Synthesis and in silico biological activity evaluation of new N-substituted pyrazolo-oxazin-2-one systems

Cyclisation of pyrazolo-beta-enaminones 3 readily obtained from 4-aceto acetyl pyrazol 2 with triphosgene led to the formation of N-substituted pyrazolo-1,3-oxazin-2-ones 4 in good yields. Estimation of pharmacotherapeutic potential, possible molecule mechanisms of action, toxic/side effects and interaction with drug-metabolizing enzymes were made for synthesised compounds on the basis of prediction of activity spectra for substances (PASS) prediction results and their analysis by PharmaExpert software. COX inhibition predicted by PASS was confirmed by experimental evaluation.     

Introduction. Extent, processes and evolutionary impact of interspecific hybridization in animals

Since the time of Charles Darwin, studies of interspecific hybridization have been a major focus for evolutionary biologists. Although this phenomenon has often been viewed as problematic in the fields of ecology, taxonomy and systematics, it has become a primary source of data for studies on speciation and adaptation. Effects from genetic/evolutionary processes, such as recombination and natural selection, usually develop over extended periods of time; however, they are accelerated in cases of hybridization. Interspecific hybrids exhibit novel genomes that are exposed to natural selection, thus providing a key to unravel the ultimate causes of adaptation and speciation. Here we provide firstly a historic perspective of hybridization research, secondly a novel attempt to assess the extent of hybridization among animals and thirdly an overview of the reviews and case studies presented in this theme issue.     

Current status of the habitat and population of the black howler monkey (Alouatta pigra) in Balancán, Tabasco, Mexico

We evaluated the habitat and populations of the black howler monkey (Alouatta pigra) in the municipality of Balancán, Tabasco, southeastern Mexico, using a combination of field surveys and remotely sensed data. We identified 21,937 ha of remnant vegetation composed of 1,348 fragments. Fragments separated by up to 200 m were grouped into "clusters" of fragments in accordance with the maximum observed open distance crossed by A. pigra. A total of 11% or 84 of the 772 clusters identified through remote sensing were selected at random, and for these we determined the vegetation type, canopy height, area, and distance to the closest human settlement. In these same 84 clusters, which included a total area of 9,817 ha, from October to June of 2006 we located a total of 1,064 black howler monkeys, including 228 troops and 49 solitary monkeys. A. pigra was found in 62 (74.7%) of all clusters visited, with a cumulative area of 6,032 ha. Troops varied in size from 2 to 15 individuals (average 6.0+/-2.9 ind/troop). Adults were 67% (n=716) of detected individuals, whereas juveniles were 20.5% (n=218) and infants were 12.5% (n=133). We found black howlers to occur at an ecological density of 10.8 ind/km(2), which is low in comparison with A. pigra in other fragmented and conserved sites. We found a statistically significant relationship between the area of clusters and the abundance of howler monkeys (r(2)=0.2, F=10.47, gl=3, P=0.002). In addition, the probability of finding A. pigra was greater in secondary vegetation, riparian vegetation, tropical dry forest, undisturbed tropical oak forest, and palm forest (F=12, gl=3, P<0.0001), as compared with disturbed tropical oak forest. Our results provide data on the distribution, abundance, and population structure of black howler monkeys in a fragmented landscape in the southeast of Mexico. These data are a necessary prerequisite for conservation planning for this species.     

Upregulation of Mitimere and Nubbin acts through cyclin E to confer self-renewing asymmetric division potential to neural precursor cells

In the Drosophila CNS, neuroblasts undergo self-renewing asymmetric divisions, whereas their progeny, ganglion mother cells (GMCs), divide asymmetrically to generate terminal postmitotic neurons. It is not known whether GMCs have the potential to undergo self-renewing asymmetric divisions. It is also not known how precursor cells undergo self-renewing asymmetric divisions. Here, we report that maintaining high levels of Mitimere or Nubbin, two POU proteins, in a GMC causes it to undergo self-renewing asymmetric divisions. These asymmetric divisions are due to upregulation of Cyclin E in late GMC and its unequal distribution between two daughter cells. GMCs in an embryo overexpressing Cyclin E, or in an embryo mutant for archipelago, also undergo self-renewing asymmetric divisions. Although the GMC self-renewal is independent of inscuteable and numb, the fate of the differentiating daughter is inscuteable and numb-dependent. Our results reveal that regulation of Cyclin E levels, and asymmetric distribution of Cyclin E and other determinants, confer self-renewing asymmetric division potential to precursor cells, and thus define a pathway that regulates such divisions. These results add to our understanding of maintenance and loss of pluripotential stem cell identity.     

GDF11 modulates NGN3+ islet progenitor cell number and promotes beta-cell differentiation in pancreas development

Identification of endogenous signals that regulate expansion and maturation of organ-specific progenitor cells is a major goal in studies of organ development. Here we provide evidence that growth differentiation factor 11 (GDF11), a member of the TGF-beta ligand family, governs the number and maturation of islet progenitor cells in mouse pancreas development. Gdf11 is expressed in embryonic pancreatic epithelium during formation of islet progenitor cells that express neurogenin 3. Mice deficient for Gdf11 harbor increased numbers of NGN3+ cells, revealing that GDF11 negatively regulates production of islet progenitor cells. Despite a marked expansion of these NGN3+ islet progenitors, mice lacking Gdf11 have reduced beta-cell numbers and evidence of arrested beta-cell development, indicating that GDF11 is also required for beta-cell maturation. Similar precursor and islet cell phenotypes are observed in mice deficient for SMAD2, an intracellular signaling factor activated by TGF-beta signals. Our data suggest that Gdf11 and Smad2 regulate islet cell differentiation in parallel to the Notch pathway, which previously has been shown to control development of NGN3+ cells. Thus, our studies reveal mechanisms by which GDF11 regulates the production and maturation of islet progenitor cells in pancreas development.     

Association of the abundance and vertical distribution of tuna and beakfish in the southeast of the Caribbean sea

The longline hooks suspension depth was estimated using the Mechanic Imitation of Flexible Systems method. The vertical distribution of tunas and billfish was determined by the relative abundance index, obtained from the catch by 11 to 25 m -long longline vessels, -based at Cumaná, Venezuela, South-eastern Caribbean Sea in depths of 65 to 142 m. The CPUE was evaluated per species, according to depth. High values were found for most of the captured species in the layer from 105 to 125 m. Yellowfin tuna (Thunnus albacares) showed the highest yield (3.37 fish/100 hooks) and blue marlin (Makaira nigricans) the lowest (0.04 fish/100 hooks). However, the statistical comparison did not allow to reject the hypothesis of lack of depth efect (Kruskal-Wallis p > .05), and demonstrated a homogeneous distribution of yellowfin tuna (Thunnus albacares), albacore (Thunnus alalunga), bigeye tuna (Thunnus obesus), sailfish (Istiophorus albicans), white marlin (Tetrapturus albidus) and blue marlin (Makaira nigricans) in the water column. The conclusion is that fish concentration in the Southern border of the Caribbean Sea is possibly due to several hydroclimatic factors--which affect tuna and billfish catching--such as water temperature and dissolved oxygen concentration which limit the distribution according to depth.     

PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure

The type 1 ryanodine receptor (RyR1) on the sarcoplasmic reticulum (SR) is the major calcium (Ca2+) release channel required for skeletal muscle excitation-contraction (EC) coupling. RyR1 function is modulated by proteins that bind to its large cytoplasmic scaffold domain, including the FK506 binding protein (FKBP12) and PKA. PKA is activated during sympathetic nervous system (SNS) stimulation. We show that PKA phosphorylation of RyR1 at Ser2843 activates the channel by releasing FKBP12. When FKB12 is bound to RyR1, it inhibits the channel by stabilizing its closed state. RyR1 in skeletal muscle from animals with heart failure (HF), a chronic hyperadrenergic state, were PKA hyperphosphorylated, depleted of FKBP12, and exhibited increased activity, suggesting that the channels are "leaky." RyR1 PKA hyperphosphorylation correlated with impaired SR Ca2+ release and early fatigue in HF skeletal muscle. These findings identify a novel mechanism that regulates RyR1 function via PKA phosphorylation in response to SNS stimulation. PKA hyperphosphorylation of RyR1 may contribute to impaired skeletal muscle function in HF, suggesting that a generalized EC coupling myopathy may play a role in HF.