural signaling from the inflamed site, as previously suggested, but is dependent on humoral signaling that involves interleukin actions on brain endothelial cells, probably facilitating PGE2 entry into the brain from the circulation and hence representing a mechanism distinct from that at work during systemic inflammation.People with strabismus acquired during childhood do not experience diplopia (double vision). To investigate how perception of the duplicate image is suppressed, we raised two male monkeys with alternating exotropia by disinserting the medial rectus muscle in each eye at age four weeks. Once the animals were mature, they were brought to the laboratory and trained to fixate a small spot while recordings were made in primary visual cortex (V1). Drifting gratings were presented to the receptive fields of 500 single neurons for eight interleaved conditions (1) right eye monocular; (2) left eye monocular; (3) right eye's field, right eye fixating; (4) right eye's field, left eye fixating; (5) left eye's field, right eye fixating; (6) left eye's field, left eye fixating; (7) both eyes' fields, right eye fixating; (8) both eyes' fields, left eye fixating. As expected, ocular dominance histograms showed a monocular bias compared with normal animals, but many cells could still be driven via both eyes. Overall, neuronalal recordings from the primary visual cortex (V1) in awake monkeys raised with strabismus. The experiments were designed to reveal how perception of double images is avoided.The ability of mammalian taste cells to respond to fatty acids (FAs) has garnered significant attention of late and has been proposed to represent a sixth primary taste. With few exceptions, studies on FA taste have centered exclusively on polyunsaturated FAs, most notably on linoleic acid. In the current study, we have identified an additional FA receptor, GPR84, in the gustatory system that responds to the medium-chain saturated FAs (MCFAs) in male mice. GPR84 ligands activate both Type II and Type III taste cells in calcium imaging and patch-clamp recording assays. MCFAs depolarize and lead to a rise in intracellular free [Ca2+] in mouse taste cells in a concentration-dependent fashion, and the relative ligand specificity in taste cells is consistent with the response profile of GPR84 expressed in a heterologous system. A systemic Gpr84 -/- mouse model reveals a specific deficit in both the neural (via chorda tympani recording) and behavioral responses to administration of oral MCFAs compared with WT mice. Together, we show that the peripheral taste system can respond to an additional class of FAs, the saturated FAs, and that the cognate receptor necessary for this ability is GPR84.The arrival of modern humans into previously unoccupied island ecosystems is closely linked to widespread extinction, and a key reason cited for Pleistocene megafauna extinction is anthropogenic overhunting. A common assumption based on late Holocene records is that humans always negatively impact insular biotas, which requires an extrapolation of recent human behavior and technology into the archaeological past. Hominins have been on islands since at least the early Pleistocene and Homo sapiens for at least 50 thousand y (ka). Over such lengthy intervals it is scarcely surprising that significant evolutionary, behavioral, and cultural changes occurred. However, the deep-time link between human arrival and island extinctions has never been explored globally. Here, we examine archaeological and paleontological records of all Pleistocene islands with a documented hominin presence to examine whether humans have always been destructive agents. We show that extinctions at a global level cannot be associated with Pleistocene hominin arrival based on current data and are difficult to disentangle from records of environmental change. It is not until the Holocene that large-scale changes in technology, dispersal, demography, and human behavior visibly affect island ecosystems. The extinction acceleration we are currently experiencing is thus not inherent but rather part of a more recent cultural complex.How coniferous forests evolved in the Northern Hemisphere remains largely unknown. Unlike most groups of organisms that generally follow a latitudinal diversity gradient, most conifer species in the Northern Hemisphere are distributed in mountainous areas at middle latitudes. It is of great interest to know whether the midlatitude region has been an evolutionary cradle or museum for conifers and how evolutionary and ecological factors have driven their spatiotemporal evolution. Here, we investigated the macroevolution of Pinus, the largest conifer genus and characteristic of northern temperate coniferous forests, based on nearly complete species sampling. Using 1,662 genes from transcriptome sequences, we reconstructed a robust species phylogeny and reestimated divergence times of global pines. We found that ∼90% of extant pine species originated in the Miocene in sharp contrast to the ancient origin of Pinus, indicating a Neogene rediversification. Surprisingly, species at middle latitudes are much older than those at other latitudes. This finding, coupled with net diversification rate analysis, indicates that the midlatitude region has provided an evolutionary museum for global pines. Analyses of 31 environmental variables, together with a comparison of evolutionary rates of niche and phenotypic traits with a net diversification rate, found that topography played a primary role in pine diversification, and the aridity index was decisive for the niche rate shift. Moreover, fire has forced diversification and adaptive evolution of Pinus Our study highlights the importance of integrating phylogenomic and ecological approaches to address evolution of biological groups at the global scale.