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Why Does a Responsible Climate Action AI Need the Arts and Humanities?
Get PDFCambridge University’s Ramit Debnath explores the potential of Responsible AI (RAI) in addressing global challenges, and explains why social sciences, philosophy, the arts and humanities have a critical role to play in shaping AI system design and presenting us with the best chance of securing a sustainable planetary future
New Ways of Seeing, New Ways of Acting
Get PDFThis Edition Two of The New Real Magazine has traced an ambitious journey: from creating simple digital tools for environmental engagement to developing new ways for humans and AI to collaborate in understanding planetary change. Through The New Real Observatory and the artworks it enabled, we\u27ve seen how artificial intelligence might help us bridge the gap between environmental data and lived experience
Histamine receptors in GtoPdb v.2025.3
Get PDFHistamine receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Histamine Receptors [82, 176]) are activated by the endogenous ligand histamine. Marked species differences exist between histamine receptor orthologues [82]. The human and rat H3 receptor genes are subject to significant splice variance [12]. The potency order of histamine at histamine receptor subtypes is H3 = H4 > H2 > H1 [176]. Some agonists at the human H3 receptor display significant ligand bias [185]. Antagonists of all 4 histamine receptors have clinical uses: H1 antagonists for allergies (e.g. cetirizine), H2 antagonists for acid-reflux diseases (e.g. ranitidine), H3 antagonists for narcolepsy (e.g. pitolisant/WAKIX; Registered) and H4 antagonists for atopic dermatitis (e.g. adriforant; Phase IIa) [176] and vestibular neuritis (AUV) (SENS-111 (Seliforant, previously UR-63325), entered and completed vestibular neuritis (AUV) Phase IIa efficacy and safety trials, respectively) [219, 8]. Histamine receptor photopharmacology has provided both agonist and antagonist tools to achieve optical control over H3 receptor function. The best-characterized agonist is VUF15000, an azobenzene-containing compound in which the trans-isomer binds the H3 receptor with nanomolar affinity (Ki = 4 nM) and behaves as a full agonist. Its cis-isomer is approximately 10-fold less active, thereby creating a reversible light-controlled switch for receptor activation that has been validated in binding, NanoBRET biosensor, and electrophysiology assays [78]. Also several photoswitchable antagonists have been established as tools for histamine H3 receptor photopharmacology. The first-generation azobenzene-based antagonists included VUF14738 and VUF14862, which are part of a bidirectional toolbox [77]. VUF14738 (trans: Ki = 631 nM) shows a light-induced 10-fold increase in affinity, while VUF14862 (trans: Ki = 1.6 nM) displays the opposite, with more than a tenfold change upon illumination. Both compounds are highly fatigue-resistant, underwent rapid trans-cis isomerization, and had long thermal half-lives, allowing reversible optical control in binding and electrophysiological assays. Building on these scaffolds, recently 2nd generation ligands were developed to overcome limitations of azobenzenes [18]. The arylazopyrazole-based antagonist VUF26063 displayed subnanomolar affinity at the H3 receptor in its trans isomer (Ki = 0.5 nM) and a 50-fold lower affinity in the cis state. This compound showed robust switching with high photostationary state efficiency and improved aqueous solubility compared to earlier analogues. Importantly, radiolabeling yielded [3H]VUF26063, the first radiolabeled photoswitchable GPCR ligand, enabling the direct study of ligand binding kinetics and photoisomerization inside the receptor pocket in real time. These antagonists, together with the agonist VUF15000, provide a well-characterized toolkit of photosensitive ligands that can be used to dissect H3 receptor pharmacology with spatiotemporal precision
Prostanoid receptors in GtoPdb v.2025.3
Get PDFProstanoid receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Prostanoid Receptors [709]) are activated by the endogenous ligands prostaglandins PGD2, PGE1, PGE2 , PGF2α, PGH2, prostacyclin [PGI2] and thromboxane A2. Differences and similarities between human and rodent prostanoid receptor orthologues, and their specific roles in pathophysiologic conditions are reviewed in [457]. Measurement of the potency of PGI2 and thromboxane A2 is hampered by their instability in physiological salt solution; they are often replaced by cicaprost and U46619, respectively, in receptor characterization studies
P2X receptors in GtoPdb v.2025.3
Get PDFP2X receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2X Receptors [49, 150]) have a trimeric topology [121, 132, 148, 201] with two putative TM domains per P2X subunit, gating primarily Na+, K+ and Ca2+, exceptionally Cl-. The Nomenclature Subcommittee has recommended that for P2X receptors, structural criteria should be the initial basis for nomenclature where possible. X-ray crystallography indicates that functional P2X receptors are trimeric and three agonist molecules are required to bind to a single trimeric assembly in order to activate it [121, 148, 97, 105, 181]. Native receptors may occur as either homotrimers (e.g. P2X1 in smooth muscle) or heterotrimers (e.g. P2X2:P2X3 in the nodose ganglion [284], P2X1:P2X5 in mouse cortical astrocytes [166], and P2X2:P2X5 in mouse dorsal root ganglion, spinal cord and mid pons [53, 238]. P2X2, P2X4 and P2X7 receptor activation can lead to influx of large cationic molecules, such as NMDG+, Yo-Pro, ethidium or propidium iodide [215]. The permeability of the P2X7 receptor is modulated by the amount of cholesterol in the plasma membrane [197]. The hemi-channel pannexin-1 was initially implicated in the action of P2X7 [216], but not P2X2, receptors [41], but this interpretation is probably misleading [219]. Convincing evidence now supports the view that the activated P2X7 receptor is immediately permeable to large cationic molecules, but influx proceeds at a much slower pace than that of the small cations Na+, K+, and Ca2+ [67]
SLC6 neurotransmitter transporter family in GtoPdb v.2025.3
No full textMembers of the solute carrier family 6 (SLC6) of sodium- and (sometimes chloride-) dependent neurotransmitter transporters [32, 2, 23, 76] are primarily plasma membrane located and may be divided into four subfamilies that transport monoamines, GABA, glycine and neutral amino acids, plus the related bacterial NSS transporters [110]. The members of this superfamily share a structural motif of 10 TM segments that has been observed in crystal structures of the NSS bacterial homolog LeuTAa, a Na+-dependent amino acid transporter from Aquiflex aeolicus [139] and in several other transporter families structurally related to LeuT [49]
SLC15 family of peptide transporters in GtoPdb v.2025.3
Get PDFThe Solute Carrier 15 (SLC15) family of peptide transporters, alias H+-coupled oligopeptide cotransporter family, is a group of membrane transporters known for their key role in the cellular uptake of di- and tripeptides (di/tripeptides). Of its members, SLC15A1 (PEPT1) chiefly mediates intestinal absorption of luminal di/tripeptides from overall dietary protein digestion, SLC15A2 (PEPT2) mainly allows renal tubular reuptake of di/tripeptides from ultrafiltration and brain-to-blood efflux of di/tripeptides in the choroid plexus, SLC15A3 (PHT2) and SLC15A4 (PHT1) interact with both di/tripeptides and histidine, e.g. in certain immune cells, and SLC15A5 has unknown physiological function. In addition, the SLC15 family of peptide transporters variably interacts with a very large number of peptidomimetics and peptide-like drugs. It is conceivable, based on the currently acknowledged structural and functional differences, to divide the SLC15 family of peptide transporters into two subfamilies [3]
Ceramide turnover in GtoPdb v.2025.3
Get PDFCeramides are a family of sphingophospholipids synthesized in the endoplasmic reticulum, which mediate cell stress responses, including apoptosis, autophagy and senescence, Serine palmitoyltransferase generates 3-ketosphinganine, which is reduced to dihydrosphingosine. N-Acylation allows the formation of dihydroceramides, which are subsequently reduced to form ceramides. Once synthesized, ceramides are trafficked from the ER to the Golgi bound to the ceramide transfer protein, CERT (COL4A3BP, Q9Y5P4). Ceramide can be metabolized via multiple routes, ensuring tight regulation of its cellular levels. Addition of phosphocholine generates sphingomyelin while carbohydrate is added to form glucosyl- or galactosylceramides. Ceramidase re-forms sphingosine or sphinganine from ceramide or dihydroceramide. Phosphorylation of ceramide generates ceramide phosphate. The determination of accurate kinetic parameters for many of the enzymes in the sphingolipid metabolic pathway is complicated by the lipophilic nature of the substrates
Endocannabinoid turnover in GtoPdb v.2025.3
Get PDFThe principle endocannabinoids are 2-acylglycerol esters, such as 2-arachidonoylglycerol (2-AG), and N-acylethanolamines, such as anandamide (N-arachidonoylethanolamine, AEA). The glycerol esters and ethanolamides are synthesised and hydrolysed by parallel, independent pathways. Mechanisms for release and re-uptake of endocannabinoids are unclear, although potent and selective inhibitors of facilitated diffusion of endocannabinoids across cell membranes have been developed [32]. FABP5 (Q01469) has been suggested to act as a canonical intracellular endocannabinoid transporter in vivo [19]. For the generation of 2-arachidonoylglycerol, the key enzyme involved is diacylglycerol lipase (DAGL), whilst several routes for anandamide synthesis have been described, the best characterized of which involves N-acylphosphatidylethanolamine-phospholipase D (NAPE-PLD, [79]). A transacylation enzyme which forms N-acylphosphatidylethanolamines has been identified as a cytosolic enzyme, PLA2G4E (Q3MJ16) [70]. In vitro experiments indicate that the endocannabinoids are also substrates for oxidative metabolism via cyclooxygenase, lipoxygenase and cytochrome P450 enzyme activities [6, 26, 81]