Cannabinoids help to unravel etiological aspects in common and bring hope for the treatment of autism and epilepsy

Desde 1843 que as propriedades anticonvulsivantes da Cannabis são conhecidas pela ciência ocidental. Em 1980, ensaios clínicos demonstraram que canabidiol possui atividade antiepilética em pacientes de epilepsia refratária, sendo sonolência o único efeito colateral. O embargo imposto pela proibição do uso medicinal da Cannabis, no entanto, prejudicou imensamente o desenvolvimento científico e a exploração dessas propriedades. Multiplicam-se, contudo, os casos bem sucedidos de uso ilegal e sem orientação para o tratamento de síndromes caracterizadas por epilepsia e autismo regressivo. Os resultados corroboram evidências científicas que indicam a existência de processos etiológicos comuns entre o autismo e a epilepsia. Estudos em modelos animais confirmam envolvimento do sistema endocanabinoide. Esses avanços apontam o início de uma revolução no entendimento e tratamento desses transtornos.Since 1843 the anticonvulsant properties of Cannabis are known by the Western science. In 1980, clinical trials have shown that cannabidiol has antiepileptic activity in refractory epilepsy patients, with drowsiness as the only side effect. The embargo imposed by banning medicinal Cannabis use, however, harmed scientific development and the exploration of these properties. However, there is a growing number of successful cases of illegal use without guidance for the treatment of syndromes characterized by epilepsy and regressive autism. The results corroborate scientific evidence that indicates the existence of common etiological aspects between autism and epilepsy. Studies in animal models have confirmed involvement of the endocannabinoid system. These advances indicate the beginning of a revolution in the understanding and treatment of these disorders

Kenya: West Kenya postmarks

HiWATER: The Multi-Scale Observation Experiment on Evapotranspiration over heterogeneous land surfaces (MUSOEXE) Dataset - Flux Observation Matrix (stable isotopic observations

The time-depth of Corded Ware burial landscapes: A comparative study of Single Grave and Battle Axe burial alignments in Denmark, The Netherlands and Sweden

Barrow landscapes appeared in the third and second millennia BC throughout North-Western Europe; these first barrows were constructed by people of the Corded Ware culture and placed in alignments. This thesis is an interregional comparative study, to determine whether there is a pattern in the time-depths of the burial alignments of Trehuse-Sjørup-Dollerup in Denmark, Angelso-Emmerhout in The Netherlands and Lilla Beddinge in Sweden. The analysis is conducted by means of a literature study and the application of typochronologies. In recent research, the Corded Ware ‘culture’ is still seen as a widespread, unified social phenomenon that is the result of migration, but more emphasis is placed on the regional variability of this phenomenon. Regional variability is also what we see in the three case-studies; in fact, perhaps one may better speak of ‘local variability’, as each case-study reveals a remarkable variety even within one alignment. Even though there do seem to be interregionally shared traits, these are expressed in local practices. Despite the limitations of establishing a time-depth by means of typochronologies, all three alignments reveal a long use-life; even in the Bronze and Iron Ages, prehistoric people buried their dead here. Temporality seems to have been an important aspect of the ‘Corded Ware’ burial landscape

Collaborative mental health care : changing the landscape of mental health care?

In this thesis two major changes in the organization of mental health care delivery are explored. The first is collaborative mental health care in primary care, developed as an alternative way to treat common mental health disorders compared to the traditional referral and treatment practice. The collaborative care program followed the principles of stepped care. The first and least intensive treatment step was provided within the collaborative care program in the primary care setting. Treatment intensity was only stepped up through referral to specialized mental health care for patients who did not sufficiently respond to the first step. The traditional practice was direct referral and treatment within specialized care. In several studies we investigated effectiveness, short- and long-term efficiency, cost-effectiveness and whether the stepped care approach was appropriate for all patients instead of the matched care approach. The second change was the integration of eHealth in the collaborative care treatment model. In this study, implementation factors that could either inhibit or promote the uptake and utilization of blended collaborative care by mental health professionals and patients were assessed

An Efficient Synthesis of the Fully Elaborated Isoindolinone Unit of Muironolide A

An efficient stereocontrolled construction of the fully substituted isoindolone subunit of muironolide A is described. The approach is centered on the intramolecular Diels–Alder reaction between the enol form of the <b>β</b>-keto amide and an <b>α</b>,<b>β</b>,<b>γ</b>,<b>δ</b>-unsaturated ester, followed by the installation of the cyclohexene double bond

An Efficient Synthesis of the Fully Elaborated Isoindolinone Unit of Muironolide A

An efficient stereocontrolled construction of the fully substituted isoindolone subunit of muironolide A is described. The approach is centered on the intramolecular Diels–Alder reaction between the enol form of the <b>β</b>-keto amide and an <b>α</b>,<b>β</b>,<b>γ</b>,<b>δ</b>-unsaturated ester, followed by the installation of the cyclohexene double bond

Total Synthesis and Structural Revision of (+)-Muironolide A

Muironolide A is a fascinating tetrachlorinated marine polyketide isolated from the sponge of <i>Phorbas</i> sp. Only 90 μg had been isolated, and the structure was established by nanoscale NMR techniques. Herein we report the total synthesis of the substance with the assigned structure of muironolide A, propose a revised structure based on NMR data, and complete the enantioselective total synthesis of muironolide A

Specificity Profiling of Protein Phosphatases toward Phosphoseryl and Phosphothreonyl Peptides

A combinatorial library method was developed to systematically profile the substrate specificity of protein phosphatases toward phosphoseryl (pS) and phosphothreonyl (pT) peptides. Application of this method and a previously reported phosphotyrosyl (pY) library screening technique to dual-specificity phosphatase (DUSP) VH1 of vaccinia virus revealed that VH1 is highly active toward both pS/pT and pY peptides. VH1 exhibits different and more stringent sequence specificity toward pS/pT than pY substrates. Unlike previously characterized protein tyrosine phosphatases (PTPs), the activity and specificity of VH1 are primarily determined by the amino acid residues C-terminal to the pS, pT, or pY residue. In contrast, the mammalian VH1-related (VHR) DUSP has intrinsically low catalytic activity toward pS and pT substrates, suggesting that its primary physiological function is to dephosphorylate pY residues in substrate proteins. This method is applicable to other DUSPs and protein-serine/threonine phosphatases, and the substrate specificity data will be useful for identifying the physiological substrates of these enzymes

1,4-Diazabicyclo[2.2.2]octane-Promoted Aminotrifluoromethylthiolation of α,β-Unsaturated Carbonyl Compounds: <i>N-</i>Trifluoromethylthio-4-nitrophthalimide Acts as Both the Nitrogen and SCF₃ Sources

A novel difunctionalization reaction is described. It uses <i>N</i>-trifluoromethylthio-4-nitrophthalimide as the reagent, which serves as both the nitrogen and SCF₃ sources. In the presence of DABCO (1,4-diazabicyclo[2.2.2]­octane), the nitrogen and SCF₃ groups can be incorporated into α,β-unsaturated carbonyl compounds easily and give versatile β-amino ketones and esters in good yields. This difunctionalization reaction features mild reaction conditions, high atom-economy, and efficient access to α-SCF₃ amino acids

Antidiabetic Disruptors of the Glucokinase−Glucokinase Regulatory Protein Complex Reorganize a Coulombic Interface

The glucokinase regulatory protein (GKRP) plays an essential role in glucose homeostasis by acting as a competitive inhibitor of glucokinase (GCK) and triggering its localization to the hepatocyte nucleus upon glucose deprivation. Metabolites such as fructose 6-phosphate and sorbitol 6-phosphate promote assembly of the GCK–GKRP complex, whereas fructose 1-phosphate and functionalized piperazines with potent in vivo antidiabetic activity disrupt the complex. Here, we establish the molecular basis by which these natural and synthetic ligands modulate the GCK–GKRP interaction. We demonstrate that a small-molecule disruptor of the protein–protein interaction utilizes a two-step conformational selection mechanism to associate with a rare GKRP conformation constituting 3% of the total population. Conformational heterogeneity of GKRP is localized to the N-terminus and deleting this region eliminates the ability of sorbitol 6-phosphate to promote the GCK–GKRP interaction. Stabilizing ligands favor an extended N-terminus, which sterically positions two arginine residues for optimal Coulombic interaction with a pair of carboxylate side chains from GCK. Conversely, disruptors promote a more compact N-terminus in which an interfacial arginine residue is stabilized in an unproductive orientation through a cation-π interaction with tyrosine 75. Eliminating the ability to sample this binding impaired conformation enhances the intrinsic inhibitory activity of GKRP. Elucidating the molecular basis of ligand-mediated control over the GCK–GKRP interaction is expected to impact the development and future refinement of therapeutic agents for diabetes and cardiovascular disease, which result from improper GKRP regulation of GCK