| 1. |
- Abbadini, Marco, et al.
(author)
-
DUALITY FOR COALGEBRAS FOR VIETORIS AND MONADICITY
- 2024
-
In: Journal of Symbolic Logic (JSL). - 0022-4812 .- 1943-5886.
-
Journal article (peer-reviewed)abstract
- We prove that the opposite of the category of coalgebras for the Vietoris endofunctor on the category of compact Hausdorff spaces is monadic over $\mathsf {Set}$ . We deliver an analogous result for the upper, lower, and convex Vietoris endofunctors acting on the category of stably compact spaces. We provide axiomatizations of the associated (infinitary) varieties. This can be seen as a version of Jonsson-Tarski duality for modal algebras beyond the zero-dimensional setting.
|
|
| 2. |
- Betari, Nibal, et al.
(author)
-
Discovery and biological characterization of a novel scaffold for potent inhibitors of peripheral serotonin synthesis
- 2020
-
In: Future Medicinal Chemistry. - : Future Science. - 1756-8919 .- 1756-8927. ; 12:16, s. 1461-1474
-
Journal article (peer-reviewed)abstract
- Aim: Tryptophan hydroxylase 1 (TPH1) catalyzes serotonin synthesis in peripheral tissues. Selective TPH1 inhibitors may be useful for treating disorders related to serotonin dysregulation.Results & methodology: Screening using a thermal shift assay for TPH1 binders yielded Compound1(2-(4-methylphenyl)-1,2-benzisothiazol-3(2H)-one), which showed high potency (50% inhibition at 98 +/- 30 nM) and selectivity for inhibiting TPH over related aromatic amino acid hydroxylases in enzyme activity assays. Structure-activity relationships studies revealed several analogs of1showing comparable potency. Kinetic studies suggested a noncompetitive mode of action of1, with regards to tryptophan and tetrahydrobiopterin. Computational docking studies and live cell assays were also performed.Conclusion: This TPH1 inhibitor scaffold may be useful for developing new therapeutics for treating elevated peripheral serotonin.
|
|
| 3. |
- Betari, Nibal, et al.
(author)
-
Inhibition of Tryptophan Hydroxylases and Monoamine Oxidase-A by the Proton Pump Inhibitor, Omeprazole-In Vitro and In Vivo Investigations
- 2020
-
In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 11
-
Journal article (peer-reviewed)abstract
- Serotonin (5-HT) is a hormone and neurotransmitter that modulates neural activity as well as a wide range of other physiological processes including cardiovascular function, bowel motility, and platelet aggregation. 5-HT synthesis is catalyzed by tryptophan hydroxylase (TPH) which exists as two distinct isoforms; TPH1 and TPH2, which are responsible for peripheral and central 5-HT, respectively. Due to the implication of 5-HT in a number of pathologies, including depression, anxiety, autism, sexual dysfunction, irritable bowel syndrome, inflammatory bowel disease, and carcinoid syndrome, there has been a growing interest in finding modulators of these enzymes in recent years. We thus performed high-throughput screening (HTS) using a fluorescence-based thermal shift assay (DSF) to search the Prestwick Chemical Library containing 1,280 compounds, mostly FDA-approved drugs, for TPH1 binders. We here report the identification of omeprazole, a proton pump inhibitor, as an inhibitor of TPH1 and TPH2 with low micromolar potency and high selectivity over the other aromatic amino acid hydroxylases. The S-enantiomer of omeprazole, esomeprazole, has recently also been described as an inhibitor of monoamine oxidase-A (MAO-A), the main enzyme responsible for 5-HT degradation, albeit with lower potency compared to the effect on TPH1 and TPH2. In order to investigate the net effect of simultaneous inhibition of TPH and MAO-A in vivo, we administered high-dose (100 mg/kg) omeprazole to CD-1 mice for 4 days, after which the animals were subjected to the tail suspension test. Finally, central (whole brain) and peripheral (serum) 5-HT content was measured using liquid chromatography-mass spectrometry (LC-MS). Omeprazole treatment significantly increased 5-HT concentrations, both in brain and in serum, and reduced the time spent immobile in the tail suspension test relative to vehicle control. Thus, the MAO-A inhibition afforded by high-dose omeprazole appears to overcome the opposing effect on 5-HT produced by inhibition of TPH1 and TPH2. Further modification of proton pump inhibitor scaffolds may yield more selective modulators of 5-HT metabolism.
|
|
| 4. |
- Betari, Nibal, et al.
(author)
-
Synthetic corticosteroids as tryptophan hydroxylase stabilizers
- 2021
-
In: Future Medicinal Chemistry. - : Future Science Ltd.. - 1756-8919 .- 1756-8927. ; 13:17, s. 1465-1474
-
Journal article (peer-reviewed)abstract
- Background: Clinically, corticosteroids are used mainly for their immune-modulatory properties but are also known to influence mood. Despite evidence of a role in regulating tryptophan hydroxylases (TPH), key enzymes in serotonin biosynthesis, a direct action of corticosteroids on these enzymes has not been systematically investigated.Methodology & results: Corticosteroid effects on TPHs were tested using an in vitro assay. The compound with the strongest modulatory effect, beclomethasone dipropionate, activated TPH1 and TPH2 with low micromolar potency. Thermostability assays suggested a stabilizing mechanism, and computational docking indicated that beclomethasone dipropionate interacts with the TPH active site.Conclusion: Beclomethasone dipropionate is a stabilizer of TPHs, acting as a pharmacological chaperone. Our findings may inspire further development of steroid scaffolds as putative antidepressant drugs.
|
|
| 5. |
- Campbell, James R., et al.
(author)
-
An Extended SNOMED CT Concept Model for Observations in Molecular Genetics
- 2016
-
In: AMIA Annual Symposium Proceedings. ; , s. 352-360
-
Conference paper (peer-reviewed)abstract
- Molecular genetics laboratory reports are multiplying and increasingly of clinical importance in diagnosis and treatment of cancer, infectious disease and managing of public health. Little of this data is structured or maintained in the EHR in format useful for decision support or research. Structured, computable reporting is limited by non-availability of a domain ontology for these data. The IHTSDO and Regenstrief Institute(RI) have been collaborating since 2008 to develop a unified concept model and ontology of observable entities - concepts which represent the results of laboratory and clinical observations. In this paper we report the progress we have made to apply that unified concept model to the structured recording of observations in clinical molecular genetic pathology including immunohistochemistry and sequence variant findings. The primary use case for deployment is the structured and coded reporting of Cancer checklist
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Ge, Changrong P, et al.
(author)
-
Anti-citrullinated protein antibodies cause arthritis by cross-reactivity to joint cartilage
- 2017
-
In: JCI INSIGHT. - : AMER SOC CLINICAL INVESTIGATION INC. - 2379-3708. ; 2:13
-
Journal article (peer-reviewed)abstract
- Today, it is known that autoimmune diseases start a long time before clinical symptoms appear. Anti-citrullinated protein antibodies (ACPAs) appear many years before the clinical onset of rheumatoid arthritis (RA). However, it is still unclear if and how ACPAs are arthritogenic. To better understand the molecular basis of pathogenicity of ACPAs, we investigated autoantibodies reactive against the C1 epitope of collagen type II (CII) and its citrullinated variants. We found that these antibodies are commonly occurring in RA. A mAb (ACC1) against citrullinated C1 was found to cross-react with several noncitrullinated epitopes on native CII, causing proteoglycan depletion of cartilage and severe arthritis in mice. Structural studies by X-ray crystallography showed that such recognition is governed by a shared structural motif "RG-TG" within all the epitopes, including electrostatic potential-controlled citrulline specificity. Overall, we have demonstrated a molecular mechanism that explains how ACPAs trigger arthritis.
|
|
| 9. |
|
|
| 10. |
|
|
