Development of pyrimidone D1 dopamine receptor positive allosteric modulators

MLS1082 is a structurally novel pyrimidone-based D1-like dopamine receptor positive allosteric modulator. Potentiation of D1 dopamine receptor (D1R) signaling is a therapeutic strategy for treating neurocognitive disorders. Here, we investigate the relationship between D1R potentiation and two prominent structural features of MLS1082, namely the pendant N-aryl and C-alkyl groups on the pyrimidone ring. To this end, we synthesized 24 new analogues and characterized their ability to potentiate dopamine signaling at the D1R and the closely related D5R. We identified structure–activity relationship trends for both aryl and alkyl modifications and our efforts afforded several analogues with improvements in activity. The most effective analogues demonstrated an approximately 8-fold amplification of dopamine-mediated D1R signaling. These findings advance the understanding of structural moieties underlying the activity of pyrimidone-based D1R positive allosteric modulators

Um novo clorofilômetro para estimar os teores de clorofila em folhas do capim Tifton 85

O propósito deste trabalho foi verificar o desempenho de um novo clorofilometro portátil, em parcelas experimentais vegetadas com o capim-Tifton 85 (Cynodon spp.). Para tal, foi utilizado um experimento de curta duração, em que três doses de N (0,75 e 150kg de N ha-1) foram combinadas com quatro datas de amostragem (8, 16, 24 e 28 dias após um corte de uniformização). As análises foram feitas em lâminas da folha mais nova totalmente expandida. Os teores das clorofilas a, b e a+b foram quantificados espectrofotometricamente após a extração com acetona 80%, enquanto que o clorofilômetro forneceu os correspondentes valores de Índice de Clorofila Falker (ICF). As leituras do aparelho foram sensíveis tanto às doses de N quanto às datas de amostragem. Foram obtidas correlações positivas entre ambos os métodos de quantificação (clorofila a: r=0,646; b: r=0,797; e total: r=0,721), que evidenciaram a utilidade desse novo clorofilometro na determinação indireta dos teores de clorofila foliar no capim-Tifton 85

Progress in muscular dystrophy research with special emphasis on gene therapy

Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle-wasting disease caused by mutations in the DMD gene. Since the disease was described by physicians in the 19th century, information about the subject has been accumulated. One author (Sugita) was one of the coworkers who first reported that the serum creatine kinase (CK) level is elevated in progressive muscular dystrophy patients. Even 50 years after that first report, an elevated serum CK level is still the most useful marker in the diagnosis of DMD, a sensitive index of the state of skeletal muscle, and useful to evaluate therapeutic effects. In the latter half of this article, we describe recent progress in the therapy of DMD, with an emphasis on gene therapies, particularly exon skipping

Anxiety as a cause of attachment avoidance in women with Turner Syndrome

Working models of attachment are internal depictions of self relative to others and have been described in terms of two dimensions: (1) attachment avoidance and (2) attachment anxiety. An exploratory qualitative study was carried out to build understandings about women with Turner Syndrome (TS) and the psychosocial impact their infertility has upon salient relationships. In one-to-one semi-structured interviews, five women with TS were asked: How do you perceive your womanhood and infertility status has affected your relationships with: (1) the opposite sex, (2) siblings and (3) peers? In opposite-sex relationships, infertility status was found to arouse fear of ending up alone and anxiety over engaging in romantic relationships. In sibling relationships, jealousy was expressed in relation to disparity with sister(s) more natural maturation to womanhood, and, within peer relationships, consequences from divulging infertility status created attachment avoidance with friends. Further investigation in this area is merited

Phylogenetic correlograms and the evolution of body size in South American owls (Strigiformes)

During the last few years, many models have been proposed to link microevolutionary processes to macroevolutionary patterns, defined by comparative data analysis. Among these, Brownian motion and Ornstein-Uhlenbeck (O-U) processes have been used to model, respectively, genetic drift or directional selection and stabilizing selection. These models produce different curves of pairwise variance between species against time since divergence, in such a way that different profiles appear in phylogenetic correlograms. We analyzed variation in body length among 19 species of South American owls, by means of phylogenetic correlograms constructed using Moran's I coefficient in four distance classes. Phylogeny among species was based on DNA hybridization. The observed correlogram was then compared with 500 correlograms obtained by simulations of Brownian motion and O-U over the same phylogeny, using discriminant analysis. The observed correlogram indicates a phylogenetic gradient up to 45 mya, when coefficients tend to stabilize, and it is similar to the correlograms produced by the O-U process. This is expected when we consider that body size of organisms is correlated with many ecological and life-history traits and subjected to many constraints that can be modeled by the O-U process, which has been used to describe evolution under stabilizing selection.<br>Nos últimos anos diversos modelos têm sido propostos a fim de realizar inferências sobre processos microevolutivos com base em padrões macroevolutivos obtidos a partir de dados comparativos. Dentre esses, o movimento Browniano e o processo Ornstein-Uhlenbeck (O-U) têm sido utilizados para modelar principalmente deriva genética e seleção estabilizadora, respectivamente. Esses modelos produzem curvas diferentes de relação entre variância interespecífica e distância no tempo, de modo que eles podem ser distingüidos com base em correlogramas filogenéticos. Neste trabalho, nós analisamos a variação interespecífica no tamanho do corpo de 19 espécies de corujas (Strigiformes) sul-americanas através de correlogramas filogenéticos, construídos utilizando índices I de Moran em quatro classes de distância. A filogenia entre as espécies foi definida com base em dados de hibridização de DNA. O correlograma observado foi então comparado a 500 correlogramas obtidos através de simulações de evolução por movimento Browniano e pelo processo O-U, sobre essa mesma filogenia. Esses correlogramas foram comparados entre si utilizando análises de variância (ANOVA e MANOVA) e através das correlações entre os índices I de Moran e as classes de distância filogenética. O correlograma observado indica a existência de um gradiente filogenético de variação até cerca de 45 milhões de anos, quando os índices se estabilizam, e é similar aos correlogramas obtidos através do processo O-U, considerando tanto a correlação do gradiente quanto a sua alocação aos dois grupos de processos através de análise discriminante. Esse padrão é esperado, considerando a importância do tamanho do corpo e sua correlação com diversos caracteres ecológicos e de história de vida, que produzem muitas restrições que podem de fato ser modeladas por um processo O-U expressando seleção estabilizadora

Patterns of non-randomness in the exotic avifauna of Florida

It is now generally recognized that human-mediated biological invasion is a multistage process, successively comprising transport, introduction, establishment, and spread, and that a complete understanding of the causes of invasion requires studies of all stages. However, while many studies address the characteristics that influence establishment, relatively few address the characteristics that influence whether or not a species transits the earlier stages of transport and introduction. Here, we use data on the rich exotic avifauna of Florida to assess non-randomness in the identities of species that have passed through the transport and introduction stages. Bird species transported and introduced to Florida are non-random with respect to their taxonomic affiliations, body mass, native geographical range size, and region of origin: introductions are more likely for widespread, large-bodied species from the Neotropics and belonging to the Anatidae, Psittacidae, Ciconiidae, and Passeridae. Data on the identities of species that have attempted to breed but failed, and on the breeding population size for most established species, also allowed us to assess the extent to which the same variables influenced various aspects of post-introduction establishment. Only native geographical range size and latitudinal range mid-point distinguish between these different classes of exotic species. Geographical range size is the most general correlate of different classes of invaders in our analyses.Tim M. Blackburn and Phillip Casse