Natural killer T cells: rapid responders controlling immunity and disease

Natural killer T (NKT) cells are a subset of T cells that share properties of natural killer cells and conventional T cells. They are involved in immediate immune responses, tumor rejection, immune surveillance and control of autoimmune diseases. Most NKT cells express both an invariant T cell antigen receptor and the NK cell receptor NK1.1, and are referred to as invariant NKT cells. This invariant T cell receptor is restricted to interactions with glycolipids presented by the non-classical MHC, CD1d. These NKT cells rapidly produce high levels of interleukin (IL)-2, IFN-gamma, TNF-alpha, and IL-4 upon stimulation through their TCR. Most also have cytotoxic activity similar to NK cells. NKT cells are involved in a number of pathological conditions, and have been shown to regulate viral infections in vivo, and control tumor growth. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma.     

Induction of metallothionein mRNA in rat liver and kidney after copper chloride injection.

The kinetics of the increase of metallothionein mRNA in rat liver and kidney after CuCl2 injection was determined by cell-free translation and dot-blot hybridization of total RNA isolated at various times after the injection. Both assay procedures gave essentially the same result: a 16-fold increase in hepatic metallothionein mRNA was observed 7h after CuCl2 injection, with a decline to basal values by 15 h. The response in the kidney was less dramatic, with a 6-fold increase in metallothionein mRNA 5 h after injection, and basal values were attained by 12h. The rise in Cu2+ concentration in both organs was closely correlated with the increase in metallothionein mRNA; hepatic Cu2+ was increased 5.9-fold by 5h after injection and renal Cu2+ was increased 4.3-fold 5h after injection. The Zn2+ concentration in the liver had not risen significantly within 5h of Cu2+ injection. Renal Zn2+ concentrations did not alter appreciably in the Cu2+-treated animals. These results support the conclusion that Cu2+ is acting as a primary inducer of metallothionein mRNA in the rat.     

Characterization of a proteinaceous antimicrobial produced by Lactobacillus helveticus CNRZ450

An antimicrobial substance which resembles a bacteriocin was identified in culture supernatant fluids of Lactobacillus helveticus strain CNRZ450. The bacteriocin was active against a narrow range of strains from closely rested species of homofermentative lactobacilli. Its mode of action appeared to be bacteriostatic. Partial purification of the bacteriocin suggested that it was a complex protein with a mol. wt of between 30 and 50 kDa, although there is some evidence that the polypeptide monomer has a mol. wt of around 17 kDa. There was no evidence indicating an extrachromosomal location for its genetic determinant. PCR generated an amplicon from total DNA from strain CNRZ450 using primers based on the helJ gene sequence. A fragment showing homology to this amplicon was located in an Eco RI digest of total DNA from strain CNRZ450. The pattern obtained was different from that obtained with the helveticin J producer strain NCFB481. It is possible, therefore, that the antimicrobial from strain CNRZ450 is related to helveticin J at the DNA sequence level although the physical properties of the two antimicrobials reveal several differences.     

Discovery of 2,5-diarylnicotinamides as selective orexin-2 receptor antagonists (2-SORAs)

The orexin (or hypocretin) system has been identified as a novel target for the treatment of insomnia due to the wealth of biological and genetic data discovered over the past decade. Recently, clinical proof-of-concept was achieved for the treatment of primary insomnia using dual (OX₁R/OX₂R) orexin receptor antagonists. However, elucidation of the pharmacology associated with selective orexin-2 receptor antagonists (2-SORAs) has been hampered by the lack of orally bioavailable, highly selective small molecule probes. Herein, the discovery and optimization of a novel series of 2,5-diarylnicotinamides as potent and orally bioavailable orexin-2 receptor selective antagonists is described. A compound from this series demonstrated potent sleep promotion when dosed orally to EEG telemetrized rats.     

Stress and domestication traits increase the relative fitness of crop-wild hybrids in sunflower

After a decade of transgenic crop production, the dynamics of gene introgression into wild relatives remain unclear. Taking an ecological genetics approach to investigating fitness in crop-wild hybrid zones, we uncovered both conditions and characteristics that may promote introgression. We compared diverse crop-wild hybrid genotypes relative to wild Helianthus annuus under one benign and three stressful agricultural environments. Whereas relative fitness of crop-wild hybrids averaged 0.25 under benign conditions, with herbicide application or competition it reached 0.45 and was more variable. In some instances, hybrid fitness matched wild fitness (approximately 1). Thus, wild populations under agronomic stress may be more susceptible to introgression. Although 'domestication' traits are typically considered unlikely to persist in wild populations, we found some (e.g. rapid growth and early flowering) that may enhance hybrid fitness, especially in stressful environments. Rigorous assessment of how particular genotypes, phenotypes, and environments affect introgression will improve risk assessment for transgenic crops.     

The Discovery of orally available thrombin inhibitors : Studies towards the optimisation of CGH1668

The chemical optimisation of CGH1668 1 is described employing an in vivo model of absorption to determine the influence on bioavailability of single point modifications to five key molecular templates. The discovery of an orally bioavailable and selective thrombin inhibitor, 24, highlights the utility of this approach.     

Inter-sexual competition in a dioecious grass

Spatial segregation of the sexes (SSS) occurs in many dioecious angiosperms, but little data are available on the fitness advantages, if any, for males and females. We examined whether reciprocally transplanted male and female seedlings of Distichlis spicata, a dioecious grass species that exhibits extreme SSS, differed in their responses to microhabitats and competition treatments. Plants grown without conspecific competitors grew equally well in both male- or female-majority habitats, suggesting that male and female plants do not have differential resource needs at the juvenile life-history stage. However, plants subject to intra-sexual competition were significantly larger than plants subject to inter-sexual competition, suggesting that niche partitioning may occur in D. spicata.     

EFFECTS OF THE PHYSICAL ENVIRONMENT ON SOME LIPOPROTEIN LAYER SYSTEMS AND OBSERVATIONS ON THEIR MORPHOGENESIS

Lipoprotein membrane systems such as chloroplasts and the endoplasmic reticulum exhibit a generalized swelling response. The initial effect is an increase in interlamellar spacing, but as swelling proceeds, the membranes are transformed into closed thin-walled spherical vesicles. Available evidence suggests that morphogenesis of the endoplasmic reticulum of Nitella and the lamellar system of the Zea chloroplasts involves fusion of small spherical vesicles to yield closed double membrane structures, which subsequently undergo further differentiation. It is suggested that the vesicles comprise a convenient "micellar" form by which lipides may be transported within the cell from the sites of lipide synthesis to regions of lamellar growth. The characteristic formation of vesicles in swelling and the apparent fusion of vesicles in morphogenesis appear to represent two aspects of a fundamental plasticity of lipoprotein layer systems.     

Laboratory gloves as a source of trace element contamination

Contamination in a trace element laboratory can come from a variety of sources, including laboratory gloves. Therefore, vinyl and latex gloves were obtained from as many manufacturers as would supply gloves. These gloves were either prepared for acid-washing and subsequent soaking in an acid solution, or immersed in an acid solution for a duration of either 1 min or 1 h. Incubation washes were analyzed for a variety of trace elements by flame atomic abosrption spectroscopy (AAS) or inductively coupled mass spectrometry (ICP-MS). Results indicated that only three brands of vinyl gloves were acceptable for use in a trace element laboratory, whereas others had contamination of different elements. Latex gloves contained such high levels of biologically important elements that they were not considered suitable for routine trace element work. Vinyl gloves of choice should be routinely acid-washed before use in a trace element laboratory.