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Background
The role of hospital water systems in the development of Pseudomonas aeruginosa (P. aeruginosa) surgical site infections (SSIs) in low-income countries is barely studied. This study characterized P. aeruginosa isolates from patients and water in order to establish possible epidemiological links.
Methods:
Between December 2014 and September 2015, rectal and wound swabs, and water samples were collected in the frame of active surveillance for SSIs in the two Tanzanian hospitals. Typing of P. aeruginosa was done by multi-locus sequence typing.
Results:
Of 930 enrolled patients, 536 were followed up, of whom 78 (14.6%, 95% CI; 11.6–17.5) developed SSIs. P. aeruginosa was found in eight (14%) of 57 investigated wounds. Of the 43 water sampling points, 29 were positive for P. aeruginosa. However, epidemiological links to wound infections were not confirmed. The P. aeruginosa carriage rate on admission was 0.9% (8/930). Of the 363 patients re-screened upon discharge, four (1.1%) possibly acquired P. aeruginosa during hospitalization. Wound infections of the three of the eight P. aeruginosa SSIs were caused by a strain of the same sequence type (ST) as the one from intestinal carriage. Isolates from patients were more resistant to antibiotics than water isolates.
Conclusions:
The P. aeruginosa SSI rate was low. There was no evidence for transmission from tap water. Not all P. aeruginosa SSI were proven to be endogenous, pointing to other routes of transmission.
Background:
Adherence to pharmacotherapeutic treatment guidelines in patients with heart failure (HF) is of major prognostic importance, but thorough implementation of guidelines in routine care remains insufficient. Our aim was to investigate prevalence and characteristics of HF in patients with coronary heart disease (CHD), and to assess the adherence to current HF guidelines in patients with HF stage C, thus identifying potential targets for the optimization of guideline implementation.
Methods:
Patients from the German sample of the European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EuroAspire) IV survey with a hospitalization for CHD within the previous six to 36 months providing valid data on echocardiography as well as on signs and symptoms of HF were categorized into stages of HF: A, prevalence of risk factors for developing HF; B, asymptomatic but with structural heart disease; C, symptomatic HF. A Guideline Adherence Indicator (GAI-3) was calculated for patients with reduced (≤40%) left ventricular ejection fraction (HFrEF) as number of drugs taken per number of drugs indicated; beta-blockers, angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and mineralocorticoid receptor antagonists (MRA) were considered.
Results:
509/536 patients entered analysis. HF stage A was prevalent in n = 20 (3.9%), stage B in n = 264 (51.9%), and stage C in n = 225 (44.2%) patients; 94/225 patients were diagnosed with HFrEF (42%). Stage C patients were older, had a longer duration of CHD, and a higher prevalence of arterial hypertension. Awareness of pre-diagnosed HF was low (19%). Overall GAI-3 of HFrEF patients was 96.4% with a trend towards lower GAI-3 in patients with lower LVEF due to less thorough MRA prescription.
Conclusions:
In our sample of CHD patients, prevalence of HF stage C was high and a sizable subgroup suffered from HFrEF. Overall, pharmacotherapy was fairly well implemented in HFrEF patients, although somewhat worse in patients with more reduced ejection fraction. Two major targets were identified possibly suited to further improve the implementation of HF guidelines: 1) increase patients´ awareness of diagnosis and importance of HF; and 2) disseminate knowledge about the importance of appropriately implementing the use of mineralocorticoid receptor antagonists.
Trial registration:
This is a cross-sectional analysis of a non-interventional study. Therefore, it was not registered as an interventional trial.
In highly polarized cells like neurons, cytoskeleton dynamics play a crucial role in establishing neuronal connections during development and are required for adult plasticity. Actin turnover is particularly important for neurite growth, axon path finding, branching and synaptogenesis. Motoneurons establish several thousand branches that innervate neuromuscular synapses (NMJs). Axonal branching and terminal arborization are fundamental events during the establishment of synapses in motor endplates. Branching process is triggered by the assembly of actin filaments along the axon shaft giving rise to filopodia formation. The unique contribution of the three actin isoforms, α-, β- and γ-actin, in filopodia stability and dynamics during this process is not well characterized. Here, we performed high resolution in situ hybridization and qRT-PCR and showed that in primary mouse motoneurons α-, β- and γ-actin isoforms are expressed and their transcripts are translocated into axons. Using FRAP experiments, we showed that transcripts for α-, β- and γ-actin become locally translated in axonal growth cones and translation hot spots of the axonal branch points. Using live cell imaging, we showed that shRNA depletion of α-actin reduces dynamics of axonal filopodia which correlates with reduced number of collateral branches and impairs axon elongation. Depletion of β-actin correlates with reduced dynamics of growth cone filopoida, disturbs axon elongation and impairs presynaptic differentiation. Also, depletion of γ-actin impairs axonal growth and decreases axonal filopodia dynamics. These findings implicate that actin isoforms accomplish unique functions during development of motor axons. Depletions of β- and γ-actin lead to compensatory upregulation of other two isoforms. Consistent with this, total actin levels remain unaltered and F-actin polymerization capacity is preserved. After the knockdown of either α- or γ-actin, the levels of β-actin increase in the G-actin pool indicating that polymerization and stability of β-actin filaments depend on α- or γ-actin. This study provides evidence both for unique and overlapping function of actin isoforms in motoneuron growth and differentiation. In the soma of developing motoneurons, actin isoforms act redundantly and thus could compensate for each other’s loss. In the axon, α-, β- and γ-actin accomplish specific functions, i.e. β-actin regulates axon elongation and plasticity and α- and γ-actin regulate axonal branching.
Furthermore, we show that both axonal transport and local translation of α-, β- and γ-actin isoforms are impaired in Smn knockout motoneurons, indicating a role for Smn protein in RNA granule assembly and local translation of these actin isoforms in primary mouse motoneurons.
The inhibitory glycine receptors are one of the major mediators of rapid synaptic inhibition in the mammalian brainstem, spinal cord and higher brain centres. They are ligand-gated ion channels that are mainly involved in the regulation of motor functions. Dysfunction of the receptor is associated with motor disorders such as hypereklepxia or some forms of spasticity. GlyR is composed of two glycosylated integral membrane proteins α and β and a peripheral membrane protein of gephyrin. Moreover, there are four known isoforms of the α-subunit (α1-4) of GlyR while there is a single β-subunit. Glycine receptors can be homomeric including α subunits only or heteromeric containing both α and β subunits. To date, strychnine is the ligand that has the highest affinity as glycine receptor ligand. It acts as a competitive antagonist of glycine that results in the inhibition of Cl- ions permeation and consequently reducing GlyR-mediated inhibition.
For a long time, the details of the molecular mechanism of GlyRs inactivation by strychnine were insufficient due to the lack of high-resolution structures of the receptor. Only homology models based on structures of other cys-loop receptors have been available. Recently, 3.0 Å X-ray structure of the human glycine receptor- α3 homopentamer in complex with strychnine, as well as electro cryo-microscopy structures of the zebra fish α1 GlyR in complex with strychnine and glycine were published. Such information provided detailed insight into the molecular recognition of agonists and antagonists and mechanisms of GlyR activation and inactivation.
Very recently, a series of dimeric strychnine analogs obtained by diamide formation of two molecules of 2-aminostrychnine with diacids of different chain length was pharmacologically evaluated at human α1 and α1β glycine receptors. None of the dimeric analogs was superior to strychnine.
The present work focused on the extension of the structure-activity relationships of strychnine derivatives at glycine receptors
All the synthesized compounds were pharmacologically evaluated at human α1 and α1β glycine receptors in a functional FLIPRTM assay and the most potent analogs were pharmacologically evaluated in a whole cell patch-clamp assay and in [3H]strychnine binding studies.
It was reported that 11-(E)-isonitrosostrychnine displayed a 2-times increased binding to both α1 and α1β glycine receptors which prompted us to choose the hydroxyl group as a suitable attachment point to connect two 11-(E)-isonitrosostrychnine molecules using a spacer. In order to explore the GlyR pocket tolerance for oxime extension, a series of oxime ethers with different spacer lengths and sterical/lipophilic properties were synthesized biologically evaluated. Among all the oxime ethers, methyl, allyl and propagyl oxime ethers were the most potent antagonists displaying IC50 values similar to that of strychnine. These findings indicated that strychnine binding site at GlyRs comprises an additional small lipophilic pocket located in close proximity to C11 of strychnine and the groups best accommodated in this pocket are (E)-allyl and (E)-propagyl oxime ethers.
Moreover, 11-aminostrychnine, and the corresponding propionamide were prepared and pharmacologically evaluated to examine the amide function at C11 as potential linker.
A series of dimeric strychnine analogs designed by linking two strychnine molecules through amino groups in position 11 with diacids were synthesized and tested in binding studies and functional assays at human α1 and α1β glycine receptors. The synthesized bivalent ligands were designed to bind simultaneously to two α-subunits of the pentameric glycine receptors causing a possibly stronger inhibition than the monomeric strychnine. However, all the bivalent derivatives showed no significant difference in potency compared to strychnine. When comparing the reference monomeric propionamide containing ethylene spacer to the dimeric ligand containing butylene spacer, a 3-fold increase in potency was observed. Since the dimer containing (CH2)10 spacer length was found to be equipotent to strychnine, it is assumed that one molecule of strychnine binds to the receptor and the ‘additional’ strychnine molecule in the dimer probably protrudes from the orthosteric binding sites of the receptor.
\(Ambra1\) is linked to autophagy and neurodevelopment. Heterozygous \(Ambra1\) deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of \(AMBRA1\) for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal \(AMBRA1\) genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower \(AMBRA1\) mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by \(in\) \(silico\) analysis. Searching for further autism-relevant characteristics in \(Ambra1^{+/−}\) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an \(in\) \(vivo\) readout of neuronal excitation–inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of \(AMBRA1/Ambra1\) partial loss-of-function genotypes for female autistic traits. Moreover, they suggest \(Ambra1\) heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
Paramagnetic heavy fermion insulators consist of fully occupied quasiparticle bands inherent to Fermi liquid theory. The gap emergence below a characteristic temperature is the ultimate sign of coherence for a many-body system, which in addition can induce a non-trivial band topology. Here, we demonstrate a simple and efficient method to compare a model study and an experimental result for heavy fermion insulators. The temperature dependence of the gap formation in both local moment and mixed valence regimes is captured within the dynamical mean field (DMFT) approximation to the periodic Anderson model (PAM). Using the topological coherence temperature as the scaling factor and choosing the input parameter set within the mixed valence regime, we can unambiguously link the theoretical energy scales to the experimental ones. As a particularly important result, we find improved consistency between the scaled DMFT density of states and the photoemission near-gap spectra of samarium hexaboride (SmB\(_{6}\)).
Terpenoids are major subcomponents in aroma substances which harbor sedative physiological potential. We have demonstrated that various monoterpenoids such as the acyclic linalool enhance GABAergic currents in an allosteric manner in vitro upon overexpression of inhibitory α1β2 GABA\(_{A}\) receptors in various expression systems. However, in plants or humans, i.e., following intake via inhalation or ingestion, linalool undergoes metabolic modifications including oxygenation and acetylation, which may affect the modulatory efficacy of the generated linalool derivatives. Here, we analyzed the modulatory potential of linalool derivatives at α1β2γ2 GABA\(_{A}\) receptors upon transient overexpression. Following receptor expression control, electrophysiological recordings in a whole cell configuration were used to determine the chloride influx upon co-application of GABA EC\(_{10-30}\) together with the modulatory substance. Our results show that only oxygenated linalool metabolites at carbon 8 positively affect GABAergic currents whereas derivatives hydroxylated or carboxylated at carbon 8 were rather ineffective. Acetylated linalool derivatives resulted in non-significant changes of GABAergic currents. We can conclude that metabolism of linalool reduces its positive allosteric potential at GABAA receptors compared to the significant potentiation effects of the parent molecule linalool itself.
Scaffold proteins are ubiquitous chaperones that promote efficient interactions between partners of multi-enzymatic protein complexes; although they are well studied in eukaryotes, their role in prokaryotic systems is poorly understood. Bacterial membranes have functional membrane microdomains (FMM), a structure homologous to eukaryotic lipid rafts. Similar to their eukaryotic counterparts, bacterial FMM harbor a scaffold protein termed flotillin that is thought to promote interactions between proteins spatially confined to the FMM. Here we used biochemical approaches to define the scaffold activity of the flotillin homolog FloA of the human pathogen Staphylococcus aureus, using assembly of interacting protein partners of the type VII secretion system (T7SS) as a case study. Staphylococcus aureus cells that lacked FloA showed reduced T7SS function, and thus reduced secretion of T7SS-related effectors, probably due to the supporting scaffold activity of flotillin. We found that the presence of flotillin mediates intermolecular interactions of T7SS proteins. We tested several small molecules that interfere with flotillin scaffold activity, which perturbed T7SS activity in vitro and in vivo. Our results suggest that flotillin assists in the assembly of S. aureus membrane components that participate in infection and influences the infective potential of this pathogen.
What does it mean to take animal autobiography seriously and how can we account for the representation of life-narrating animals? The article investigates animal autobiographies as ‘literary autozoographies’, drawing attention to both the generic contexts and the epistemological premises of these texts. Adopting a double-bind approach stemming from autobiographical research as well as cultural animal studies, the article focuses on early nineteenth-century equine autozoographies from the German-speaking tradition. These texts are discussed exemplarily in relation to the parameters of fictional autobiographies, before they are contextualized with historical discourses regarding horses in natural history and so-called ‘horse-science’. Due to the fact that the poetics and aesthetics of the genre are modeled on the templates of factual autobiographies, the article argues that literary autozoographies can be read as fictional autobiographies as well as meta-auto/biographical discourse undermining autobiographical conventions. Furthermore, it shows that literary autozoography and zoology share a common historical and ideological epistemology accounting for the representation of animals in both fields. Literary autozoographies thus participate in the negotiation and production of species-specific knowledge. Reading Life of the Mecklenburg Mare Amante (1804), Life of a Job Horse (1807) and Life of a Worn-Out Hack (1819) alongside equine-centric discourses around 1800, the article demonstrates in what ways these texts can be regarded as part of a regime of knowledge attributing emotions and cognitive capacities to horses, while simultaneously arguing for humane treatment on the basis of interspecies homologies.
Synthesis of Dualsteric Ligands for Muscarinic Acetylcholine Receptors and Cholinesterase Inhibitors
(2017)
The study is dealing with the synthesis and pharmacological investigation of newly designed dualsteric ligands of muscarinic acetylcholine receptors belonging to the superfamily of G protein-coupled receptors. Such bipharmacophoric ligands combine the advantages of the orthosteric binding site (high-affinity) and of the topographically distinct allosteric binding site (subtype-selectivity) resulting in compounds with reduced side effects. This opens the way to a new therapeutic approach in the treatment of e.g. chronic pain, drug withdrawal, Parkinson`s and Alzheimer`s disease. Furthermore, the newly synthesized dualsteric compounds were pharmacologically investigated in order to get a better understanding of the activation and signaling processes in muscarinic acetylcholine receptors, especially with regard to partial agonism.
The development of the “dynamic ligand binding” concept offers new perspectives for ligand binding and signaling at G protein-coupled receptors. GPCRs are no longer considered as simple on/off switches. Dualsteric ligands can bind in a dualsteric pose, reflecting an active receptor state as well as in a purely allosteric binding pose, characterized by an inactive receptor state resulting in partial agonism. The degree of partial agonism depends on the ratio of active versus inactive receptor populations. On this basis, orthosteric/orthosteric hybrid ligands consisting of the antagonist atropine and scopolamine, respectively, as well as of the agonist iperoxo and isoxazole, respectively, linked via different alkyl chain length were synthesized in order to investigate partial agonism (Figure 1).
Figure 1: Structures of the synthesized iperoxo/isoxazole-atropine/scopolamine-hybrids.
Furthermore, different sets of quaternary and tertiary homodimers consisting either of two iperoxo or two acetylcholine units were synthesized in order to study their extent on partial agonism (Figure 2). The two agonists were connected by varying alkyl chain length. Binding studies on CHO-hM2 cells of the quaternary compounds revealed that dimerization of the agonist results in a loss of potency. The iperoxo-dimers reached higher maximum effects on the Gi- as well as on the Gs pathway in comparison to the acetylcholine-dimers. Besides the choice of the orthosteric building block (potency of the agonist), the alkyl chain length is also crucial for the degree of partial agonism.
Figure 2: Structures of the synthesized quat./tert. iperoxo/acetylcholine-homodimers.
Quinolone-based hybrids connected to the superagonist iperoxo and to the endogenous ligand acetylcholine, respectively, linked through an alkyl chain of different length were synthesized in order to develop further partial agonists (Figure 3). FRET studies confirmed M1 subtype-selectivity as well as linker dependent receptor response. The greatest positive FRET signal was observed with quinolone-C6-iper resulting from a positive cooperativity between the two separated moieties, alloster and orthoster. However, the corresponding hybrids with a longer linker led to an inverse FRET signal indicating a different binding mode, e.g. purely allosteric, in contrast to the shorter linked hybrids. Furthermore, the flexible alkyl spacer was replaced by a rigidified linker resulting in the hybrid quinolone-rigid-iperoxo (Figure 3). FRET studies on the M1 receptor showed reduced FRET kinetics, resulting from interactions between the bulky linker and the aromatic lid, located between the orthosteric and allosteric binding site. A bitopic binding mode of the rigidified hybrid is presumed. For further clarity, mutational studies are necessary.
Figure 3: M1-selective hybrid compounds.
Another aim of this work was the design and synthesis of new hybrid compounds, acting as agonists at the M1 and M2 receptor and as inhibitors for AChE and BChE in the context of M. Alzheimer. Several sets of hybrid compounds consisting of different pharmacophoric units (catalytic active site: phthalimide, naphthalimide, tacrine; peripheric anionic site: iperoxo, isoxazole) linked through a polymethylene chain of varying length were synthesized. Tac-C10-iper (Figure 4), consisting of tacrine and the superagonist iperoxo linked by a C10 polymethylene spacer, was found to have excellent anticholinesterase activity for both AChE (pIC50 = 9.81) and BChE (pIC50 = 8.75). Docking experiments provided a structural model to rationalize the inhibitory power towards AChE. Additionally, the tacrine related hybrids showed affinity to the M1 and M2 receptor. Such compounds, addressing more than one molecular target are favorable for multifactorial diseases such as Alzheimer.
Figure 4: Structure of the most active compound regarding anticholinesterase activity.
In summary, the choice of the pharmacophoric units, their connecting point as well as the nature, length, and flexibility of the linker play an important role for the activity of designed bivalent ligands. A shorter linker length cannot bridge both binding sites simultaneously in contrast to longer linker chains. On the other hand, too long linker chains can result in unwanted steric interactions. Further investigations with respect to structural variations of hybrid compounds, with or without quaternary ammonium groups, are necessary in the light of drug development.