Equilibrium unfolding of mutant apomyoglobins with substitutions of conserved nonfunctional residues by alanine

The problems of protein aggregation and protein misfolding in the cell are connected with the appearance of many genetic diseases. Both processes can be a consequence of substitutions of certain amino acid residues in proteins. The substitutions can influence the protein stability and protein folding rates in both the intermediate and the native states. We have studied equilibrium urea unfolding of mutant forms of apomyoglobin with substitutions of conserved nonfunctional residues by Ala to estimate their influence on protein stability. These residues include Val10, Trp14, Ilel11, Leu115, Met131 and Leu135. Conformational transitions were monitored by intrinsic Trp fluorescence and by circular dichroism spectra in the far UV region. Free energy changes upon the transition from the native to intermediate state and from the intermediate to unfolded state were determined. It was shown that all substitutions used lead to an appreciable decrease of the apomyoglobin native state stability, whereas the stability of the intermediate state is affected substantially smaller.     

Ontogenetic variability in external morphology of native (Canadian) and non-native (Slovak) populations of pumpkinseed Lepomis gibbosus (Linnaeus 1758)

External morphology of native Canadian (River Otonabee, Looncall Lake) and non‐native Slovak (River Danube) pumpkinseed was examined using both triple regression analysis (distance‐based measurements) and geometrical analysis (coordinate‐based measurements) within an ontogenetical aspect. In general, the results from the geometrical analysis comply with those from the triple regression analysis. The smallest pumpkinseed (predominantly juveniles) differed significantly from the largest pumpkinseed (predominantly adults) in all the three populations. The major difference was that adults had a deeper body and larger belly area than juveniles, which is probably associated with more space for gonads in mature fish. Developmental patterns and external morphology in pumpkinseed from the River Otonabee seemed to be closer to pumpkinseed from the Danube than to those from Lake Looncall. This suggests that, in the pumpkinseed examined, ontogenetic changes in external shape depend on environmental conditions (epigenetical information) rather than on geographical and/or genetical isolation. Further examination of early development, fecundity, number of spawning acts per season, parental care, egg size, age at maturation, etc., will follow to test this hypothesis.     

Variability of the Upper Palaeolithic skulls from Predmostí near Prerov (Czech Republic): craniometric comparison with recent human standards.

One of the largest skeletal series of the Upper Palaeolithic period from Predmostí was destroyed during the Second World War, but the study of this material continues up to the present. The discovery of Matiegka's original photographic documentation on glass plates [Velemínská et al., 2004. The use of recently re-discovered glass plate photo-documentation of those human fossil finds from Predmostí u Prerova destroyed during World War II. J. Nat. Mus. Nat. Hist. Ser. 173, 129-132] gives an opportunity to perform a new and detailed craniometric analysis of five adult skulls in their lateral projection. The craniometric data were analysed using specialised Craniometrics software, and the analysis included morphological and dimensional comparisons with current Central European norms. The aim of the study was not only to monitor the skull shape as a whole, but predominantly, to evaluate the size and shape of various parts of the splanchnocranium. The Upper Palaeolithic skulls are significantly longer, and male skulls are also higher than the current norms. The crania of anatomically modern humans are characterised by two general structural features: mid-lower facial retraction and neurocranial globularity. The height of the face of the Palaeolithic skulls corresponds to that of the current Central European population. The face has a markedly longer mandibular body (3-4 SD), while female mandibular rami are shorter. The skulls are further characterised by a smaller gonial angle, the increased steepness of the mandibular ramus, and the greater angle of the chin. These changes in the size and shape associated with anterior rotation of the face produce a strong protrusion of both jaws, but the sagittal inter-maxillary relationships remain unchanged. The observed facial morphology is similar to the Czech Upper Palaeolithic skulls from Dolní Vestonice. This study confirms the main diachronic changes between skulls of Upper Palaeolithic and present-day human populations.     

Ethanol modifies the ion selectivity of sodium channels in the rat sensory neurons]

Ethanol was shown to decrease the reversal potential of tetrodotoxin-resistant (TTXr) and TTX-sensitive channels in short-term culture of the dorsal root ganglion cells. The ethanol led to alterations in ionic selectivity of the TTXr channels (its shifting from the X-th Eisenmann selectivity sequence to the XI-th one). The data obtained suggest that the findings were due to selectivity filter modification because of disturbed hydrogen bounds in the channel macromolecule.     

Age and growth in a newly-established invasive population of topmouth gudgeon

Specimens of invasive topmouth gudgeon, Pseudorasbora parva, from Šúr Pond (Bratislava, Slovakia) were examined to assess age and growth, and to determine whether this recently-established invasive population employs a less specialized ontogenetic trajectory than the specialized form typical of native and/or long-time established populations. Samples were collected in October 2004 (n=143). Standard length (SL) ranged from 18.16 mm to 67.57 mm (mean 32.56 mm), and eviscerated body weight ranged from 0.10 to 5.02 g (mean 0.63 g). Scale caudal diameter ranged from 0.52 to 2.42 mm (mean 1.08 mm). SL at which the scales started to form was estimated to be 1.58 mm. The population was represented with 5 age groups, from 0+ to 4+. Relative to other populations for which comparable data are available the recently-established population of topmouth gudgeon was found to mature at smaller size and at a younger age compared to native and/or long-time established populations (all specimens bigger than 25.0 mm SL, and 94% of specimens from the age group I were already mature).     

Synthesis and structural activity relationship of 11beta-HSD1 inhibitors with novel adamantane replacements

A series of structurally novel and metabolically stable bridged bicyclic carbocycle and heterocycle adamantane replacements have been synthesized and biologically evaluated. Several of these compounds exhibit excellent human and mouse 11beta-HSD1 potency and 11beta-HSD2 selectivity.     

Discovery of orally active butyrolactam 11beta-HSD1 inhibitors

A series of metabolically stable butyrolactam 11beta-HSD1 inhibitors have been synthesized and biologically evaluated. These compounds exhibit excellent HSD1 potency and HSD2 selectivity, pharmacokinetic, and pharmacodynamic profiles.     

The effect of psychoemotional load on ventricular repolarization reflected in integral body surface potential maps

The aim of the present study was to investigate the reflection of psychoemotional stress in the body surface potential distribution as documented by isointegral maps of cardiac activation and recovery. In 72 young men (18.3+/- 7.3 y.) with no cardiovascular history body surface potential maps (BSPMs) at rest and during the test of mental arithmetic were recorded. The digitalized data for each point of the QRS, STT and QRST integral maps, for each subject in both situations, were processed and evaluated by methods of univariate as well as spatial mathematical and statistical modeling. The results showed during MA a significant decrease of repolarization integral values over the sternum and right precordium, which contributed to analogically localized decrements also in the QRST BSM. The decrease occurred in more than 2/3 of lead points. The most pronounced changes were observed in the right precordial area, where potentials decreased in more than in 70 % of subjects. In conclusion, the discriminative power of the difference STT and QRST integral maps was strong enough to distinguish the mental arithmetic induced changes in the superficial cardiac electric field. These adrenergic transient alterations in ventricular recovery may be of importance in subjects at risk for ventricular arrhythmias.     

Arachidonic acid stimulates formation of a novel complex containing nucleolin and RhoA

Arachidonic acid (AA) stimulates cell adhesion through a p38 mitogen activated protein kinase-mediated RhoA signaling pathway. Here we report that a proteomic screen following AA-treatment identified nucleolin, a multifunctional nucleolar protein, in a complex with the GTPase, RhoA, that also included the Rho kinase, ROCK. AA-stimulated cell adhesion was inhibited by expression of nucleolin-targeted shRNA and formation of the multiprotein complex was blocked by expression of dominant-negative RhoA. AA-treatment also induced ROCK-dependent serine phosphorylation of nucleolin and translocation of nucleolin from the nucleus to the cytoplasm, where it appeared to co-localize with RhoA. These data suggest the existence of a new signaling pathway through which the location and post-translational state of nucleolin are modulated.