3-Nitro-4-amino benzoic acids and 6-amino nicotinic acids are highly selective agonists of GPR109b

A series of 3-nitro-4-substituted-aminobenzoic acids were prepared and found to act as potent and highly selective agonists of the orphan human GPCR GPR109b, a low affinity receptor for niacin. No activity was observed at the closely homologous high affinity niacin receptor, GPR109a. A second series, comprising 6-amino-substituted nicotinic acids was, also prepared and several analogues showed comparable activity to the nitroaryl series.     

SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL

SHIP1 is an SH2 domain containing inositol-5-phosphatase that appears to be a negative regulator of hematopoiesis. The tyrosine kinase oncogene BCR/ABL drastically reduces expression of SHIP1. The major effect of re-expressing SHIP1 in BCR/ABL-transformed cells is reduction of hypermotility. To investigate the potential signaling pathways involving SHIP1 in hematopoietic cells, we overexpressed SHIP1 in a murine BCR/ABL-transformed Ba/F3 cell line and identified SHIP1-associated proteins. SHIP1 was found to form a novel signaling complex with BCR/ABL that includes DOK1 (p62(DOK)), phosphatidylinositol 3-kinase (PI3K), and CRKL, each of which has been previously shown to regulate migration in diverse cell types. We found that DOK1 binds directly through its PTB domain to SHIP1. Direct interaction of SHIP1 with CRKL was mediated through the CRKL-SH2 domain. Co-precipitation experiments suggest that Tyr(917) and Tyr(1020) in SHIP1 are likely to mediate interactions with DOK1. In contrast to wild type SHIP1, expression of tyrosine mutant SHIP1 by transient transfection did not alter migration. PI3K was likely linked to this complex by CRKL. Thus, this complex may serve to generate a very specific set of phosphoinositol products, possibly involved in regulating migration. Overall, these data suggest that proteins that interact with SHIP1 through Tyr(917) and Tyr(1020), such as DOK1 and SHC, are likely to be involved in the regulation of SHIP1 dependent migration.     

Evaluating suitable low-cost agar substitutes,clarity, stability,and toxicity for resource-poor countries' tissue culture media

In Vitro Cellular & Developmental Biology - Plant - Over 20% of plant species assessed are threatened with extinction. Most of these plants have food security implications, especially in...     

Concerted evolution between duplicated genetic elements in Helicobacter pylori

The Helicobacter pylori genome includes a family of outer membrane proteins (OMPs) with substantial N and C-terminal identity. To better understand their evolution, the nucleotide sequences for two members, babA and babB, were determined from a worldwide group of 23 strains. The geographic origin of each strain was found to be the major determinant of phylogenetic structure, with strains of Eastern and Western origin showing greatest divergence. For strains 96-10 (Japan) and 96-74 (USA), the 5' regions of babB are replaced with babA sequences, demonstrating that recombination occurs between the two loci. babA and babB have nearly equivalent variation in nucleotide and amino acid identity, and frequencies of synonymous and non-synonymous substitutions. Both genes have segmental conservation but within the 3' segment, substitution patterns are nearly identical. Although babA and babB 5' and midregion segment phylogenies show strong interstrain similarity, the 3' segments show strong intrastrain similarity, indicative of concerted evolution. Within these 3' segments, the lower intrastrain than interstrain frequencies of nucleotide substitutions, which are below mean background H. pylori substitution frequencies, indicate selection against intrastrain diversification. Since babA/babB gene conversions likely underlie the concerted evolution of the 3' segments, in an experimental system, we demonstrate that gene conversions can frequently (10(-3)) occur in H. pylori. That these events are recA-dependent and DNase-resistant indicates their likely cause is intragenomic recombination.     

Fluorinated pyrazole acids are agonists of the high affinity niacin receptor GPR109a

A series of 5-alkyl pyrazole-3-carboxylic acids were prepared and found to act as potent and selective agonists of the human GPCR, GPR109a, the high affinity nicotinic acid receptor. No activity was observed at the highly homologous low affinity niacin receptor, GPR109b. A further series of 4-fluoro-5-alkyl pyrazole-3-carboxylic acids were shown to display similar potency. One example from the series was shown to have improved properties in vivo compared to niacin.     

Sex differences in social interaction behavior following social defeat stress in the monogamous California mouse (Peromyscus californicus)

Stressful life experiences are known to be a precipitating factor for many mental disorders. The social defeat model induces behavioral responses in rodents (e.g. reduced social interaction) that are similar to behavioral patterns associated with mood disorders. The model has contributed to the discovery of novel mechanisms regulating behavioral responses to stress, but its utility has been largely limited to males. This is disadvantageous because most mood disorders have a higher incidence in women versus men. Male and female California mice (Peromyscus californicus) aggressively defend territories, which allowed us to observe the effects of social defeat in both sexes. In two experiments, mice were exposed to three social defeat or control episodes. Mice were then behaviorally phenotyped, and indirect markers of brain activity and corticosterone responses to a novel social stimulus were assessed. Sex differences in behavioral responses to social stress were long lasting (4 wks). Social defeat reduced social interaction responses in females but not males. In females, social defeat induced an increase in the number of phosphorylated CREB positive cells in the nucleus accumbens shell after exposure to a novel social stimulus. This effect of defeat was not observed in males. The effects of defeat in females were limited to social contexts, as there were no differences in exploratory behavior in the open field or light-dark box test. These data suggest that California mice could be a useful model for studying sex differences in behavioral responses to stress, particularly in neurobiological mechanisms that are involved with the regulation of social behavior.     

Impact of mass rearing and gamma irradiation on thermal tolerance of Eldana saccharina

Mating ability, survival, and fitness of mass‐produced sterile insects when released into the wild, are critical to the success of the sterile insect technique (SIT) as a pest management strategy, but their field performance remains one of the greatest challenges. Thermal stress tolerance by irradiated insects is a determinant of sterile insect quality, hence knowledge of their physiological competitiveness is essential for developing the SIT. Here, we report the results of experiments investigating effects of laboratory rearing and increasing radiation dosage on thermal limits to activity of the adult stage of Eldana saccharina Walker (Lepidoptera: Pyralidae). The critical thermal maximum (CTmax) and critical thermal minimum (CTmin) were assayed using a dynamic method on both sexes of E. saccharina moths in laboratory vs. wild populations (to determine effect of rearing history). Furthermore, the laboratory population was exposed to 150, 200, and 250 Gy, to determine the effect of radiation dose. Laboratory‐reared E. saccharina were more heat tolerant compared to wild moths for both sexes (CTmax = 44.5 vs. 44.3 °C), whereas in the case of CTmin (3.7 vs. 4.4 °C), wild moths were more cold tolerant than their laboratory‐reared counterparts. Irradiation had a negative effect on both CTmax and CTmin. Moths treated at the lowest radiation dose were more cold and heat tolerant than those treated at the highest dosages (CTmin = 4.5 vs. 6.2 °C; CTmax = 43.9 vs. 43.5 °C), thereby reinforcing the importance of lower dosages rather than those that induce full sterility against E. saccharina. In general, sex had no influence on critical thermal limits in all moth treatments except for those irradiated at 150 Gy. The data presented in this article provide evidence that increasing radiation dose impacts on fitness of laboratory‐produced moths relative to their wild counterparts, which in turn could affect the effectiveness of the SIT programme.     

Motor neuron disease in Nova Scotia

Fifty-two cases of motor neuron disease seen in two Halifax hospitals were reviewed.Thirty-three (63.5%) had amyotrophic lateral sclerosis, 14 (26.9%) had primary muscular atrophy, four (7.7%) had bulbar palsy and one (1.9%) had primary lateral sclerosis. There were no unusual features in this series when compared with a similar series from the United States. These cases were used to illustrate the features of this disorder and to comment on recent research observations.     

Changes in lung mechanics during asthma induced by exercise.

Pulmonary and airway mechanics were assessed in seven asthmatic patients in remission, when asthma was induced by exercise and again after spontaneous recovery or bronchodilator treatment. After exercise there was a sustained fall in forced expiratory volume in 1 s (FEV 1.0) in all patients, varying from 30 to 80 percent of the initial value. Total lung capacity (TLC) increased significantly in four of the seven patients. In one of the four patients the increase in TLC was associated with an increase in static transpulmonary pressure at full inflation but in the remaining three patients it was associated with a parallel shift of the pressure-volume curve of the lung without change in its slope. In all patients residual volume increased, regardless of change in TLC; both pressure-volume and maximum expiratory flow-volume curves suggested that widespread airway closure (or virtual closure) occurred at positive transpulmonary pressures when asthma was induced. Loss of lung recoli pressure sometimes contributed to the reduction in maximum expiratory flow but diffuse airway narrowing was probably the dominant abnormality. When air-flow obstruction became more severe the ratio of expiratory to inspiratory time was increased and although expiratory flow limitation was present excessive expiratory pressures were not generated.     

Infant Killing, Wounding and Predation in Eulemur and Lemur

Infant killing by primates is highly controversial. Sexual selection of infanticidal males has been disputed, especially for seasonally breeding species, in which death of an infant does not advance conception of the next infant. We report attacks, infants found wounded, and predation in seasonally breeding Eulemur and Lemur at Berenty, Beza Mahafaly and Duke University Primate Center, and review cases seen elsewhere. Observed attacks leading to wounds or death conservatively total twelve by extratroop males, two by troop males, and seven by troop females. Eulemur are occasional vertebrate predators, whose prey includes infant Lemur catta. Wounds inflicted by lemurs are usually abdominal canine slashes or bites to the head, with rare eating, a pattern distinct from carnivore and raptor kills. Infant killing as inferred from corpses is more frequent than previously thought, but still rare. Adaptive advantages of killing plausibly include eliminating resource competitors of females, and sexual selection on males.