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Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF). Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. Methods and Results. Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17%of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. Conclusion. Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure.
Staphylococcus aureus is a frequent human commensal bacterium and pathogen. Here we report the complete genome sequence of strain 6850 (spa type t185; sequence type 50 [ST50]), a highly cytotoxic and clinically virulent methicillin-sensitive strain from a patient with complicated S. aureus bacteremia associated with osteomyelitis and septic arthritis.
Background: Males in some species of the genus Xiphophorus, small freshwater fishes from Meso-America, have an extended caudal fin, or sword - hence their common name "swordtails". Longer swords are preferred by females from both sworded and - surprisingly also, non-sworded (platyfish) species that belong to the same genus. Swordtails have been studied widely as models in research on sexual selection. Specifically, the pre-existing bias hypothesis was interpreted to best explain the observed bias of females in presumed ancestral lineages of swordless species that show a preference for assumed derived males with swords over their conspecific swordless males. However, many of the phylogenetic relationships within this genus still remained unresolved. Here we construct a comprehensive molecular phylogeny of all 26 known Xiphophorus species, including the four recently described species (X. kallmani, X. mayae, X. mixei and X. monticolus). We use two mitochondrial and six new nuclear markers in an effort to increase the understanding of the evolutionary relationships among the species in this genus. Based on the phylogeny, the evolutionary history and character state evolution of the sword was reconstructed and found to have originated in the common ancestral lineage of the genus Xiphophorus and that it was lost again secondarily.
Results: We estimated the evolutionary relationships among all known species of the genus Xiphophorus based on the largest set of DNA markers so far. The phylogeny indicates that one of the newly described swordtail species, Xiphophorus monticolus, is likely to have arisen through hybridization since it is placed with the southern platyfish in the mitochondrial phylogeny, but with the southern swordtails in the nuclear phylogeny. Such discordance between these two types of markers is a strong indication for a hybrid origin. Additionally, by using a maximum likelihood approach the possession of the sexually selected sword trait is shown to be the most likely ancestral state for the genus Xiphophorus. Further, we provide a well supported estimation of the phylogenetic relationships between the previously unresolved northern swordtail groups.
Conclusions: This comprehensive molecular phylogeny of the entire genus Xiphophorus provides evidence that a second swordtail species, X. monticolus, arose through hybridization. Previously, we demonstrated that X. clemenciae, another southern swordtail species, arose via hybridization. These findings highlight the potential key role of hybridization in the evolution of this genus and suggest the need for further investigations into how hybridization contributes to speciation more generally.
KasA is a key enzyme which plays an essential part in the biosynthetic pathway of mycolic acids, the building block of cell wall in Mycobacterium tuberculosis. Its importance was demonstrated by the finding that the depletion of KasA leads to the cell lysis of Mycobacterium tuberculosis. Since Mycobacterium tuberculosis is a pathogen of tuberculosis, the second leading cause of death from an infectious disease worldwide, KasA has drawn attention as one of the attractive drug targets against tuberculosis. Due to the emergence of extensively drug-resistant strains which make most of the known antibiotics for treating tuberculosis ineffective, it became an urgent issue to develop new drugs against tuberculosis. In chapter 3.1, the protonation state of the catalytic residues in the resting state was mainly addressed. The FEP computation and MD simulations were employed for this investigation, and the results showed that the zwitterionic state is most probable. To underpin this conclusion with more solid data, The PESs for the proton transfer between the neutral and zwitterionic state were computed in the context of QM/MM. However, due to the strong dependency of the QM/MM optimization on the initial structure, it was not possible to obtain consistent results from these computations. To circumvent this problem, QM/MM based umbrella sampling was carried out with a semi-empirical method (RM1), and the resulting PMF surface indicated that the zwitterionic state is more stable than the neutral state. In chapter 3.2, the protonation state of significant residues in the acyl-enzyme state was investigated. Unlike other catalytic residues, the protonation state of His311 is ambiguous in the acyl-enzyme state, and different decarboxylation mechanisms can be derived depending on the protonation state of His311 in the acyl-enzyme state. Therefore, FEP computations were carried out to find most probable protonation state of His311 in terms of free energy, and the results showed that the pKa value at Nδ is considerably lowered by the enzyme environment while that of Nε is not. Additionally, the PMF profiles for the proton transfer between Lys340 and Glu354 were computed using QM/MM based umbrellas sampling method, and the results showed that the property of the Lys340/Glu354 pair is neutral rather than ionic when His311 is protonated at Nε. Moreover, a relatively larger ionic character of the Lys340/Glu354 pair when His311 is doubly protonated provides a valuable insight into how the Lys340/Glu354 pair plays a role in shifting the protonated state from Nδ to Nε in His311 after the acyl-transfer step. Overall, the results demonstrated that His311 is neutral and protonated at Nε, and the Lys340/Glu354 pair is also neutral in the acyl-enzyme state. Those computational results lead to the conclusion that the decarboxylation reaction is facilitated by an oxyanion hole which is comprised of two catalytic histidines. In chapter 3.3, the protonation state of catalytic residues in the resting state was revisited because a recent benchmark study showed that the employed semi-empirical method (RM1) in chapter 3.1 tends to overestimate the stabilization of the zwitterionic state. Furthermore, the Lys340/Glu354 pair was considered as purely ionic in chapter 3.1, while it actually has a mixed neutral and ionic character as demonstrated in chapter 3.2. The new investigations employed a larger QM region including the Lys340/Glu354 pair with the BLYP/6-31G** approach, which was proven to be accurate enough for the present purpose by benchmark computations. The new results from the QM/MM MD and FEP computations indicated the catalytic residues to be neutral most probably in the resting state, and this in turn brought up the question how KasA can be activated to initiate the catalytic reaction. On the basis of the results from the MD simulations and FEP computations for the His311Ala mutant in chapter 3.1, we hypothesized that the open conformation of Phe404 would trigger the activation of the catalytic residues by the formation of a strong hydrogen bond. The QM/MM MD simulation proved that the activation of the catalytic residues can indeed be accomplished by the open conformation of Phe404 we suggested, and the corresponding force field based PMF profile also indicated that this conformational change is energetically feasible. The distribution of hydrophilic and hydrophobic residues in the malonyl binding pocket in conjunction with our computational results further provided a valuable insight into the detailed process how the catalytic residues is activated upon the substrate entering.
Background: Heterococcus is a microalgal genus of Xanthophyceae (Stramenopiles) that is common and widespread in soils, especially from cold regions. Species are characterized by extensively branched filaments produced when grown on agarized culture medium. Despite the large number of species described exclusively using light microscopic morphology, the assessment of species diversity is hampered by extensive morphological plasticity.
Results: Two independent types of molecular data, the chloroplast-encoded psbA/rbcL spacer complemented by rbcL gene and the internal transcribed spacer 2 of the nuclear rDNA cistron (ITS2), congruently recovered a robust phylogenetic structure. With ITS2 considerable sequence and secondary structure divergence existed among the eight species, but a combined sequence and secondary structure phylogenetic analysis confined to helix II of ITS2 corroborated relationships as inferred from the rbcL gene phylogeny. Intra-genomic divergence of ITS2 sequences was revealed in many strains. The 'monophyletic species concept', appropriate for microalgae without known sexual reproduction, revealed eight different species. Species boundaries established using the molecular-based monophyletic species concept were more conservative than the traditional morphological species concept. Within a species, almost identical chloroplast marker sequences (genotypes) were repeatedly recovered from strains of different origins. At least two species had widespread geographical distributions; however, within a given species, genotypes recovered from Antarctic strains were distinct from those in temperate habitats. Furthermore, the sequence diversity may correspond to adaptation to different types of habitats or climates.
Conclusions: We established a method and a reference data base for the unambiguous identification of species of the common soil microalgal genus Heterococcus which uses DNA sequence variation in markers from plastid and nuclear genomes. The molecular data were more reliable and more conservative than morphological data.
Morphemes are the smallest meaningful parts of words and therefore represent a natural unit to study the evolution of words. To analyze the influence of language change on morphemes, we performed a large scale analysis of German and English vocabulary covering the last 200 years. Using a network approach from bioinformatics, we examined the historical dynamics of morphemes, the fixation of new morphemes and the emergence of words containing existing morphemes. We found that these processes are driven mainly by the number of different direct neighbors of a morpheme in words (connectivity, an equivalent to family size or type frequency) and not its frequency of usage (equivalent to token frequency). This contrasts words, whose survival is determined by their frequency of usage. We therefore identified features of morphemes which are not dictated by the statistical properties of words. As morphemes are also relevant for the mental representation of words, this result might enable establishing a link between an individual’s perception of language and historical language change.
Hotels are popular settings in European and American literature. They fire readers’ imagination and many of them have a personal relationship to hotels. These institutions are not only alive in the realm of literature but are real existing buildings which have become fixed parts of modern society. Conrad Hilton (1887–1979), founder of the international hotel chain of the same name, was very aware of the glamorous aspects of his field of profession and published his experiences in the autobiography Be My Guest (1957). One copy of the book was placed in each room of the Hilton chain. Due to this Hilton was reaching an enormous audience which inspired other writers to fictionalize Hilton and turn him into a character in their own books. In this paper I will show how Conrad Hilton achieved world-wide fame, partly with the help of his life account. Furthermore, the methods will be explained that he used to present himself as a prototypical American of the Cold War era. I will then focus on two fictional texts, Arthur Hailey’s novel Hotel (1965) and the TV-show Mad Men (2007) by Matthew Weiner, which both incorporated Hilton as a character, yet in very different ways. The aim of this article is to show the potential of celebrity autobiographies to inspire other cultural creations and how authors react very differently to these texts according to their own socio-historical background.
Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HT1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HTP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HTP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.
Sustained anxiety is considered as a chronic and future-oriented state of apprehension that does not belong to a specific object. It is discussed as an important characteristic of anxiety disorders including panic disorder, generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Experimentally, sustained anxiety can be induced by contextual fear conditioning in which aversive events are unpredictably presented and therefore the whole context becomes associated with the threat. This thesis aimed at investigating important mechanisms in the development and maintenance of sustained anxiety: (1) facilitated acquisition and resistant extinction of contextual anxiety due to genetic risk factors (Study 1), and (2) the return of contextual anxiety after successful extinction using a new reinstatement paradigm (Study 2). To this end, two contextual fear conditioning studies were conducted in virtual reality (VR). During acquisition one virtual office was paired with unpredictable mildly painful electric stimuli (unconditioned stimulus, US), thus becoming the anxiety context (CXT+). Another virtual office was never paired with any US, thus becoming the safety context (CXT-). Extinction was conducted 24 h later, i.e. no US was presented, and extinction recall was tested another 24 h later on Day 3. In both studies context-evoked anxiety was measured on three different response levels: behavioral (anxiety-potentiated startle reflex), physiological (skin conductance level), and verbal (explicit ratings). In Study 1, participants were stratified for 5-HTTLPR (S+ risk allele vs. LL no risk allele) and NPSR1 rs324981 (T+ risk allele vs. AA no risk allele) polymorphisms, resulting in four combined genotype groups with 20 participants each: S+/T+, S+/LL, LL/T+, and LL/AA. Results showed that acquisition of anxiety-potentiated startle was influenced by a gene × gene interaction: only carriers of both risk alleles (S+ carriers of the 5-HTTLPR and T+ carriers of the NPSR1 polymorphism) exhibited significantly higher startle magnitudes in CXT+ compared to CXT-. However, extinction recall as measured with anxiety-potentiated startle was not affected by any genotype. Interestingly, the explicit anxiety level, i.e. valence and anxiety ratings, was only influenced by the NPSR1 genotype, in a way that no risk allele carriers (AA) reported higher anxiety and more negative valence in response to CXT+ compared to CXT-, whereas risk allele carriers (T+) did not. Study 2 adopted nearly the same paradigm with the modification that one group (reinstatement group) received one unsignaled US at the beginning of the experimental session on Day 3 before seeing CXT+ and CXT-. The second group served as a control group and received no US, but was immediately exposed to CXT+ and CXT-. Results showed a return of anxiety on the implicit and explicit level (higher startle responses and anxiety ratings in response to CXT+ compared to CXT-) in the reinstatement group only. Most important, the return of contextual anxiety in the reinstatement group was associated with a change of state anxiety and mood from extinction to test, that is the more anxiety and negative mood participants experienced before the reinstatement procedure, the higher their return of anxiety was. In sum, results of Study 1 showed that facilitated contextual fear conditioning on an implicit behavioral level (startle response) could be regarded as an endophenotype for anxiety disorders, which can contribute to our understanding of the etiology of anxiety disorders. Results of Study 2 imply that anxiety and negative mood after extinction could be an important facilitator for the return of anxiety. Furthermore, the present VR-based contextual fear conditioning paradigm seems to be an ideal tool to experimentally study mechanisms underlying the acquisition and the return of anxiety. Future studies could investigate clinical samples and extend the VR paradigm to evolutionary-relevant contexts (e.g., heights, darkness, open spaces).