Includes unlimited streaming via the free Bandcamp app, plus high-quality downloads of GIGA ULTIMATE, ADvantage, AD:HOUSE 10, Stream Palette 3, works.12, works.after 2, AD:HOUSE Winter 2, AD:TRANCE 8, and 154 more. , and , . Purchasable with gift card Buy Digital Discography 106,450 JPY (50% OFF) Send as Gift Share / Embed 1. Feryquitous - II.諦観 04:00 buy track 2. Juggernaut. - nihil 03:26 buy track 3. satie - Glimmer 04:21 buy track 4. BlackY - Albireo 03:43 buy track 5. Elliot Hsu - Celestial Intertwine 04:37 buy track 6. Cansol vs. Raimukun - 量子力学のためのピアノ協奏曲 04:34 buy track 7. Ice feat. Kero - Frog Rappa 03:34 buy track 8. xi - The End of Dreams 04:24 buy track 9. cosMo@暴走P - Tachyon 03:28 buy track 10. yuichi NAGAO - 回転体 03:12 buy track 11. 黒魔 - Fragmented Happiness 04:37 buy track 12. ARForest - Neglected Pianist 04:08 buy track 13. Sad Keyboard Guy feat. AKA - Lullaby For an Android 05:07 buy track 14. bqスタヂオ - ずれる 03:22 buy track 15. Sobrem - Segue 03:21 buy track 16. Blacklolita - 漂泊の旅 03:34 buy track 17. Error Signal - Stigma 03:51 buy track 18. 削除 (Vo. 削除) - Requiem Cantata "祈り" 04:53 buy track credits released December 31, 2021 license all rights reserved tags Tags electronic dubstep house techno trance Japan Shopping cart total USD Check out about Diverse System Tokyo, Japan
Preliminary research suggests that pervasive tobacco waste may be detrimental to our natural environment. Chemicals released from remnants of the tobacco in cigarette butts have the potential to pollute aquatic ecosystems and harm organisms [14,15,16]. Both smoked and un-smoked cigarettes demonstrate the potential for rapid and prolonged metal contamination of the immediate environment in which they are discarded: in a laboratory study, both released numerous heavy metals into water [15]. Likewise, other research found that one cigarette butt soaked in a liter of water killed half of the fish exposed [14].
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A recent observation brings RORγt back full circle to its original description as a cousin of the melatonin receptors RORα and RORβ.6, 7, 8 RORγ is a component of the transcriptional network of peripheral circadian clocks,26, 27 which regulates the transcription factor Nfil3, which in turn represses the expression of RORγt.28 Deregulation of the circadian clock thus leads to a deregulation of Th17 cells and increased susceptibility to inflammatory pathology. Finally, and no less intriguing, cholesterol metabolites are natural ligands of RORγt,29, 30 possibly linking type 3 immunity to the endocrine system and metabolism, even though the biology of these ligands remains to be understood.
Given their common dependence on RORγt and their similar cytokine profiles, LTi cells and NK22 cells were grouped together as ILC3s, whereas lymphoid cells that produce the type 2 cytokines IL-4, IL-5, and IL-13 were grouped as ILC2s, and those that produce IFNγ as ILC1s.23, 24 A difficulty arose when it was found that ILC3s can downregulate RORγt and upregulate T-bet to produce IFNγ in a context of intense inflammation.52 These cells were termed ex-ILC3s. Another form of ILC3 plasticity was found in vitro using human ILC lines. When stimulated through TLR2, such lines expressed IL-5 and IL-13 in addition to IL-22.53 It remains to be assessed to what extent such plasticity is operational in vivo, underlying for example the rapid response of ILCs to diverse types of tissue perturbations.
RORγt has turned out to be an extraordinary nuclear receptor and transcription factor, which controls type 3 immunity, a critical branch of immune responses that contains the symbiotic microbiota at mucosal surfaces and fights bacterial and fungal pathogens, but also leads to autoimmunity and cancer. The links between RORγt, oxysterols, and clock genes makes RORγt a potential node connecting immunity with metabolism and circadian rhythms. The biology of RORγt blossoms at an exciting time as immunology expands into a more transversal field of research connecting different physiological systems.
Vitamin D production in the skin under the influence of sunlight (UVB) is maximized at levels of sunlight exposure that do not burn the skin. Further metabolism of vitamin D to its major circulating form (25(OH)D) and hormonal form (1,25(OH)2D) takes place in the liver and kidney, respectively, but also in other tissues where the 1,25(OH)2D produced serves a paracrine/autocrine function: examples include the skin, cells of the immune system, parathyroid gland, intestinal epithelium, prostate, and breast. Parathyroid hormone, FGF23, calcium and phosphate are the major regulators of the renal 1-hydroxylase (CYP27B1, the enzyme producing 1,25(OH)2D); regulation of the extra renal 1-hydroxylase differs from that in the kidney and involves cytokines. The major enzyme that catabolizes 25(OH)D and 1,25(OH)2D is the 24-hydroxylase; like the 1-hydroxylase it is tightly controlled in the kidney in a manner opposite to that of the 1-hydroxylase, but like the 1-hydroxylase it is widespread in other tissues where its regulation is different from that of the kidney. Vitamin D and its metabolites are carried in the blood bound to vitamin D binding protein (DBP) and albumin--for most tissues it is the free (i.e., unbound) metabolite that enters the cell; however, DBP bound metabolites can enter some cells such as the kidney and parathyroid gland through a megalin/cubilin mechanism. Most but not all actions of 1,25(OH)2D are mediated by the vitamin D receptor (VDR). VDR is a transcription factor that partners with other transcription factors such as retinoid X receptor that when bound to 1,25(OH)2D regulates gene transcription either positively or negatively depending on other cofactors to which it binds or interacts. The VDR is found in most cells, not just those involved with bone and mineral homeostasis (i.e., bone, gut, kidney) resulting in wide spread actions of 1,25(OH)2D on most physiologic and pathologic processes. Animal studies indicate that vitamin D has beneficial effects on various cancers, blood pressure, heart disease, immunologic disorders, but these non-skeletal effects have been difficult to prove in humans in randomized controlled trials. Analogs of 1,25(OH)2D are being developed to achieve specificity for non-skeletal target tissues such as the parathyroid gland and cancers to avoid the hypercalcemia resulting from 1,25(OH)2D itself. The level of vitamin D intake and achieved serum levels of 25(OH)D that are optimal and safe for skeletal health and the non-skeletal actions remain controversial, but are likely between an intake of 800-2000IU vitamin D in the diet and 20-50ng/ml 25(OH)D in the blood. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
Nutritional vitamin D deficiency, altered vitamin D responsiveness such as vitamin D receptor mutations (hereditary vitamin D resistant rickets), and deficient production of 1,25(OH)2D such as mutations in the CYP27B1 gene (pseudo vitamin D deficiency) all have rickets as their main phenotype. This would suggest that vitamin D, and in particular 1,25(OH)2D, is of critical importance to bone. Furthermore, VDR are found in bone cells (238,239), and vitamin D metabolites have been shown to regulate many processes in bone. However, the rickets resulting from vitamin D deficiency or VDR mutations (or knockouts) can be corrected by supplying adequate amounts of calcium and phosphate either by infusions or orally [214-217]. Moreover, deletion of VDR from bone cells does not result in rickets (240). This would suggest either that vitamin D metabolites do not directly impact bone, or that substantial redundancy has been built into the system. However, arguing for a physiologically non-redundant direct action of vitamin D on bone is the development of osteoporosis and decreased bone formation in these VDR or CYP27B1 null mice not corrected by the high calcium/phosphate diet (241). A further complicating factor in determining the role of vitamin D metabolites in bone is the multitude of effects these metabolites have on systemic calcium homeostatic mechanisms which themselves impact on bone. The lack of vitamin D results in hypocalcemia and hypophosphatemia that as implied above is sufficient to cause rickets. Moreover, part of the skeletal phenotype in vitamin D deficiency is also due to the hyperparathyroidism that develops in the vitamin D deficient state as PTH has its own actions on bone and cartilage. Furthermore, within bone the vitamin D metabolites can alter the expression and/or secretion of a large number of skeletally derived factors including insulin like growth factor-1 (IGF-I) (242), its receptor (243), and binding proteins (244,245), transforming growth factor β (TGFβ) (246), vascular endothelial growth factor (VEGF) (247), interleukin-6 (IL-6) (248), IL-4 (249), and endothelin receptors (250) all of which can exert effects on bone of their own as well as modulate the actions of the vitamin D metabolites on bone. Understanding the impact of vitamin D metabolites on bone is additionally complicated by species differences, differences in responsiveness of bone and cartilage cells according to their states of differentiation, and differences in responsiveness in terms of the vitamin D metabolite being examined. Thus, the study of vitamin D on bone has had a complex history, and uncertainty remains as to how critical the direct actions of the vitamin D metabolites on bone are for bone formation and resorption.
The adaptive immune response is initiated by cells specialized in antigen presentation, DC and macrophages in particular, activating the cells responsible for subsequent antigen recognition, T and B lymphocytes. These cells are capable of a wide repertoire of responses that ultimately determine the nature and duration of the immune response. Activation of T and B cells occurs after a priming period in tissues of the body, e.g., lymph nodes, distant from the site of the initial exposure to the antigenic substance, and is marked by proliferation of the activated T and B cells accompanied by post translational modifications of immunoglobulin production that enable the cellular response to adapt specifically to the antigen presented. Importantly, the type of T cell activated, CD4 or CD8, or within the helper T cell class Th1, Th2, Th17, Treg, and subtle variations of those, is dependent on the context of the antigen presented by which cell and in what environment. Systemic factors such as vitamin D influence this process. Vitamin D in general exerts an inhibitory action on the adaptive immune system. 1,25(OH)2D3 decreases the maturation of DC as marked by inhibited expression of the costimulatory molecules HLA-DR, CD40, CD80, and CD86, decreasing their ability to present antigen and so activate T cells (421). Furthermore, by suppressing IL-12 production, important for Th1 development, and IL-23 and IL-6 production important for Th17 development and function, 1,25(OH)2D3 inhibits the development of Th1 cells capable of producing IFN-γ and IL-2, and Th17 cells producing IL-17 (422). These actions prevent further antigen presentation to and recruitment of T lymphocytes (role of IFN-γ), and T lymphocyte proliferation (role of IL-2). Suppression of IL-12 increases the development of Th2 cells leading to increased IL-4, IL-5, and IL-13 production, which further suppresses Th1 development shifting the balance to a Th2 cell phenotype. Treatment of DCs with 1,25(OH)2D3 can also induce CD4+/CD25+ regulatory T cells (Treg) cells (423) as shown by increased FoxP3 expression, critical for Treg development. These cells produce IL-10, which suppresses the development of the other Th subclasses. Treg are critical for the induction of immune tolerance (424). In addition, 1,25(OH)2D3 alters the homing of properties of T cells for example by inducing expression of CCR10, the receptor for CCL27, a keratinocyte specific cytokine, while suppressing that of CCR9, a gut homing receptor (425). The actions of 1,25(OH)2D3 on B cells have received less attention, but recent studies have demonstrated a reduction in proliferation, maturation to plasma cells and immunoglobulin production (426).
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