Determination of kinetic parameters of enantiomerization of benzothiadiazines by DCXplorer

Benzothiadiazines differently substituted at the sulfonamidic nitrogen atom, at the stereogenic carbon atom and at the anilinic nitrogen atom have been synthesized and fully characterized. Enantioseparation of these compounds has revealed rapid on‐column enantiomerization. The recently developed software DCXplorer has been successfully applied to calculate enantiomerization kinetic parameters. Enantiomerization barriers of 3‐phenyl substituted benzothiadiazines, calculated in this work, have indicated a higher enantiomerization rate suggesting that the aromatic substituent exerts a strong effect on the enantiomerization process. Methyl substitution on N² position led to higher free energy barriers of enantiomerization, suggesting negative influence of methyl in the N² position on enantiomerization kinetics. However, methylation on N⁴ position increases the enantiomerization rates significantly. The results obtained have been employed to postulate an enantiomerization mechanism for chiral benzothiadiazine type compounds. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Medium molecular weight polar substances of the cuticle as tools in the study of the taxonomy,systematics and chemical ecology of tropical hover wasps (Hymenoptera: Stenogastrinae)

The Stenogastrinae wasps have been proposed as a key group for an understanding of social evolution in insects, but the phylogeny of the group is still under discussion. The use of chemical characters, in particular cuticular hydrocarbons, for insect taxonomy is relatively recent and only a few studies have been conducted on the cuticular polar substances. In this work, we ascertain, by the matrix‐assisted laser desorption ionization‐time of flight mass spectrometry technique, that different species of primitively eusocial hover wasps have different compositions of the epicuticular polar compounds ranging from 900 to 3600 Da. General linear model analysis and discriminant analysis showed that the average spectral profiles of this fraction can be diagnostic for identification of the species. Moreover, for the first time we show population diversification in the medium MW polar cuticular mixtures in insects. In conclusion, the results demonstrate that the chemical characters are consistent with the physical characters and the study support the importance of medium MW polar substances as powerful tools for systematics (chemosystematics) and chemical ecology (fertility signal and population characterization) in a primitively social insect taxon.     

Diet and seed dispersal by five marsupials (Didelphimorphia: Didelphidae) in a Brazilian cerrado reserve

The food habits and seed dispersal promoted by five didelphid marsupials, were investigated through fecal analysis in a cerrado reserve located in the central part of the Espinhaço mountain range in Minas Gerais state, southeastern Brazil. The studied species presented a remarkable constancy in their diets and just for C. philander a seasonal change in diet seems to be present with a high consumption of fruits during the wetter season. Arthropods such as hymenopterans, coleopterans and homopterans were the main food resource detected but seeds belonging to pioneer plants were found with high frequencies in samples of all didelphids. Fruits of pioneer plants belonging to the families Melastomataceae (Clidemia urceolata and Miconia holocericea) and Rubiaceae (Psychotria barbiflora and P. capitata) present high germination rates and were among the mostly consumed. In spite of the differences observed in food preferences, all of the didelphids studied must be considered effective seed dispersers of pioneer plants.     

Evolution of the prevalence and incidence of consumption of antidepressants in a Spanish region (2002-2007)

Background The treatment of depressive disorders involves the administration of drugs of proven efficacy at the correct doses and for specific periods of time, in conjunction with psychotherapeutic support.Aim To assess the evolution of the consumption of antidepressants in the Health Region of Lleida (Spain).Method A retrospective cohort study of the antidepressant medication prescribed via the Spanish National Health System in the Health Region of Lleida between 2002 and 2007. The variables recorded in the study were age, sex, number of patients in antidepressant treatment in the Health Region of Lleida, length of treatment and type of drug. The prevalence of the population of the health region who were receiving antidepressant drugs and the incidence for each particular year was calculated.Results The mean prevalence of patients in treatment with antidepressant drugs was 8.5% (5% in men and 12.1% in women). The highest prevalence was observed in the higher age groups. By therapeutic groups, selective serotonin reuptake inhibitors (SSRIs) were the most frequently prescribed, five times more than the next group, tricyclics/heterocyclics. The follow-up assessment of the medication prescribed showed that one out of every four patients did not continue treatment after the first month, and 38.4% did not continue after three months. Very few were treated for more than six months.Conclusion This study stresses the high rate of antidepressant treatment in the older women's group. One of every four treatments initiated did not last more than one month. Over the six-year period, 16 506 patients dropped out of treatment.     

Molecular Requirements for Ethanol Differential Allosteric Modulation of Glycine Receptors Based on Selective Gβγ Modulation

It is now believed that the allosteric modulation produced by ethanol in glycine receptors (GlyRs) depends on alcohol binding to discrete sites within the protein structure. Thus, the differential ethanol sensitivity of diverse GlyR isoforms and mutants was explained by the presence of specific residues in putative alcohol pockets. Here, we demonstrate that ethanol sensitivity in two ligand-gated ion receptor members, the GlyR adult α₁ and embryonic α₂ subunits, can be modified through selective mutations that rescued or impaired Gβγ modulation. Even though both isoforms were able to physically interact with Gβγ, only the α₁ GlyR was functionally modulated by Gβγ and pharmacological ethanol concentrations. Remarkably, the simultaneous switching of two transmembrane and a single extracellular residue in α₂ GlyRs was enough to generate GlyRs modulated by Gβγ and low ethanol concentrations. Interestingly, although we found that these TM residues were different to those in the alcohol binding site, the extracellular residue was recently implicated in conformational changes important to generate a pre-open-activated state that precedes ion channel gating. Thus, these results support the idea that the differential ethanol sensitivity of these two GlyR isoforms rests on conformational changes in transmembrane and extracellular residues within the ion channel structure rather than in differences in alcohol binding pockets. Our results describe the molecular basis for the differential ethanol sensitivity of two ligand-gated ion receptor members based on selective Gβγ modulation and provide a new mechanistic framework for allosteric modulations of abuse drugs.     

Fine- and local- scale genetic structure of <Emphasis Type="Italic">Dysoxylum malabaricum,</Emphasis> a late-successional canopy tree species in disturbed forest patches in the Western Ghats,India

Dysoxylum malabaricum (white cedar) is an economically important tree species, endemic to the Western Ghats, India, which is the world’s most densely populated biodiversity hotspot. In this study, we used variation at ten nuclear simple sequence repeat loci to investigate genetic diversity and fine scale spatial genetic structure (FSGS) in seedlings and adults of D. malabaricum from four forest patches in the northern part of the Western Ghats. When genetic variation was compared between seedlings and adults across locations, significant differences were detected in allelic richness, observed heterozygosity, fixation index (F _IS), and relatedness (P < 0.05). Reduced genetic diversity and increased relatedness at the seedling stage might be due to fragmentation and disturbance. There was no FSGS at the adult stage and FSGS was limited to shorter distance classes at the seedling stage. However, there was clear spatial genetic structure at the landscape level (<50 km), regardless of age class, due to limited gene flow between forest patches. A comparison of the distributions of size classes in the four locations with published data from a more southern area, showed that large trees (diameter at breast height, DBH, >130 cm) are present in the southern sacred forests but not in the northern forest reserves. This pattern is likely due to stronger harvesting pressure in the north compared to the south, because in the north there are no cultural taboos regulating the extraction of natural resources. The implications for forest conservation in this biodiversity hotspot are discussed.     

Hydrological alterations enhance fish invasions: lessons from a Neotropical coastal river

Hydrobiologia - With the aim of assessing whether hydrological alterations differently affect non-native and native fish species in coastal systems, we investigated fish assemblages along the...     

Long non‐coding RNA TINCR suppresses metastatic melanoma dissemination by preventing ATF4 translation

Transition from proliferative‐to‐invasive phenotypes promotes metastasis and therapy resistance in melanoma. Reversion of the invasive phenotype, however, is challenged by the poor understanding of mechanisms underlying its maintenance. Here, we report that the lncRNA TINCR is down‐regulated in metastatic melanoma and its silencing increases the expression levels of invasive markers, in vitro migration, in vivo tumor growth, and resistance to BRAF and MEK inhibitors. The critical mediator is ATF4, a central player of the integrated stress response (ISR), which is activated in TINCR‐depleted cells in the absence of starvation and eIF2α phosphorylation. TINCR depletion increases global protein synthesis and induces translational reprogramming, leading to increased translation of mRNAs encoding ATF4 and other ISR proteins. Strikingly, re‐expression of TINCR in metastatic melanoma suppresses the invasive phenotype, reduces numbers of tumor‐initiating cells and metastasis formation, and increases drug sensitivity. Mechanistically, TINCR interacts with mRNAs associated with the invasive phenotype, including ATF4, preventing their binding to ribosomes. Thus, TINCR is a suppressor of the melanoma invasive phenotype, which functions in nutrient‐rich conditions by repressing translation of selected ISR RNAs.     

Phenyl-substituted aminomethylene-bisphosphonates inhibit human P5C reductase and show antiproliferative activity against proline-hyperproducing tumour cells

In certain cancers, such as breast, prostate and some lung and skin cancers, the gene for the enzyme catalysing the second and last step in proline synthesis, δ¹-pyrroline-5-carboxylate (P5C) reductase, has been found upregulated. This leads to a higher proline content that exacerbates the effects of the so-called proline-P5C cycle, with tumour cells effectively using this method to increase cell survival. If a method of reducing or inhibiting P5C reductase could be discovered, it would provide new means of treating cancer. To address this point, the effect of some phenyl-substituted derivatives of aminomethylene-bisphosphonic acid, previously found to interfere with the catalytic activity of plant and bacterial P5C reductases, was evaluated in vitro on the human isoform 1 (PYCR1), expressed in E. coli and affinity purified. The 3.5-dibromophenyl- and 3.5-dichlorophenyl-derivatives showed a remarkable effectiveness, with IC₅₀ values lower than 1 µM and a mechanism of competitive type against both P5C and NADPH. The actual occurrence in vivo of enzyme inhibition was assessed on myelogenous erythroleukemic K562 and epithelial breast cancer MDA-MB-231 cell lines, whose growth was progressively impaired by concentrations of the dibromo derivative ranging from 10⁻⁶ to 10⁻⁴M. Interestingly, growth inhibition was not relieved by the exogenous supply of proline, suggesting that the effect relies on the interference with the proline-P5C cycle, and not on proline starvation.