Potent dihydroquinolinone dopamine D2 partial agonist/serotonin reuptake inhibitors for the treatment of schizophrenia

A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D₂ ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D₂ partial agonists and serotonin reuptake inhibitors. Structure–activity studies revealed that the linker plays a key role in contributing to D₂ affinity, function, and SRI activity.     

Genetic variation and structuring in the threatened koala populations of Southeast Queensland

Habitat fragmentation can act to cause reproductive isolation between conspecifics and undermine species’ persistence, though most studies have reported the genetic condition of populations that have already declined to a very small size. We examined genetic diversity within the vulnerable, declining koala (Phascolarctos cinereus) population in Southeast Queensland, Australia to determine the genetic impact of ongoing threatening processes. Five hundred and twelve koalas from ten Southeast Queensland Local Government Areas on the mainland and one island were genotyped at six polymorphic microsatellite loci. Based on Bayesian cluster analysis incorporating spatial data, the regional koala population was subdivided into six clusters, with location of major roads and rivers appearing to be consistent with being barriers to gene flow. The distribution of mtDNA control region haplotypes identified distinct coastal and inland clades suggesting that historically there was gene flow between koalas along the coast (though little interchange between coastal and inland animals). In contrast, koalas from the Koala Coast (Brisbane City, Logan City and Redland Shire) were shown by microsatellite analysis to be genetically distinct from adjacent areas. It is likely, therefore, that more recent reductions in population size and restricted gene flow through urbanisation have contributed to the genetic differentiation of koalas in the Koala Coast region.     

A conformational change in heparan sulfate 3-O-sulfotransferase-1 is induced by binding to heparan sulfate

The 3-O-sulfation of glucosamine by heparan sulfate 3-O-sulfotransferase-1 (3-OST-1) is a key modification step during the biosynthesis of anticoagulant heparan sulfate (HS). In this paper, we present evidence of a conformational change that occurs in 3-OST-1 upon binding to heparan sulfate. The intrinsic fluorescence of 3-OST-1 was increased in the presence of HS, suggesting a conformational change. This apparent conformational change was further investigated using differential chemical modification of 3-OST-1 to measure the solvent accessibility of the lysine residues. 3-OST-1 was treated with acetic anhydride in either the presence or absence of HS using both acetic anhydride and hexadeuterioacetic anhydride under nondenaturing and denaturing conditions, respectively. The relative reactivity of the lysine residues to acetylation and [2H] acetylation in the presence or absence of HS was analyzed by measuring the ratio of acetylated and deuterioacetylated peptides using matrix-assisted laser desorption ionization mass spectrometry. The solvent accessibilities of the lysine residues were altered differentially depending on their location. In particular, we observed a group of lysine residues in the C-terminus of 3-OST-1 that become more solvent accessible when 3-OST-1 binds to HS. This observation indicates that a conformational change could be occurring during substrate binding. A truncated mutant of 3-OST-1 that lacked this C-terminal region was expressed and found to exhibit a 200-fold reduction in sulfotransferase activity. The results from this study will contribute to our understanding of the interactions between 3-OSTs and HS.     

ACTH does not mediate divergent stress responsiveness in rainbow trout.

Two lines of rainbow trout selected for high (HR) and low (LR) responsiveness to a standardised confinement stressor displayed a sustained divergence in plasma cortisol levels during a 3-h period of confinement (max.: HR: 167+/-13 ng ml(-1); LR: 103+/-8 ng ml(-1); P<0.001). However, no significant difference in plasma ACTH levels was evident (max: HR: 153+/-9 pg ml(-1); LR: 142+/-7 pg ml(-1)). Dexamethasone (DEX) was administered to HR and LR fish to block endogenous adrenocorticotropin (ACTH) release. Administration of a weight-adjusted dose of ACTH to the DEX-blocked fish elevated plasma cortisol levels to a significantly greater extent in HR (233+/-24 ng ml(-1)) than LR (122+/-14 ng ml(-1)) fish (P<0.001). Plasma cortisol levels in DEX-blocked HR and LR fish after sham injection were low but also significantly different (HR: 6.7+/-1 ng ml(-1); LR: 2.2+/-0.2 ng ml(-1); P<0.001). These results indicate that modulation of cortisol responsiveness to stressors in HR and LR fish resides, at least in part, downstream of the hypothalamic-pituitary axis.     

Observations of spermiogenesis and epididymal sperm maturation in the rufous hare wallaby, Lagorchestes hirsutus (Metatheria, Mammalia)

Acrosomal development in the early spermatid of the rufous hare wallaby shows evidence of formation of an acrosomal granule, similar to that found in eutherian mammals, the Phascolarctidae and Vombatidae. Unlike the other members of the Macropodidae so far examined, the acrosome of this species appears to be fully compacted at spermiation and extends evenly over 90% of the dorsal aspect of the nucleus. During spermiogenesis, the nucleus of the rufous hare wallaby spermatid showed evidence of uneven condensation of chromatin; this may also be related to the appearance of unusual nucleoplasm evaginations from the surface of the fully condensed spermatid. This study was unable to find evidence of the presence of Sertoli cell spurs or nuclear rotation during spermiogenesis in the rufous hare wallaby. The majority of spermatozoa immediately before spermiation had a nucleus that was essentially perpendicular to the long axis of the sperm tail. Nuclei of spermatozoa found in the process of being released or isolated in the lumen of the seminiferous tubule were rotated almost parallel to the long axis of the flagellum; complete parallel alignment occurred during epididymal maturation. At spermiation spermatozoa have characteristically small cytoplasmic remnants compared to those of other macropods. Unlike the majority of macropodid spermatozoa so far described, the spermatozoa of the rufous hare wallaby showed little evidence of morphological change during epididymal transit. There was no formation of a fibre network around the midpiece or of plasma membrane specializations in this region; the only notable change was a distinctive flattening of midpiece mitochondria and scalloping of the anterior mitochondrial sheath to accommodate the sperm head. Preliminary evidence from spermiogenesis and epididymal sperm maturation supports the classification of the rufous hare wallaby as a separate genus but also indicates that its higher taxonomic position may need to be re‐evaluated.     

Aspects of the structure and development of monotreme spermatozoa and their relevance to the evolution of mammalian sperm morphology

Summary The elongated spermatid nuclei of monotremes exhibit a circumferentially arranged spiral pattern of chromatin condensation, and ultimately form helical filiform sperm heads up to 50 m long and either circular or slightly oval in transverse section. The acrosome is formed by the collapse of the proacrosomal vacuole onto the rostral surface of the elongating nucleus. However, genesis of acrosomal material occurs in the absence of a prominent proacrosomal granule. The flagellum becomes inserted into the distal extremity of the nucleus, the most proximal mitochondria of the midpiece directly abutting the nuclear membrane, so that a prominent neck region is absent. The axoneme is simple and, in the midpiece, small dense peripheral fibres are closely applied to the outer surface of each of the nine microtubule doublets. The cortical fibrous sheath of the principal piece is an anastomosing spiral that lacks lateral columnar elements.The spermatozoal cytoplasmic droplet undergoes migration and is lost during epididymal passage.Monotreme spermatozoa exhibit a montage of features, some of these being also found in marsupials and some in sauropsidan vertebrates, as well as a number of their own distinctive features. It is concluded that monotreme spermatozoa also have a close affinity with the unspecialised spermatozoa of some eutherian mammals.We wish to thank Dr. Mervyn E. Griffiths for providing the Zaglossus material. Permits to collect these native mammals were provided by the National Parks and Wildlife Services, and State Fisheries Services of New South Wales and Queensland. Portion of this work was supported by grants from the Australian Research Grants Committee. The provision of skilled technical assistance and access to electron microscope facilities were kindly provided by Dr. C.D. Shorey, formerly Acting Director of the University of Sydney Electron Microscope Unit, and by Mr. John Hardy, Senior Lecturer-in-Charge of the University of Queensland Electron Microscope Centre. Members of the technical staff of the Departments of Anatomy and Veterinary Anatomy are also acknowledged for their assistance     

DO PHYSICAL FACTORS REGULATE PHYTOPLANKTON DISTRIBUTION PATTERNS IN LARGE, SHALLOW LAKES?

Factors that regulate phytoplankton dynamics in shallow, productive lakes are poorly understood, due to their predisposition for frequent algal blooms and sediment resuspension events. In Lake Apopka, greatest phytoplankton biomass reflects wind-induced resuspension of algae (meroplankton) that exists on the aphotic lake bottom in a layer approximately 5 cm thick; this assemblage is dominated by diatoms (>60% of total biomass) that can occur in resting stages. Once exposed to moderate light, meroplankton are capable of growth and photosynthetic rates comparable with surface populations. In Lake Okeechobee, remote sensing was used to assess the basin-wide distribution of suspended particles. Satellite reflectance values agreed well with in situ particle densities at 20 in-lake stations (average r²; LANDSAT = 0.81, AVHRR = 0.53), and maps of algal blooms (r² = 0.79, p ≤ 0.01). The greatest chlorophyll concentrations occurred in the vicinity of tributary nutrient inputs at the lake's perimeter, while turbidity increased towards the center of the lake reflecting predominant water circulation patterns. These results underscore the importance of physical-biological interactions in lakes.