Propriedades mesomórficas de tensioactivos cataniónicos

Dissertação apresentada à Universidade de Coimbra para cumprimento dos requisitos necessário à obtenção de grau de Mestre em Química, na especialidade de Química FísicaNeste trabalho foram preparados vários compostos de uma nova classe de moléculas anfifílicas, os tensioactivos cataniónicos, resultantes da formação de um par tensioactivo aniónico-catiónico com remoção dos respectivos contra-iões. Após a síntese dos compostos, foi efectuado um estudo do seu comportamento de fase térmico (termotrópico) e em meio aquoso (liotrópico). Os tensioactivos preparados diferem quanto ao número total de caudas (2 ou 3 caudas), quanto ao número de carbonos nas caudas (de 8 até 18) e quanto à natureza química das cabeças hidrofílicas (amónio, sulfato e carboxilato). Dada a diversidade dos compostos preparados, pretendeu-se esclarecer a influência da geometria e natureza química dos compostos no comportamento de fase desta classe de tensioactivos. A caracterização da fase sólida e a análise dos comportamentos termotrópicos e liotrópicos dos compostos foram realizadas com base nas técnicas de: microanálise elemental, absorção atómica, condutividade, microscopia óptica com luz polarizada, análise térmica diferencial (DTA), calorimetria diferencial de varrimento (DSC), difracção de raios-X de pequeno ângulo (SAXS), penetração de fase com varrimento e microscopia de transmissão electrónica com criogenia (Cryo-TEM). Com base nos resultados experimentais pretende-se fazer um estudo de descrição e racionalização das propriedades dos tensioactivos cataniónicos, nomeadamente o estudo do efeito da assimetria estrutural das moléculas na natureza e sequência de mesofases formadas

Heterozygous missense variants of LMX1A lead to nonsyndromic hearing impairment and vestibular dysfunction

Unraveling the causes and pathomechanisms of progressive disorders is essential for the development of therapeutic strategies. Here, we identified heterozygous pathogenic missense variants of LMX1A in two families of Dutch origin with progressive nonsyndromic hearing impairment (HI), using whole exome sequencing. One variant, c.721G > C (p.Val241Leu), occurred de novo and is predicted to affect the homeodomain of LMX1A, which is essential for DNA binding. The second variant, c.290G > C (p.Cys97Ser), predicted to affect a zinc-binding residue of the second LIM domain that is involved in protein–protein interactions. Bi-allelic deleterious variants of Lmx1a are associated with a complex phenotype in mice, including deafness and vestibular defects, due to arrest of inner ear development. Although Lmx1a mouse mutants demonstrate neurological, skeletal, pigmentation and reproductive system abnormalities, no syndromic features were present in the participating subjects of either family. LMX1A has previously been suggested as a candidate gene for intellectual disability, but our data do not support this, as affected subjects displayed normal cognition. Large variability was observed in the age of onset (a)symmetry, severity and progression rate of HI. About half of the affected individuals displayed vestibular dysfunction and experienced symptoms thereof. The late-onset progressive phenotype and the absence of cochleovestibular malformations on computed tomography scans indicate that heterozygous defects of LMX1A do not result in severe developmental abnormalities in humans. We propose that a single LMX1A wild-type copy is sufficient for normal development but insufficient for maintenance of cochleovestibular function. Alternatively, minor cochleovestibular developmental abnormalities could eventually lead to the progressive phenotype seen in the families

Rilmenidine activates postjunctianal alpha1- and alpha2-adrenoceptors in the canine saphenous vein

Experiments were performed to determine the subtypes of alpha-adrenoceptors involved in the contraction induced by rilmenidine in isolated canine cutaneous veins. Rings of saphenous vein (without endothelium) were suspended for the recording of isometric force in physiological salt solution. All experiments were performed in the presence of propranolol (to antagonize beta-adrenoceptors), cocaine (to inhibit neuronal uptake) and hydrocortisone (to inhibit extraneuronal uptake). In the presence of rauwolscina (an alpha2-adrenegic blocker), rilmenidine caused concentration-dependent contractions which were inhibited by prazosin (nonselective alpha1-antagonist) and by (+)niguldipine (selective alpha(1A)-adrenergic antagonist), but not by (-)nigurdipine. After treatment with phenoxybenzamine (to alkylate alpha1-adrenoceptors), rilmenidine evoked contractions of the canine saphenous vein which were antagonized competitively by rauwolscine. The combination of rauwolscine and prazosin did not abolish contractions evoked by the highest concentrations of rilmenidine. Although binding experiments using 3H-idazoxan suggested the existence of a nonadrenergic binding site (around 20% of the total binding), contractile studies failed to demonstrate their involvement in the increases in tension evoked by rilmenidine. These experiments suggest that the contractions evoked by rilmenidine in isolated canine veins are mediated by both alpha(1A)- and alpha2-adrenoceptors

Supplementary Material for: No Protective Effect of Constitutive Activation of AMPK in Endothelial Cells on Vascular Function in Aged Obese Mice but Augmented α1-Adrenergic Contractions in Renal Arteries Reversible by Weight Loss

<b><i>Background:</i></b> Aging, obesity, and diabetes favor vascular dysfunction. Endothelial activation of adenosine monophosphate-activated protein kinase (AMPK) has protective effects in diabetes. <b><i>Methods:</i></b> Mice with constitutive endothelial activation of AMPK (CA-AMPK) were given a high fat diet to induce obesity or kept on standard chow as lean controls for up to 2 years. A subset of obese animals was changed to standard chow after 30 weeks of high fat feeding. En­dothelium-dependent and endothelium-independent responses were examined by isometric tension recording. <b><i>Results and Conclusion:</i></b> Endothelium-dependent nitric oxide (NO)- and apamin <i>plus</i> charybdotoxin-sensitive relaxations were preserved and similar between aortic or renal arterial preparations of lean and obese CA-AMPK mice and their wild-type littermates. Despite comparable release of vasoconstrictor prostanoids, cyclooxygenase-dependent contractions were enhanced during NO synthase inhibition in carotid arterial rings of obese CA-AMPK mice. Contractions to the α₁-adrenoceptor agonist phenylephrine were augmented in renal arteries of obese animals, a genotype-independent phenomenon reversible by weight loss. These data indicate a higher α₁-adrenergic reactivity in renal arteries of aged mice with obesity. The current results highlight the potential of weight loss to alleviate vascular dysfunction. However, endothelial activation of the AMPK pathway in obesity may not be sufficient to prevent vascular dysfunction without lifestyle changes