Most evidence indicates that, as for family C G protein-coupled receptors (GPCRs), family A GPCRs form homo- and heteromers. Homodimers seem to be a predominant species, with potential dynamic ...formation of higher-order oligomers, particularly tetramers. Although monomeric GPCRs can activate G proteins, the pentameric structure constituted by one GPCR homodimer and one heterotrimeric G protein may provide a main functional unit, and oligomeric entities can be viewed as multiples of dimers. It still needs to be resolved if GPCR heteromers are preferentially heterodimers or if they are mostly constituted by heteromers of homodimers. Allosteric mechanisms determine a multiplicity of possible unique pharmacological properties of GPCR homomers and heteromers. Some general mechanisms seem to apply, particularly at the level of ligand-binding properties. In the frame of the dimer-cooperativity model, the two-state dimer model provides the most practical method to analyze ligand-GPCR interactions when considering receptor homomers. In addition to ligand-binding properties, unique properties for each GPCR oligomer emerge in relation to different intrinsic efficacy of ligands for different signaling pathways (functional selectivity). This gives a rationale for the use of GPCR oligomers, and particularly heteromers, as novel targets for drug development. Herein, we review the functional and pharmacological properties of GPCR oligomers and provide some guidelines for the application of discrete direct screening and high-throughput screening approaches to the discovery of receptor-heteromer selective compounds.
Let A/\mathbb{Q} be an abelian variety of dimension g\geq 1 that is isogenous over \overline {\mathbb{Q}} to E^g, where E is an elliptic curve. If E does not have complex multiplication (CM), by ...results of Ribet and Elkies concerning fields of definition of elliptic \mathbb{Q}-curves, E is isogenous to a curve defined over a polyquadratic extension of \mathbb{Q}. We show that one can adapt Ribet's methods to study the field of definition of E up to isogeny also in the CM case. We find two applications of this analysis to the theory of Sato-Tate groups: First, we show that 18 of the 34 possible Sato-Tate groups of abelian surfaces over \mathbb{Q} occur among at most 51 \overline {\mathbb{Q}}-isogeny classes of abelian surfaces over \mathbb{Q}. Second, we give a positive answer to a question of Serre concerning the existence of a number field over which abelian surfaces can be found realizing each of the 52 possible Sato-Tate groups of abelian surfaces.
We introduce a tensor decomposition of the
ℓ
-adic Tate module of an abelian variety
A
0
defined over a number field which is geometrically isotypic. If
A
0
is potentially of
GL
2
-type and defined ...over a totally real number field, we use this decomposition to describe its Sato–Tate group and to prove the Sato–Tate conjecture in certain cases.
More than 20 years after the identification of the sigma receptors as a unique binding site in the brain and in the peripheral organs, several questions regarding this receptor are still open. Only ...one of the subtypes of the receptor has been cloned to date, but the endogenous ligand still remains unknown, and the possible association of the receptor with a conventional second messenger system is controversial. From the very beginning, the sigma receptors were associated with various central nervous system disorders such as schizophrenia or movement disorders. Today, after hundreds of papers dealing with the importance of sigma receptors in brain function, it is widely accepted that sigma receptors represent a new and different avenue in the possible pharmacological treatment of several brain-related disorders. In this review, what is known about the biology of the sigma receptor regarding its putative structure and its distribution in the central nervous system is summarized first. The role of sigma receptors regulating cellular functions and other neurotransmitter systems is also addressed, as well as a short overview of the possible endogenous ligands. Finally, although no specific sigma ligand has reached the market, different pharmacological approaches to the alleviation and treatment of several central nervous system disorders and deficits, including schizophrenia, pain, memory deficits, etc., are discussed, with an overview of different compounds and their potential therapeutic use.
Objective
The first aim was to demonstrate a previously hypothesized increased sensitivity of corticostriatal glutamatergic terminals in the rodent with brain iron deficiency (BID), a pathogenetic ...model of restless legs syndrome (RLS). The second aim was to determine whether these putative hypersensitive terminals could constitute a significant target for drugs effective in RLS, including dopamine agonists (pramipexole and ropinirole) and α2δ ligands (gabapentin).
Methods
A recently introduced in vivo optogenetic–microdialysis approach was used, which allows the measurement of the extracellular concentration of glutamate upon local light‐induced stimulation of corticostriatal glutamatergic terminals. The method also allows analysis of the effect of local perfusion of compounds within the same area being sampled for glutamate.
Results
BID rats showed hypersensitivity of corticostriatal glutamatergic terminals (lower frequency of optogenetic stimulation to induce glutamate release). Both hypersensitive and control glutamatergic terminals were significant targets for locally perfused pramipexole, ropinirole, and gabapentin, which significantly counteracted optogenetically induced glutamate release. The use of selective antagonists demonstrated the involvement of dopamine D4 and D2 receptor subtypes in the effects of pramipexole.
Interpretation
Hypersensitivity of corticostriatal glutamatergic terminals can constitute a main pathogenetic mechanism of RLS symptoms. Selective D4 receptor agonists, by specifically targeting these terminals, should provide a new efficient treatment with fewer secondary effects. Ann Neurol 2017;82:951–960
Background
Cardiovascular outcomes trials (CVOTs) have assessed the effects of glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) on major adverse cardiovascular events (MACE) and mortality in ...high cardiovascular (CV) risk populations. Observational research can provide complementary evidence about these effects in unselected populations.
Aim
To systematically review retrospective observational cohort studies conducted in electronic healthcare databases (EHDs) assessing GLP‐1 RAs´ effects on MACE and/or hospitalisation for heart failure (HHF) and/or all‐cause mortality in Type 2 diabetes mellitus (T2DM) patients.
Methods
We systematically searched studies meeting inclusion criteria, compared design, methods and population characteristics, assessed risk for bias and did a meta‐analysis (MA) using a random‐effects model to calculate overall hazard ratios (HRs) and 95% CI (confidence intervals).
Results
Sixteen studies included 285,436 T2DM patients exposed to GLP‐1 RAs (exenatide bid, liraglutide, lixisenatide, long‐acting exenatide), n ranged from 219 to 160,803 patients. Comparators included: no exposure, other antidiabetic medications (OADs), combined OADs, canagliflozin or multiple comparators. Ten studies estimated all‐cause mortality, hazard ratios (HRs) ranged from 0.17 (95% CI 0.02‐1.22) to 1.29 (95% CI 0.54‐3.13). Thirteen studies assessed cardiovascular events and/or MACE; HRs ranged from 0.27 (95% CI 0.14‐0.53) to 1.11 (95% CI 0.99‐1.24). Eight studies assessed HHF, HRs ranged from 0.12 (95% CI 0.02‐0.66) to 1.64 (95% CI 1.28‐2.13). Excluding two studies because of temporal bias, we obtained pooled estimates for all‐cause mortality: HR 0.63 (0.44‐0.89), CV outcomes HR 0.84 (0.75‐0.94) and HHF; HR 0.94 (0.78‐1.14), (high between‐study variability: I2 = 83.35%; I2 = 70.3%; and I2 = 90.1%, respectively).
Conclusion
Pooled results of EHDs’ studies assessing GLP‐1 RAs effects favoured GLP‐1 RAs for all‐cause mortality and MACE while were neutral for HHF. Results should be interpreted cautiously because of studies’ substantial heterogeneity and limitations of observational research.
We extend the algorithm of Darmon-Green and Darmon-Pollack for computing p \Gamma _1({\mathfrak{N}}) {\mathfrak{N}}-integers. We use these extensions to provide additional evidence in support of the ...conjectures on the rationality of Darmon points.
Drug provocation tests (DPT) are considered the gold standard procedure to ascertain the diagnosis of beta-lactam (BL) allergy. Regarding route of administration, current recommendations prioritize ...oral challenges, considering them safer, and reserving the intravenous route for drugs for which this is the only formulation.
To compare in terms of tolerance and safety two protocols of BL DPT, using an oral protocol (OR-DPT) and an intravenous protocol (IV-DPT).
A descriptive, retrospective study was performed, including adult patients who underwent IV-DPT or OR-DPT for suspected immediate or delayed hypersensitivity to BL antibiotics, over a period of 4 years (between January 2018 and December 2021). Demographical data, index hypersensivity reactions’ characteristics and tolerance to DPT were reviewed.
A total of 1036 patients underwent DPT, mean age of 56.8 (standard deviation, SD, 17.8) years, 655 were women (63.2%). Immediate drug hypersensitivity reactions (DHR) had occurred in 564 of patients (54.4%). OR-DPT were performed in 439 (42.4%) and IV-DPT in 597 (57.6%). The frequency of reactions during DPT, regardless of the route used, was low (3.6%): only 16 (3.6%) in OR-DPT and 21 (3.5%) in IV-DPT. From IV-DPT, 16 out 21 DHR during DPT were immediate compared with 4 out of 16 in OR-DPT. Adjusted relative risk of developing a hypersensitivity reaction during IV-DPT versus OR-DPT was 1.13 (95% confidence interval (CI)0.57–2.22).
The results suggest that OR-DPT and IV-DPT are both safe procedures when adequately performed. However, IV-DPT protocols showed a higher rate of immediate DHR during DPT probably due to the selection of basal high-risk patients to undergo IV-DPT. In conclusion, IV-DPT may be considered as an option for challenges in drug-allergy studies, entailing a precise administration.
The symptomatology of Restless Legs Syndrome (RLS) includes periodic leg movements during sleep (PLMS), dysesthesias, and hyperarousal. Alterations in the dopaminergic system, a presynaptic ...hyperdopaminergic state, seem to be involved in PLMS, while alterations in glutamatergic neurotransmission, a presynaptic hyperglutamatergic state, seem to be involved in hyperarousal and also PLMS. Brain iron deficiency (BID) is well-recognized as a main initial pathophysiological mechanism of RLS. BID in rodents have provided a pathogenetic model of RLS that recapitulates the biochemical alterations of the dopaminergic system of RLS, although without PLMS-like motor abnormalities. On the other hand, BID in rodents reproduces the circadian sleep architecture of RLS, indicating the model could provide clues for the hyperglutamatergic state in RLS. We recently showed that BID in rodents is associated with changes in adenosinergic transmission, with downregulation of adenosine A
receptors (A1R) as the most sensitive biochemical finding. It was hypothesized that A1R downregulation leads to hypersensitive striatal glutamatergic terminals and facilitation of striatal dopamine release. Hypersensitivity of striatal glutamatergic terminals was demonstrated by an optogenetic-microdialysis approach in the rodent with BID, indicating that it could represent a main pathogenetic factor that leads to PLMS in RLS. In fact, the dopaminergic agonists pramipexole and ropinirole and the α
δ ligand gabapentin, used in the initial symptomatic treatment of RLS, completely counteracted optogenetically-induced glutamate release from both normal and BID-induced hypersensitive corticostriatal glutamatergic terminals. It is a main tenet of this essay that, in RLS, a single alteration in the adenosinergic system, downregulation of A1R, disrupts the adenosine-dopamine-glutamate balance uniquely controlled by adenosine and dopamine receptor heteromers in the striatum and also the A1R-mediated inhibitory control of glutamatergic neurotransmission in the cortex and other non-striatal brain areas, which altogether determine both PLMS and hyperarousal. Since A1R agonists would be associated with severe cardiovascular effects, it was hypothesized that inhibitors of nucleoside equilibrative transporters, such as dipyridamole, by increasing the tonic A1R activation mediated by endogenous adenosine, could represent a new alternative therapeutic strategy for RLS. In fact, preliminary clinical data indicate that dipyridamole can significantly improve the symptomatology of RLS.
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