Synthesis and structure-activity relationship of 2-(aminoalkyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives: a novel series of 5-HT(2A/2C) receptor antagonists. Part 2.

Following the programme started at Janssen Research Foundation searching for 5-HT(2A/2C) antagonists, we now report on the synthesis of a series of substituted 2-(Dimethylaminomethyl)-2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine derivatives. The 5-HT(2A), 5-HT(2C) and H(1) receptor affinities as well as the mCPP antagonistic activity of the compounds synthesised is described.     

TBCD Links Centriologenesis,Spindle Microtubule Dynamics,and Midbody Abscission in Human Cells

Microtubule-organizing centers recruit α- and β-tubulin polypeptides for microtubule nucleation. Tubulin synthesis is complex, requiring five specific cofactors, designated tubulin cofactors (TBCs) A–E, which contribute to various aspects of microtubule dynamics in vivo. Here, we show that tubulin cofactor D (TBCD) is concentrated at the centrosome and midbody, where it participates in centriologenesis, spindle organization, and cell abscission. TBCD exhibits a cell-cycle-specific pattern, localizing on the daughter centriole at G1 and on procentrioles by S, and disappearing from older centrioles at telophase as the protein is recruited to the midbody. Our data show that TBCD overexpression results in microtubule release from the centrosome and G1 arrest, whereas its depletion produces mitotic aberrations and incomplete microtubule retraction at the midbody during cytokinesis. TBCD is recruited to the centriole replication site at the onset of the centrosome duplication cycle. A role in centriologenesis is further supported in differentiating ciliated cells, where TBCD is organized into “centriolar rosettes”. These data suggest that TBCD participates in both canonical and de novo centriolar assembly pathways.     

Changes in fish condition and mercury vary by region,not Bythotrephes invasion: a result of climate change?

We compared changes in body condition (relative weight) and mercury concentrations ([Hg]) in two species of coregonid fish (lake herring Coregonus artedi, lake whitefish C. clupeaformis) among discrete populations in Ontario between 1967 and 2006. Temporal comparisons among populations were made to determine whether 1) the establishment of Bythotrephes longimanus had affected coregonid populations, or 2) if changes in body condition or [Hg] were related to regional differences in the degree of climate change during the time period investigated. Climate data from northwestern, northeastern and southern Ontario showed a general warming trend in all regions over the period of study. However, greater temporal changes in climate were observed in the northwest where growing degree days >5°C (GDD) increased and precipitation declined over the study period compared with relatively little change in southern or northeastern Ontario. Correspondingly, northwestern Ontario coregonid populations demonstrated significantly greater declines in body condition relative to those from northeastern or southern Ontario. Declines in [Hg] of both species were also greater among northwestern populations compared with those from northeastern or southern Ontario but only significantly so for lake herring. These declines were independent of the invasion of non‐native Bythotrephes, and declines in [Hg] were opposite predictions based on the hypothesis that Bythotrephes invasion lengthened aquatic food chains. Based on our findings and further evidence from the literature, we propose that warming regional climates are capable of contributing to declines in both condition and [Hg] of fishes. Because fish condition affects both reproductive success and overwinter survival, observed condition declines of the magnitude reported here could have profound implications for the structure of future aquatic ecosystems in a warming climate.     

Effects of lateral amygdala lesions on the responses to novelty in mice

Bilateral electrolytic lesions restricted to the lateral, basolateral and basomedial amygdaloid nuclei in mice produced a lack of avoidance responses towards novel stimuli. While controls showed avoidance and burying reactions to a novel object introduced into their familiar environment, lesioned mice displayed a high number of approach responses and a low level of burying reactions. Furthermore, when given the opportunity to move around freely in simultaneously presented novel and familiar places, control mice at first exhibited avoidance reactions to the novel environment before showing novelty preference. There were no avoidance reactions in lesioned mice. These data are consistent with the hypothesis that amygdala plays a specific role in the regulation of defensive reactions.     

Effect of foliar‐applied potassium silicate on coffee leaf infection by Hemileia vastatrix

Coffee leaf rust, caused by Hemileia vastatrix, is the most devastating disease of coffee. Since limited information is available in the literature on silicon (Si) affecting plant diseases in coffee, this study was designed to investigate foliar application of potassium silicate (PS), a source of soluble (Si), on infection process of coffee leaf rust at the microscopic level. The foliar Si concentration for plants sprayed with water and PS has no significant difference (0.24 and 0.30 dag kg^?1, respectively). X‐ray microanalysis indicated that the deposition of Si on the leaves of the plants that were sprayed with PS was greater in comparison to the leaf samples from the plants sprayed with water. Rust severity on leaves of plants sprayed with water or sprayed with PS reached 44% and 32%, respectively, at 36 days after inoculation (dai). Plates of polymerised PS were observed on the leaf surfaces of the plants sprayed with the product, in contrast to its absence on the leaf surfaces of plants sprayed with water. At 36 dai, a greater number of uredia were observed on the leaf surfaces of plants sprayed with water in comparison to the leaf surfaces of plants sprayed with PS. On fractured leaf tissues that were sprayed with PS, less fungal colonisation was observed in comparison to the leaves of plants sprayed with water. In conclusion, the results of this study suggest that the effect of foliar‐applied Si on the control of the coffee leaf rust development may be attributed to the physical role of the polymerised PS, its osmotic effect against urediniospores germination, or both.     

Other developments regarding the concept of energy in biological systems

In order to recognize the realizability of inputs with different physical natures through a component, Yoneda's Lemma is applied. The major utility of this Lemma is when the components produce only energy. From this, it is assumed that a new material input must exist which was not recognized in the original developments in biological systems representation. Moreover, simple transfers of energy, between objects, components, and among both objects and components are developed under the generic name; energetical evolution. Thus, energetical evolution appears as anew element in the abstract representation of biological systems. These new concepts are incorporated into a new abstract diagram and a newM _β category. This paper was made possible by a Fellowship from the Consejo Nacional de Investigaciones Científicas y Técnicas of the República Argentina.     

Co-fermentation of xylose and cellobiose by an engineered Saccharomyces cerevisiae

We have integrated and coordinately expressed in Saccharomyces cerevisiae a xylose isomerase and cellobiose phosphorylase from Ruminococcus flavefaciens that enables fermentation of glucose, xylose, and cellobiose under completely anaerobic conditions. The native xylose isomerase was active in cell-free extracts from yeast transformants containing a single integrated copy of the gene. We improved the activity of the enzyme and its affinity for xylose by modifications to the 5′-end of the gene, site-directed mutagenesis, and codon optimization. The improved enzyme, designated RfCO*, demonstrated a 4.8-fold increase in activity compared to the native xylose isomerase, with a K_m for xylose of 66.7?mM and a specific activity of 1.41?μmol/min/mg. In comparison, the native xylose isomerase was found to have a K_m for xylose of 117.1?mM and a specific activity of 0.29?μmol/min/mg. The coordinate over-expression of RfCO* along with cellobiose phosphorylase, cellobiose transporters, the endogenous genes GAL2 and XKS1, and disruption of the native PHO13 and GRE3 genes allowed the fermentation of glucose, xylose, and cellobiose under completely anaerobic conditions. Interestingly, this strain was unable to utilize xylose or cellobiose as a sole carbon source for growth under anaerobic conditions, thus minimizing yield loss to biomass formation and maximizing ethanol yield during their fermentation.