BackgroundUnder physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i.e., food intake is decreased and energy expenditure is increased—a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here.Methods and resultsBL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile.ConclusionThe properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i.e., decreased food intake and increased energy expenditure, with one drug.

Dystrophin deficiency is the underlying molecular cause of progressive muscle weakness observed in Duchenne muscular dystrophy (DMD). Loss of functional dystrophin leads to elevated levels of intracellular Ca(2+), a key step in the cellular pathology of DMD. The cysteine protease calpain is activated in dystrophin-deficient muscle, and its inhibition is regarded as a potential therapeutic approach. In addition, previous work has shown that the ubiquitin-proteasome system also contributes to muscle protein breakdown in dystrophic muscle and, therefore, also qualifies as a potential target for therapeutic intervention in DMD. The relative contribution of calpain- and proteasome-mediated proteolysis induced by increased Ca(2+) levels was characterized in cultured muscle cells and revealed initial Ca(2+) influx-dependent calpain activity and subsequent Ca(2+)-independent activity of the ubiquitin-proteasome system. We then set out to optimize novel small-molecule inhibitors that inhibit both calpain as well as the 20S proteasome in a cellular system with impaired Ca(2+) homeostasis. On administration of such inhibitors to mdx mice, quantitative histological parameters improved significantly, in particular with compounds strongly inhibiting the 20S proteasome. To investigate the role of calpain inhibition without interfering with the ubiquitin-proteasome system, we crossed mdx mice with transgenic mice, overexpressing the endogenous calpain inhibitor calpastatin. Although our data show that proteolysis by calpain is strongly inhibited in the transgenic mdx mouse, this calpain inhibition did not ameliorate muscle histology. Our results indicate that inhibition of the proteasome rather than calpain is required for histological improvement of dystrophin-deficient muscle. In conclusion, we have identified novel proteasome inhibitors that qualify as potential candidates for pharmacological intervention in muscular dystrophy.

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The pupa of Trichognathus marginipennis Latreille, 1829 is described for the first time and the adult is redescribed. Habitus and important structures of larva, pupa and adult are illustrated. This work improves the knowledge on immatures and adults of Trichognathus marginipennis.

The scorpion mud turtle (Kinosternon scorpioides) is a small freshwater turtle broadly distributed in South America and commonly consumed in some Brazilian regions. This study aimed to identify the species of helminths that parasitize the digestive tract of K. scorpioides and report infection parameters such as parasite prevalence, mean intensity of the infection, abundance, and the relationship between these nematodes and host body size in this species. We captured 20 adult male K. scorpioides, and 6 animals had nematodes in their gastrointestinal tract. These animals had Serpinema magathi (prevalence = 0.3) and Spiroxys figueiredoi (prevalence = 0.25). There were no correlations between the number of total parasites and carapace length (rs = 0.17, n = 6, P = 0.74) or the length of the gastrointestinal tract (rs = 0.18, n = 6, P = 0.73).

Here presented is an annotated catalogue of the Membracidae types deposited at the Museu de Zoologia da Universidade de São Paulo (MZSP), with information on 106 primary types and 171 secondary types. These type specimens represent 82 nominal species currently classified in 8 treehopper subfamilies and 17 tribes. According to our estimates, at least 10 primary types and 44 secondary types are missing in the collection. A comprehensive list of literature sources, taxonomic remarks, label data and descriptions on the state of preservation of specimens are given.

Neil Peart, Everyday Glory vi Agradecimentos Começo agradecendo aos meus pais pelo apoio, compreensão e incentivo em todas as minhas conquistas. Da mesma forma agradeço meus parentes, também sempre ao meu lado. Zé, valeu pelos momentos mais engraçados da minha vida ! Agradeço muito à Joana, que há mais de seis anos não exitou em me ajudar e me confortar nos momentos em que tudo parecia não ter mais solução. Te amo muito ! Agradeço muito também à Professora Sônia Casari, minha orientadora, sempre bem humorada e disposta para me ajudar e responder minhas mais absurdas e teimosas dúvidas. Não apenas limitou-se a me ajudar em meus estudos, mas sempre me incentivou em minhas atividades fora da universidade.Agradeço aos Professores Miguel Monné, Sérgio Ide e Lúcia Massutti de Almeida, que me receberam com toda a gentileza e hospitalidade nos institutos Museu Nacional do Rio de Janeiro, Instituto Biológio e Universidade Federal do Paraná, respectivamente, ajudando-me bastante na busca por mais exemplares do grupo aqui estudado.Muito obrigado José Albertino Rafael, por me ajudar com as coordenadas dos exemplares do INPA, Professor Ubirajara Martins pela ajuda com as localidades dos rótulos e discussões sobre nomenclatura, Carlos Campaner pela ajuda na localização de exemplares na coleção do MZUSP e pela solução de "enigmas" contidos nas etiquetas.Obrigado também Professor Sérgio Vanin por sempre me apoiar nos estudos dos Coleoptera e que durante meu mestrado me ajudou a entender a condição braquiptera de certos besouros e também me ajudou com dúvidas de nomenclatura. Muito obrigado Professora Cleide Costa, por sempre mostrar-se disposta a me ajudar a entender as diversas e complicadas estruturas dos besouros e que, neste trabalho, ajudou-me muito com os complexos segmentos genitais e genitália feminina do meu grupo de estudo.Professor Pedro Gnaspini Neto, que me ajudou com problemas nomenclaturais, atendendo-me de prontidão sempre que solicitado e Professor Marcelo Duarte, que apesar de estudar um grupo menos diverso, ajudou-me a esclarecer algumas dúvidas de redação e deu-me importantes conselhos na elaboração de um trabalho científico.Professor Nelson Papavero, que mesmo não estando no Museu de Zoologia, ajudou-me (por e-mail) em algumas dúvidas nomenclaturais.Não posso também esquecer dos funcionários do Museu de Zoologia, que fazem do Museu um excelente local de trabalho; muito obrigado bibliotecárias do Museu de Zoologia pela ajuda na localização dos livros, tão essenciais para minha pesquisa.Amigos do Museu de Zoologia, sem vocês a vida acadêmica seria um tédio! Valeu Peterson pelos toques e conselhos que foram muito úteis durante meu aprendizado; Fernadoso valeu pela insistência nos estudos dos louvas; Mauricioso pelos momentos hilários dentro e fora do Museu; Daniella, que mesmo pelo curto tempo que está no Museu também ajudou para deixar o clima da sala sempre divertido e Henrique, que sempre me ajudou com dúvidas relacionadas à fotografia e que "me deu uma mão" para fotografar alguns espécimens.Por fim, sou ex...