Dendroecology in the tropics: a review

Over the last decade the field of tropical dendroecology has developed rapidly and major achievements have been made. We reviewed the advances in three main themes within the field. First, long chronologies for tropical tree species were constructed which allowed climate reconstructions, revealed sources of climatic variation and clarified climate–growth relations. Other studies combined tree-ring data and stable isotope (¹³C and ¹⁸O) measurements to evaluate the response of tropical trees to climatic variation and changes. A second set of studies assessed long-term growth patterns of individual trees throughout their life. These studies enhanced the understanding of growth trajectories to the canopy, quantified autocorrelated tree growth and yielded new estimates of tree ages. Such studies were also used to reconstruct the disturbance history of tropical forests. The last set of studies applied tree-ring data to growth models. Tree-ring data can replace diameter measurements from research plots, provide additional information to construct population models, improve timber yield models and validate model output. Based on our review, we propose two main directions for future research. (1) An evaluation of the causes and consequences of growth variation within and among trees and their relation to environmental variation. Studies evaluating this directly contribute to improved understanding of tropical tree ecology. (2) The simultaneous measurement of widths and stable isotope fractions in tree rings offers the potential to study responses of trees to climatic change. Given the major role of tropical forests in the global carbon cycle, knowing these responses is of high priority.     

The discovery of novel cyclohexylamide CCR2 antagonists

As a result of further SAR studies on a piperidinyl piperidine scaffold, we report the discovery of compound 44, a potent, orally bioavailable CCR2 antagonist. While having some in vitro hERG activity, this molecule was clean in an in vivo model of QT prolongation. In addition, it showed excellent efficacy when dosed orally in a transgenic murine model of acute inflammation.     

Inhibition of xc⁻ transporter-mediated cystine uptake by sulfasalazine analogs

A series of sulfasalazine analogs were synthesized and tested for their ability to block cystine-glutamate antiporter system xc? using L-[(14)C]cystine as a substrate. Replacement of sulfasalazine's diazo group with an alkyne group led to an equally potent inhibitor, 2-hydroxy-5-((4-(N-pyridin-2-ylsulfamoyl)phenyl)ethynyl)benzoic acid 6. Our SAR studies also revealed that the carboxylate group of sulfasalazine is essential for its inhibitory activity while the phenolic hydroxyl group is dispensable. Truncated analogs lacking an N-pyridin-2-ylsulfamoyl moiety were less potent than sulfasalazine, but may serve as more tractable templates because of their low molecular weight by applying a variety of fragment growing approaches. Given that sulfasalazine is rapidly metabolized through cleavage of the diazo bond, these analogs may possess a more desirable pharmacological profile as system xc- blockers, in particular, for in vivo studies.     

Novel series of pyrrolotriazine analogs as highly potent pan-Aurora kinase inhibitors

The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.     

Direct interaction of mitochondrial targeting presequences with purified components of the TIM23 protein complex

Precursor proteins that are imported from the cytosol into the matrix of mitochondria carry positively charged amphipathic presequences and cross the inner membrane with the help of vital components of the TIM23 complex. It is currently unclear which subunits of the TIM23 complex recognize and directly bind to presequences. Here we analyzed the binding of presequence peptides to purified components of the TIM23 complex. The interaction of three different presequences with purified soluble domains of yeast Tim50 (Tim50IMS), Tim23 (Tim23IMS), and full-length Tim44 was examined. Using chemical cross-linking and surface plasmon resonance we demonstrate, for the first time, the ability of purified Tim50IMS and Tim44 to interact directly with the yeast Hsp60 presequence. We also analyzed their interaction with presequences derived from precursors of yeast mitochondrial 70-kDa heat shock protein (mHsp70) and of bovine cytochrome P450SCC. Moreover, we characterized the nature of the interactions and determined their KDs. On the basis of our results, we suggest a mechanism of translocation where stronger interactions of the presequences on the trans side of the channel support the import of precursor proteins through TIM23 into the matrix.     

KPC-2-producing <Emphasis Type="Italic">Klebsiella pneumoniae</Emphasis> isolated from a Czech patient previously hospitalized in Greece and in vivo selection of colistin resistance

Carbapenemase-producing Gram-negative bacteria peak clinical interest due to their ability to hydrolyze most β-lactams, including carbapenems; moreover, their genes spread through bacterial populations by horizontal transfer. Bacteria with acquired carbapenemase have sporadically been reported in the Czech Republic, so far only in Enterobacteriaceae and Pseudomonas aeruginosa. In this study, we described the first finding of a KPC-2-producing strain of Klebsiella pneumoniae, which was isolated from a surgical wound swab, decubitus ulcer, and urine of a patient previously hospitalized in Greece. The patient underwent various antibiotic therapies including a colistin treatment. However, after approximately 20 days of the colistin therapy, the strain developed a high-level resistance to this drug. All the isolates were indistinguishable by pulsed field gel electrophoretic analysis and belonged to the international clone ST258, which is typical of KPC-producing K. pneumoniae isolates. The bla _KPC-2 gene was located on a Tn4401a transposon variant. The OmpK35 and OmpK36 genes analysis performed due to the high resistance level of the strains to β-lactams exhibited no changes in their sequence or in their expression when compared with carbapenem-susceptible isolates.     

Thyroid hormone regulation by stress and behavioral differences in adult male rats

Thyroid hormones are essential regulators of growth, development and normal bodily function and their release is coordinated by the hypothalamic-pituitary-thyroid (HPT) axis. While the HPT axis has been established as an acutely stress-responsive neuroendocrine system, relatively little is known about the mechanisms of its stress regulation. The present study examined acute stress-induced changes in peripheral hormone levels [triiodothyronine (T3); thyroxine (T4), thyroid-stimulating hormone (TSH), reverse triiodothyronine (rT3)] and central mRNA levels of regulators of the HPT axis [thyrotropin-releasing hormone (TRH), somatostatin (SST), type II deiodinase (D2)] in response to an inescapable tail-shock, a rodent model of stress. Additionally, we examined whether individual differences in spontaneous exploratory behavior in an open field test predicted basal levels of TH or differential susceptibility to the effects of stress. The stress condition was associated with decreases in peripheral T3, T4 and TSH, but not rT3, when compared with controls. No changes were observed in TRH or SST mRNA levels, but there was a trend suggesting stress-related increases in D2 mRNA. We also found that an animal's exploratory behavior in an unfamiliar open field arena was positively related to peripheral thyroid hormone levels and predicted the magnitude of stress-induced changes.In conclusion, we found suggestive evidence for stress-induced decrease in central drive HPT axis, but the central mechanisms of its stress regulation remain to be elucidated. Additionally, we found that individual differences in animals' exploratory behavior were correlated with peripheral TH levels.     

IL-13 receptor α1 differentially regulates aeroallergen-induced lung responses

IL-13 and IL-4 are hallmark cytokines of Th2-associated diseases including asthma. Recent studies revealed that IL-13Rα1 regulates asthma pathogenesis by mediating both IL-4- and IL-13-mediated responses. Nonetheless, the relative contribution of each cytokine in response to aeroallergen challenge and the degree of functional dichotomy between IL-4 and IL-13 in asthma remains unclear. Consistent with prior publications, we demonstrate that IL-13Rα1 regulates aeroallergen-induced airway resistance and mucus production but not IgE and Th2 cytokine production. We demonstrate that aeroallergen-induced eosinophil recruitment and chemokine production were largely dependent on IL-13Rα1 after Aspergillus but not house dust mite (HDM) challenges. Notably, Aspergillus-challenged mice displayed increased IL-13Rα1-dependent accumulation of dendritic cell subsets into lung-draining lymph nodes in comparison with HDM-challenged mice. Comparison of IL-4 and IL-13 levels in the different experimental models revealed increased IL-4/IL-13 ratios after HDM challenge, likely explaining the IL-13Rα1-independent eosinophilia and chemokine production. Consistently, eosinophil adoptive transfer experiments revealed near ablation of lung eosinophilia in response to Aspergillus in Il13ra1(-/-) mice, suggesting that Aspergillus-induced lung eosinophil recruitment is regulated by IL-13-induced chemokine production rather than altered IL-13 signaling in eosinophils. Furthermore, the near complete protection observed in Il13ra1(-/-) mice in response to Aspergillus challenge was dependent on mucosal sensitization, as alum/Aspergillus-sensitized mice that were rechallenged with Aspergillus developed IL-13Rα1-independent eosinophilia although other asthma parameters remained IL-13Rα1 dependent. These results establish that IL-13Rα1 is required for aeroallergen-induced airway resistance and that allergen-induced chemokine production and consequent eosinophilia is dictated by the balance between IL-4 and IL-13 production in situ.