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

High-Throughput Synthesis and Screening of Cyclic Peptide Antibiotics

Cyclic peptides are a rich source of biologically active compounds and are produced in nature by plants, bacteria, fungi, and lower sea animals. A high-throughput methodology has been developed for the combinatorial synthesis, screening, and identification of cyclic peptide natural product analogues with improved biological activities or useful new activities. The methodology was applied to generate a library of 1716 tyrocidine A analogues, which were screened for antibacterial activity in 96-well plates. The identity of the active peptides was determined by partial Edman degradation/mass spectrometry. This has resulted in the discovery of a series of tyrocidine analogues that have significantly improved therapeutic indices compared to the natural product. The availability of tyrocidine analogues with varying antibacterial activities has provided important insights into the structure−function relationship of tyrocidine A, which should help reveal its mechanism of action

One-Pot Synthesis of Bicyclic β-Alkoxy Amides from Cyanohydrin Ethers

In this manuscript we report that intramolecular Friedel−Crafts alkylation reactions of aryl-substituted α-alkoxy acylimines proceed in the presence of mild Lewis acids to afford bicyclic β-alkoxy amides. The intermediate acylimines are prepared through cyanohydrin ether hydrozirconation and acylation of the resulting metalloimine, providing an operationally facile one pot protocol. A two-step variant of the procedure has also been developed to effect cyclizations from acylimines that undergo competitive tautomerization

DataSheet1_Combined hydrodynamic and control analysis on optimal kinematic parameters for bio-inspired autonomous underwater vehicle manoeuvring.pdf

To investigate the manoeuvring performance of a body-caudal fin robot fish, a numerical framework combining computational fluid dynamics and multi-body dynamics with a closed-loop control algorithm was established in this study. Within this framework, we modelled a body-caudal fin swimmer as a multi-body system with the shape of a NACA0012 hydrofoil. The manoeuvring performance was investigated by using different curvature magnitudes and distributions along the centre line (the curvature is defined by means of a curvature envelop function as part of the general body undulation equation). To characterize the turning performance, a new parameter named cost of manoeuvring (CoM) is proposed. This parameter provides a combined assessment of the turning radius, linear and angular velocity components, and power. It is found that when the body curvature is introduced, the swimmer switches from straight-line swimming to quasi-steady turning at a constant speed. Further investigations were conducted to study contributions of head and tail deformations on the turning performance by comparing predominantly head and tail curved envelopes. Results reveal that a tail-dominated envelope improves performance, whereas a head-dominated envelope has a negative effect.</p

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

Stereoselective Synthesis of Spirooxindole Amides through Nitrile Hydrozirconation

Spirooxindole amides can be prepared by the intramolecular addition of functionalized indoles into acylimines that are accessed from nitriles by hydrozirconation and acylation. The stereochemical outcome at the quaternary center was controlled by the steric bulk of the substituent at the 2-position of the indole unit. The products are well-suited for diversification to prepare libraries

Influence of Deamidation on the Formation of Pyrazines and Proline-Specific Compounds in Maillard Reaction of Asparagine and Proline with Glucose

Maillard reaction products obtained from the model system of binary amino acids (asparagine and proline) with glucose were first studied. GC-MS results showed that proline-specific aromatic compounds, 2,3-dihydro-1H-pyrrolizines and cyclopent[b]azepin-8(1H)-ones, were dominant among overall products, followed by pyrazines at different temperatures. Aspartic acid was first applied to model reactions as the precise control of asparagine deamidation, and lysine was further introduced into model systems for improving pyrazine formation. Quantitative results of model reaction products demonstrated that pyrazines were not significantly increased in deamidated states (Asn-Asp-Pro and Asp-Pro) while proline-specific compounds had a rapid enhancement at the same time. With excellent ability to form pyrazines, lysine did help to increase the formation of pyrazines, but still far fewer than pyrrolizines and azepines. It was assumed that proline would preferentially react with α-dicarbonyl compounds in Maillard reaction cascades with lower activation energies

Profiling the Substrate Specificity of Protein Kinases by On-Bead Screening of Peptide Libraries

A robust, high-throughput method has been developed to screen one-bead–one-compound peptide libraries to systematically profile the sequence specificity of protein kinases. Its ability to provide individual sequences of the preferred substrates permits the identification of sequence contextual effects and nonpermissive residues. Application of the library method to kinases Pim1, MKK6, and Csk revealed that Pim1 and Csk are highly active toward peptide substrates and recognize specific sequence motifs, whereas MKK6 has little activity or sequence selectivity against peptide substrates. Pim1 recognizes peptide substrates of the consensus RXR­(H/R)­X­(S/T); it accepts essentially any amino acid at the S/T–2 and S/T+1 positions, but strongly disfavors acidic residues (Asp or Glu) at the S/T–2 position and a proline residue at the S/T+1 position. The selected Csk substrates show strong sequence covariance and fall into two classes with the consensus sequences of (D/E)­EPIYϕXϕ and (D/E)­(E/D)­S­(E/D/I)­YϕXϕ (where X is any amino acid and ϕ is a hydrophobic amino acid). Database searches and in vitro kinase assays identified phosphatase PTP-PEST as a Pim1 substrate and phosphatase SHP-1 as a potential Csk substrate. Our results demonstrate that the sequence specificity of protein kinases is defined not only by favorable interactions between permissive residue(s) on the substrate and their cognate binding site(s) on the kinase but also by repulsive interactions between the kinase and nonpermissive residue(s)