Novel 3-nitro-1H-1,2,4-triazole-based piperazines and 2-amino-1,3-benzothiazoles as antichagasic agents

We have previously shown that 3-nitro-1H-1,2,4-triazole-based amines demonstrate significant trypanocidal activity, in particular against Trypanosoma cruzi, the causative parasite of Chagas disease. In the present work we further expanded our research by evaluating in vitro the trypanocidal activity of nitrotriazole-based piperazines and nitrotriazole-based 2-amino-1,3-benzothiazoles to establish additional SARs. All nitrotriazole-based derivatives were active or moderately active against T. cruzi; however two of them did not fulfill the selectivity criteria. Five derivatives were active or moderately active against Trypanosoma brucei rhodesiense while one derivative was moderately active against Leishmania donovani. Active compounds against T. cruzi demonstrated selectivity indexes (toxicity to host cells/toxicity to T. cruzi amastigotes) from 117 to 1725 and 12 of 13 compounds were up to 39-fold more potent than the reference compound benznidazole. Detailed SARs are discussed.     

The effects of alkalinity and hypertonicity on the morphology and motility of Leptospira interrogans (biflexa) strain B16.

Effects of alkalinity and hypertonicity on the motile behaviour of Leptospira interrogans (biflexa) B16 were observed, quantified, and compared with effects previously shown by similar factors on the motility of eubacteria. Leptospira interrogans tolerated relatively high concentrations of hydroxide ions. Motility similar to that in controls was observed at pH values up to 9-8; but at pH 10-0 motility declined sharply with time of exposure, and there was structural alteration, visible as a blebbing of the cell envelope. Unlike the behaviour of eubacteria, immobilization of L. interrogans induced by hydroxide ions could not be reversed by lowering the pH. It is suggested that by restricting entry of hydroxide ions, the cell envelope protects its motility apparatus from adverse effects. Leptospira interrogans was completely immobilized in 0-5 M and 1-0 M-sucrose solutions. Unlike the eubacteria, leptospires were incapable of spontaneous reversion to motile forms and resumption of motility was dependent on both concentration and time of exposure to sucrose. Deuterium oxide did not affect movement, suggesting that even though leptospire endoflagella and the exoflagella of eubacteria are analogous, the motile behaviour of L. interrogans is significantly different from that of eubacteria.     

Antiprotease activity in tears and nasal secretions

Summary A trypsin-inhibitory capacity in tears and nasal secretions is demonstrated. No correlation exists between the serum a₁-AT genotype and the level of trypsin-inhibitory capacity in these secretions. Application of the radial-immunodiffusion technique indicates that the antiprotease activity in tears is different from that associated with a₁ globulin.

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Zusammenfassung Im Nasen- und Tränensekret gelang der Nachweis von Antiproteasen-aktivität (Trypsin-Hemmkapazität). Zwischen dem Serum a₁-AT-Genotyp und dem Ausmaß der Trypsin-Hemmkapazität in diesen Sekreten besteht keine Korrelation. Mittels der Radial-Immunodiffusionstechnik konnte gezeigt werden, daß die Antiproteasenkapazität im Tränensekret immunologisch nicht mit dem Serum-a₁-Antitrypsin identisch ist.

     

Can We Use Tree Rings of Black Alder to Reconstruct Lake Levels? A Case Study for the Mecklenburg Lake District,Northeastern Germany

In this study, we explore the potential to reconstruct lake-level (and groundwater) fluctuations from tree-ring chronologies of black alder (Alnus glutinosa L.) for three study lakes in the Mecklenburg Lake District, northeastern Germany. As gauging records for lakes in this region are generally short, long-term reconstructions of lake-level fluctuations could provide valuable information on past hydrological conditions, which, in turn, are useful to assess dynamics of climate and landscape evolution. We selected black alder as our study species as alder typically thrives as riparian vegetation along lakeshores. For the study lakes, we tested whether a regional signal in lake-level fluctuations and in the growth of alder exists that could be used for long-term regional hydrological reconstructions, but found that local (i.e. site-specific) signals in lake level and tree-ring chronologies prevailed. Hence, we built lake/groundwater-level reconstruction models for the three study lakes individually. Two sets of models were considered based on (1) local tree-ring series of black alder, and (2) site-specific Standardized Precipitation Evapotranspiration Indices (SPEI). Although the SPEI-based models performed statistically well, we critically reflect on the reliability of these reconstructions, as SPEI cannot account for human influence. Tree-ring based reconstruction models, on the other hand, performed poor. Combined, our results suggest that, for our study area, long-term regional reconstructions of lake-level fluctuations that consider both recent and ancient (e.g., archaeological) wood of black alder seem extremely challenging, if not impossible.     

Parasternal intercostal muscle remodeling in severe chronic obstructive pulmonary disease.

Studies in experimental animals indicate that chronic increases in neural drive to limb muscles elicit a fast-to-slow transformation of fiber-type proportions and myofibrillar proteins. Since neural drive to the parasternal intercostal muscles (parasternals) is chronically increased in patients with severe chronic obstructive pulmonary diseases (COPDs), we carried out the present study to test the hypothesis that the parasternals of COPD patients exhibit an increase in the proportions of both slow fibers and slow myosin heavy chains (MHCs). Accordingly, we obtained full thickness parasternal muscle biopsies from the third interspace of seven COPD patients (mean +/- SE age: 59 +/- 4 yr) and seven age-matched controls (AMCs). Fiber typing was done by immunohistochemistry, and MHC proportions were determined by SDS-PAGE followed by densitometry. COPD patients exhibited higher proportions of slow fibers than AMCs (73 +/- 4 vs. 51 +/- 3%; P < 0.01). Additionally, COPD patients exhibited higher proportions of slow MHC than AMCs (56 +/- 4 vs. 46 +/- 4%, P < 0.04). We conclude that the parasternal muscles of patients with severe COPD exhibit a fast-to-slow transformation in both fiber-type and MHC proportions. Previous workers have demonstrated that remodeling of the external intercostals, another rib cage inspiratory muscle, elicited by severe COPD is characterized by a slow-to-fast transformation in both fiber types and MHC isoform proportions. The physiological significance of this difference in remodeling between these two inspiratory rib cage muscles remains to be elucidated.     

Cell fate and organogenesis in bacteria.

Intercellular signaling through the Notch receptor and its ligands leads to the spatial differentiation of cell fate in vertebrates and invertebrates. In Myxococcus xanthus, fruiting-body development requires the transmission of a cell-bound intercellular signal by the protein called C-factor, which is functionally equivalent to the eukaryotic Notch ligands. Functional parallels between these two signaling systems include strong positive and negative feedback, and a consequent role in spatial differentiation. Consideration of these parallels enables us to make testable experimental predictions about Notch and C-signaling.     

Extension of the Swiss Lateglacial tree-ring chronologies

Fossil wood finds reveal a high resolution paleoclimatic proxy record of Lateglacial and Early Holocene. Eighty-one buried fossil pine stumps have been excavated on the construction site (Gaenziloo) of the A4-highway tunnel through Uetliberg near Zurich (Switzerland). The trees were buried during their lifetime by loamy alluvia washed down from the upper part of the slopes. The stumps have remained well preserved for more than 13,500 years. The cross sections of the trunks were analyzed dendrochronologically. The sections were dated by ¹⁴C, and ¹⁴C age vs. ring number were obtained from decadal sample segments.Three floating chronologies were built. They cover a time span of 428 years in the Mid-Allerød (GAEALLCH_A), 561 years in the Late-Allerød (GAEALLCH_D) and 212 years in the Younger Dryas (GAEYD_A). Visual synchronization, t-values, percentages of parallel variation (‘Gleichlaeufigkeit’) and radiocarbon wiggle matching (¹⁴C age determinations on a decadal scale) as well as a check by the program Cofecha support the validity of the resulting chronologies.The two Allerød-chronologies from Gaenziloo were linked with two chronologies from Daettnau (DAEALCH_1 and DAEALCH_2) published by Kaiser, K.F. (1993. Beiträge zur Klimageschichte vom Hochglazial bis ins frühe Holozän, rekonstruiert mit Jahrringen und Molluskenschalen aus verschiedenen Vereisungsgebieten. Ziegler Druck- und Verlags-AG, Winterthur. 206pp). They extend the existing floating Swiss chronology in the Late-Allerød by a total of 186 years. Unfortunately independent chronology GAEYD_A does not overlap with the actual absolute chronology developed by the tree-ring laboratory of the University of Hohenheim (Friedrich, M. et al., 2004. The 12,460 year Hohenheim oak and pine tree-ring chronology from Central Europe – A unique annual record for radiocarbon calibration and paleo-environment reconstructions. Radiocarbon 46(3), 1111–22.).