Search

ObjectiveFerroptosis is a regulated cell death modality that occurs upon iron-dependent lipid peroxidation. The recent decade of research has uncovered many regulators driving ferroptosis as well as cellular gatekeepers preventing ferroptosis. Yet, many processes and networks remain to be elucidated.Methods and resultsIn this study, we performed a chemical screen using small molecules with known mode of action and identified two agonists (Turofexorate and Fexaramine) of the nuclear receptor Farnesoid X Receptor (FXR), also known as NR1H4, to suppress ferroptosis, but not apoptosis or necroptosis. Further, we demonstrate that in liver cells with high FXR protein levels, inhibition of FXR sensitizes cells to undergo ferroptotic cell death, while activation of FXR inhibits ferroptosis. Importantly, FXR also inhibits ferroptosis in ex vivo primary mouse hepatocytes. Activation of FXR by Turofexorate and Fexaramine significantly reduces lipid peroxidation. Mechanistically, overexpression of FXR or activation of FXR by bile acids upregulates the ferroptosis-inhibitory regulators FSP1, PPARα, GPX4, SCD1, and ACSL3 to reduce peroxidized lipids and to counteract ferroptosis.ConclusionIn this study, we demonstrate that activation of FXR inhibits ferroptotic cell death via upregulation of a number of ferroptosis-inhibitory proteins (FSP1, PPARα, GPX4, SCD1, and ACSL3) to reduce lipid peroxidation. Hence, modulating FXR activity may be beneficial to overcome ferroptosis-mediated degenerative diseases.

Background & Aims Selective elimination of virus-infected hepatocytes occurs through virus-specific CD8 T cells recognizing peptide-loaded MHC molecules. Herein, we report that virus-infected hepatocytes are also selectively eliminated through a cell-autonomous mechanism. Methods We generated recombinant adenoviruses and genetically modified mouse models to identify the molecular mechanisms determining TNF-induced hepatocyte apoptosis in vivo and used in vivo bioluminescence imaging, immunohistochemistry, immunoblot analysis, RNAseq/proteome/phosphoproteome analyses, bioinformatic analyses, mitochondrial function tests. Results We found that TNF precisely eliminated only virus-infected hepatocytes independently of local inflammation and activation of immune sensory receptors. TNF receptor I was equally relevant for NF-kB activation in healthy and infected hepatocytes, but selectively mediated apoptosis in infected hepatocytes. Caspase 8 activation downstream of TNF receptor signaling was dispensable for apoptosis in virus-infected hepatocytes, indicating an unknown non-canonical cell-intrinsic pathway promoting apoptosis in hepatocytes. We identified a unique state of mitochondrial vulnerability in virus-infected hepatocytes as the cause for this non-canonical induction of apoptosis through TNF. Mitochondria from virus-infected hepatocytes showed normal biophysical and bioenergetic functions but were characterized by reduced resilience to calcium challenge. In the presence of unchanged TNF-induced signaling, reactive oxygen species-mediated calcium release from the endoplasmic reticulum caused mitochondrial permeability transition and apoptosis, which identified a link between extrinsic death receptor signaling and cell-intrinsic mitochondrial-mediated caspase activation. Conclusion Our findings reveal a novel concept in immune surveillance by identifying a cell-autonomous defense mechanism that selectively eliminates virus-infected hepatocytes through mitochondrial permeability transition. Lay summary The liver is known for its unique immune functions. Herein, we identify a novel mechanism by which virus-infected hepatocytes can selectively eliminate themselves through reduced mitochondrial resilience to calcium challenge.

To evaluate the correlation between flow density, as measured by optical coherence tomography angiography (OCTA), and structural and functional parameters in patients with open-angle glaucoma. Thirty-four eyes of 34 patients with open-angle glaucoma and 35 eyes of 35 healthy subjects were prospectively included in this study. OCTA was performed using RTVue XR Avanti with AngioVue. The macula was imaged with a 3 × 3 mm scan and the optic nerve head (ONH) with a 4.5 × 4.5 mm scan. Visual field parameters [mean deviation (MD), pattern standard deviation (PSD) and visual field index (VFI)], Bruch’s membrane opening minimal rim width (BMO-MRW), retinal nerve fiber layer thickness (RNFLT) and the stereometric parameters rim area, cup/disc area (HRT III, Heidelberg Retina Tomograph, Heidelberg Engineering) were tested for correlation with flow density data. The flow density (whole en face) in the retinal OCT angiograms (superficial: p = 0.01; deep: p = 0.005), in the radial peripapillary capillary network (p

PURPOSE: To determine the diurnal variations in peripapillary and macular flow density (FD), as measured using optical coherence tomography angiography (OCTA) and to elaborate on the relationship between diurnal FD, circulatory parameters and intraocular pressure (IOP) variations in primary open-angle glaucoma (POAG). METHODS: Forty eyes of 40 POAG patients were drawn into this cross-sectional study. The retinal microvasculature of the macula (superficial and deep layers) and optic nerve [radial peripapillary capillary (RPC)] was examined by OCTA (AngioVue® , Optovue). Optical coherence tomography angiography (OCTA) measurements were conducted at 08:00, 11:00, 15:00 and 20:00 over the course of two consecutive days. Intraocular pressure (IOP) and circulatory parameters were assessed accordingly. Diurnal variations in FD were analysed using linear mixed models. RESULTS: While superficial macular FD and RPC FD revealed not to be affected by diurnal variations (p = 0.492, p = 0.319), FD in the deep layer of the macula increased throughout the day (p < 0.001). Superficial macular FD was influenced significantly by mean arterial pressure (MAP) (p = 0.006) and heart rate (HR) (p = 0.033), whereas FD in the RPC layer was significantly affected by HR (p = 0.010). No statistically significant effect of IOP fluctuations on FD was observed. CONCLUSION: This study shows diurnal fluctuations of deep macular FD measured by OCTA and outlines the relationship between FD and hemodynamic parameters (MAP/HR) in POAG patients.

Understanding complex (bio/geo)systems is a pivotal challenge in modern sciences that fuels a constant development of modern analytical technology, finding innovative solutions to resolve and analyse. In this introductory paper to the Faraday Discussion "Challenges in the analysis of complex natural systems", we aim to present concepts of complexity, and complex chemistry in systems subjected to biotic and abiotic transformations, and introduce the analytical possibilities to disentangle chemical complexity into its elementary parts (i.e. compositional and structural resolution) as a global integrated approach termed systems chemical analytics.

Objective: The recently developed vocal extent measure (VEM) quantifies a patient’s vocal capacity as documented in the voice range profile (VRP). This study presents the first reference ranges of ...

Reduced nitrogen species are key nutrients for biological productivity in the oceans. Ammonium is often present in low and growth-limiting concentrations, albeit peaks occur during collapse of algal blooms or via input from deep sea upwelling and riverine inflow. Autotrophic phytoplankton exploit ammonium peaks by storing nitrogen intracellularly. In contrast, the strategy of heterotrophic bacterioplankton to acquire ammonium is less well understood. This study revealed the marine bacterium Phaeobacter inhibens DSM 17395, a Roseobacter group member, to have already depleted the external ammonium when only ∼⅓ of the ultimately attained biomass is formed. This was paralleled by a three-fold increase in cellular nitrogen levels and rapid buildup of various nitrogen-containing intracellular metabolites (and enzymes for their biosynthesis) and biopolymers (DNA, RNA and proteins). Moreover, nitrogen-rich cells secreted potential RTX proteins and the antibiotic tropodithietic acid, perhaps to competitively secure pulses of external ammonium and to protect themselves from predation. This complex response may ensure growing cells and their descendants exclusive provision with internal nitrogen stocks. This nutritional strategy appears prevalent also in other roseobacters from distant geographical provenances and could provide a new perspective on the distribution of reduced nitrogen in marine environments, i.e. temporary accumulation in bacterioplankton cells., Phaeobacter inhibens DSM 17395 uncouples NH4+-utilization from growth to build up a broad array of intracellular nitrogen stocks, paralleled by the secretion of RTX-like proteins and the antibiotic tropodithietic acid.

Isoprene is a small lipophilic molecule with important functions in plant protection against abiotic stresses by improving membrane structure and scavenging reactive oxygen species. Here, we studied the lipid composition of thylakoid membranes and chloroplast ultrastructure in isoprene emitting (IE) and non-isoprene emitting (NE) poplars. We demonstrated that the total amount of mono- (MGDG), di-galactosyldiacylglycerols (DGDG), phospholipids (PL), and fatty acids is reduced in chloroplasts when isoprene biosynthesis is blocked. A significantly lower amount of unsaturated fatty acids, particularly linolenic acid (18:3) in NE chloroplasts was associated with the reduced fluidity of thylakoid membranes, which in turn negatively affects PSII photochemical efficiency (ΦPSII). The low ΦPSII in NE plants was negatively correlated with non-photochemical quenching (NPQ) and the energy-dependent (qE) component of NPQ. Transmission electron microscopy (TEM) revealed alterations in the chloroplast ultrastructure in NE compared with IE plants. NE chloroplasts were more rounded and contained less grana stacks and longer stroma thylakoids, more plastoglobules, and larger associative zones between chloroplasts and mitochondria. These results strongly support the idea that in isoprene-emitting species, the function of this molecule is closely associated with the structural organization and functioning of plastidic membranes.

Wikipedia (2011) beschreibt Marketing neben anderen, je nach Sichtweise orientierten Definitionen, allgemein wie folgt: „Der Begriff Marketing (veraltet Absatzwirtschaft) bezeichnet zum einen den Unternehmensbereich, dessen Aufgabe (Funktion) es ist, Waren und Dienstleistungen zu vermarkten; zum anderen beschreibt dieser Begriff ein Konzept der ganzheitlichen, marktorientierten Unternehmensfuhrung zur Befriedigung der Bedurfnisse und Erwartungen der Kunden und anderer Interessengruppen (Stakeholder). Damit entwickelt sich das Marketingverstandnis von einer operativen Beeinflussungstechnik (Marketing-Mix-Instrumente) hin zu einer Fuhrungskonzeption, die andere Funktionen wie zum Beispiel Beschaffung, Produktion, Verwaltung und Personal mit einschliest.“

Sie haben sich in den vorstehenden Kapiteln eingehend damit auseinandergesetzt, was es bedeutet, Unternehmer zu sein. Die rechtlichen Zusammenhange sind Ihnen klar, bzw. Sie wissen, wo Sie sich entsprechenden Rat holen konnen. Sie haben sich entschieden, sich als Zahnarzt allein oder zusammen mit anderen selbststandig zu machen, oder Sie sind bereits selbststandig und mochten sich verandern. Sie wollen eine Praxis neu grunden oder ubernehmen. Doch wie gehen Sie vor, damit das Projekt zum Erfolg wird? Was ist alles zu beachten?

Purpose. To evaluate changes in flow density after the implantation of a trabecular microbypass stent (iStent) in combination with cataract surgery. Methods. A total of 48 eyes of 48 patients, who underwent either cataract surgery alone (cataract group) or cataract surgery with implantation of two iStent inject devices (iStent group), were prospectively included in this study. Intraocular pressure (IOP) and flow density data before and after surgery were extracted and analyzed. Results. In the iStent group, the mean IOP was 18.2 ± 3.3 mmHg prior to surgery and 13.2 ± 2.3 at follow-up, and this difference was statistically significant (p<0.001). The mean IOP in the cataract group also improved significantly after surgery (before: 17.1 ± 2.4; after: 15.1 ± 2.7 p=0.003). The flow density (whole en face) in the superficial and deep retinal OCT angiogram of the macula (superficial: p=0.002; deep: p=0.034) and in the ONH (p=0.011) improved significantly after surgery in the iStent group. The differences in the cataract group were not significant. Conclusions. Flow density of the macula and ONH, as measured by OCTA, improved significantly after cataract surgery with iStent. Noninvasive quantitative analyses of flow density provide a new parameter, which can help for the monitoring of therapy success after glaucoma surgery.

Wir wollen Sie mit diesem Kapitel nicht zum Betriebswirtschaftler fur Zahnarztpraxen machen. Wir mochten aber, dass Sie sich qualifiziert mit Ihrem Steuerberater und der Bank auseinandersetzen konnen. Dazu sind einige Begriffe und Zusammenhange wichtig, die wir in diesem Kapitel erortern werden. Teilweise wurden sie bereits im Rahmen der Finanzplanung in ▶ Kap. 4 erlautert, dort aber mit einem anderen Ziel. Einige Begriffe mussen daher hier noch einmal naher erklart werden. Fur die ubrigen Begriffe wird auf ▶ Kap. 4 verwiesen.

Grundsatzlich kann ein Darlehen auf zwei verschiedene Weisen getilgt sowie die Zinsen dafur bezahlt werden: Annuitatendarlehen Tilgungsdarlehen

In ► Kap. 4 haben Sie sich mit grundsatzlichen Entscheidungen bei der Praxisplanung und – Konzeptionierung beschaftigt: Sie haben sich fur eine bestimmte Praxisform, ihren Standort, Schwerpunkt, Raumgestaltung und technische Ausstattung entschieden. Sie wissen im Prinzip, was Sie wollen.

Voice range profile (VRP) and evaluation using the dysphonia severity index (DSI) represent essentials of instrument-based objective voice diagnostics and are implemented in different standardized registration programs. The respective measurement results, however, show differences. The aim of the study was to prove these differences statistically and to develop a new parameter, the Vocal Extent Measure (VEM), which is not influenced by the measurement program. VRPs of 97 subjects were recorded by two examiners using the established registration programs DiVAS (XION medical) and LingWAVES (WEVOSYS) simultaneously. The VEM was developed on the basis of VRP area and perimeter. All 194 VRP files were analyzed for various parameters and gender independence. The registration programs exhibited significant differences in several vocal parameters. A significant gender influence for DSI was found with DiVAS (p<0.01), but not with LingWAVES. The VEM quantified the dynamic performance and frequency range by a unidimensional, interval-scaled value without unit, mostly between 0 and 120. This novel parameter represents an intelligible and user-friendly positive measure of vocal function, allows simple and stable VRP description, and seems to be suitable for quantification of vocal capacity. In contrast to DSI, the VEM proved to be less susceptible to registration program and gender.

Dieser Beitrag legt den Fokus auf die parodontale Therapie furkationsbeteiligter Molaren. Der Therapieentscheid ist anspruchsvoll, da zahlreiche Faktoren berücksichtigt werden müssen. Therapeutisches Ziel ist die Wiederherstellung der uneingeschränkten Plaquekontrolle in allen durch Attachmentverlust entstandenen unzugänglichen Nischen im Bereich der Furkation. Die Tunnelierung stellt eine mögliche Therapieoption dar. Je nach Indik ation erfolgt sie nicht chirurgisch (geschlossenes Scaling und Wurzelglätten) oder chirurgisch (mit offenem Scaling und Wurzelglätten, Osteo­ und/oder Odontoplastik). Bei den Verfahren wird die weichgewebige und wenn nötig zusätzlich die hartgewebige Furkation geöffnet, um sie für Interdentalbürstchen zugänglich zu machen. Hier können Gummiligaturen als Hilfsmittel eingesetzt werden. Diese bewirken im Rahmen der nicht chirurgischen Therapie eine Weichgewebsverdrängung während einer siebentägigen Einlage in eine Furkation mit Grad III. Im Rahmen der chirurgischen T unnelierung können sie adjuvant eingesetzt werden, um die Furkation während der postoperativen Heilungsphase offen zu halten. Anhand von vier klinischen Beispielen wird die Systematik dieser Tunnelierungsmethoden unter Zuhilfenahme der Gummiligaturen beschrieben, und es werden Schlussf olgerungen für die Praxis gezogen.

Effective growth and replication of obligate intracellular pathogens depend on host cell metabolism. How this is connected to host cell mitochondrial function has not been studied so far. Recent studies suggest that growth of intracellular bacteria such as Chlamydia pneumoniae is enhanced in a low oxygen environment, arguing for a particular mechanistic role of the mitochondrial respiration in controlling intracellular progeny. Metabolic changes in C. pneumoniae infected epithelial cells were analyzed under normoxic (O2 ≈ 20%) and hypoxic conditions (O2 < 3%). We observed that infection of epithelial cells with C. pneumoniae under normoxia impaired mitochondrial function characterized by an enhanced mitochondrial membrane potential and ROS generation. Knockdown and mutation of the host cell ATP synthase resulted in an increased chlamydial replication already under normoxic conditions. As expected, mitochondrial hyperpolarization was observed in non-infected control cells cultured under hypoxic conditions, which was beneficial for C. pneumoniae growth. Taken together, functional and genetically encoded mitochondrial dysfunction strongly promotes intracellular growth of C. pneumoniae.

Marine algae represent an important source of novel natural products. While their bioactive potential has been studied to some extent, limited information is available on marine algae from the Red Sea. This study aimed at the broad discovery of new bioactivities from a collection of twelve macroalgal species from the Central Red Sea. We used imaging-based High-Content Screening (HCS) with a diverse spectrum of cellular markers for detailed cytological profiling of fractionated algal extracts. The cytological profiles for 3 out of 60 algal fractions clustered closely to reference inhibitors and showed strong inhibitory activities on the HIV-1 reverse transcriptase in a single-enzyme biochemical assay, validating the suggested biological target. Subsequent chemical profiling of the active fractions of two brown algal species by ultra-high resolution mass spectrometry (FT-ICR-MS) revealed possible candidate molecules. A database query of these molecules led us to groups of compounds with structural similarities, which are suggested to be responsible for the observed activity. Our work demonstrates the versatility and power of cytological profiling for the bioprospecting of unknown biological resources and highlights Red Sea algae as a source of bioactives that may serve as a starting point for further studies. published

RATIONALE The ionization of neutral diacylglycerols (DAGs) by electrospray ionization mass spectrometry (ESI-MS) is challenging compared with other lipid classes which possess ionic head group conjugations. Although ESI-MS is the method of choice in lipidomic analysis, it is questionable whether all lipid classes can be efficiently ionized by this method. Actually, various lipids were not efficiently detected (due to poor ionization) in many studies which claimed to comprehensively describe lipid profiles. Since neutral lipids are precursors for the biosynthesis of most other lipid classes, the necessity for improved or alternative ionization and identification schemes becomes obvious. METHODS We identified the 1,2-diacylglycerol (DAG) dimer ion formation in the gas phase by ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) in negative electrospray ionization ((−)ESI) mode. The geometry of the dimer ion was investigated by accurate density functional theory (DFT) calculations at the B3LYP/6-311+G(d)//B3LYP/LANL2DZ level of theory. Fragmentation of the dimer ions of many investigated DAGs has been achieved via collision-induced dissociation (CID) experiments with several elevated collision energies (0–12 eV). RESULTS We revealed the possibility to ionize neutral DAGs as dimer ions in the negative ESI mode. Quantum mechanical calculations revealed a polar head-to-head intermolecular interaction between one charged DAG and one DAG neutral. This represents an energy minimum structure for the DAG dimer ions. We could furthermore detect CID fragmentation product ions that can only result from intermolecular reactions in this head-to-head conformation (SN2 nucleophilic substitution reactions inside the dimer DAG ion). CONCLUSIONS Here, we present for the first time the opportunity to ionize and identify DAGs as dimer ions. This new finding provides a new alternative for investigations of important diacylglycerol lipids and provides the opportunity to obtain complementary and more comprehensive results in future lipidomic studies. Copyright © 2014 John Wiley & Sons, Ltd.

Background Chronic immune diseases, such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals, such as probiotics, for the prevention of allergic disease. However, clinical trials have produced inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host's microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty. Objective We sought to identify and characterize a bioactive probiotic metabolite for potential prevention of allergic airway disease. Methods Probiotic supernatants were screened for their ability to concordantly decrease the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells. Results Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of 2 supernatants according to polarity, followed by total ion chromatography and mass spectrometry, yielded C 11 H 12 N 2 O 2 as the molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-tryptophan. In contrast, L-tryptophan and 11 other D-amino acids were inactive. Feeding D-tryptophan to mice before experimental asthma induction increased numbers of lung and gut regulatory T cells, decreased lung T H 2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced gut microbial diversity, which was increased by D-tryptophan. Conclusions D-tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products can be exploited in novel preventative strategies for chronic immune diseases.

Background: The use of probiotic bacteria has been proposed for prevention of allergic diseases. However, clinical trials have given inconsistent results. This may be explained by the complexity of the crosstalk between probiotic bacteria, the host´s microbiota and immune cells. The identification a biochemically defined, bioactive substances from probiotic bacteria could circumvent these problems. We have previously detected the metabolite D-Tryptophan (D-Trp) that had immunomodulatory properties in in vitro screening assays. Objective: To obtain insight into potential mechanisms of D-Trp, such as a modulation of the murine gut microbiota and the differentiation of primary T cells. Methods: Balb/creceived 50 mM D-Trp via drinking water and AAI was induced by Ovalbumin. Gut microbiota was assessed from caecum by 16S qPCR. Primary, naive splenic CD4 + T cells were isolated from Balb/c mice and differentiated in vitro in the presence of 10 or 50 µM DTrp by using anti-CD3/CD28 microbeads and cytobox Th1, cytobox Th2 (Miltenyi Biotech) or 5 ng/ml Tgf-s for Tregs. Differentiation was assessed by intracellular flow cytometry, cytometric bead array (CBA) and qRT-PCR. Results: Feeding D-tryptophan to mice prior to experimental asthma induction restored the AAI-induced reduction in microbial diversity in the gut. In vitro DTrp addition slightly increased Foxp3 + Tregs and decreased Il4 + Th2 cells dose-dependently . Conclusion: Our findings indicate a potential beneficial effect on the gut microbiota, as well as a reduced Th2 differentiation in vitro. Thus, defined bacterial products might able to modulate the host9s immune system.

Human physical attractiveness appears to be an important signal of mate value that is utilized in mate choice We argue that performancerelated physical fitness (PF) was an important facet of ancestral male mate value and, therefore, that a positive relationship exists between PF and physical attractiveness as well as mating success. We investigated these relationships in a sample of 80 young men. In line with our predictions, we found that (i) a composite measure of PF correlated substantially with body attractiveness (r=.43, after controlling for confounds) but not with facial attractiveness; (ii) PF was positively related to various measures of self-reported mating success (rS 6 .22); (iii) the relationship between PF and self-reported mating success was partly mediated by body attractiveness. We conclude it is a key function of men’s body attractiveness to signal their PF and that men’s faces and bodies signal different facets of mate value.

Background: Previously, D-Tryptophan has been identified as soluble bacterial molecule with Th2-lowering activity in vitro from prebiotic supernatants using bioassay-guided fractionation. However, the in vivo effects of D-Tryptophan on Th2-mediated disease are unknown. Here, we studied the effects of oral D-Tryptophan supplementation on allergic airway inflammation in mice. Methods: Six - eight weeks old female Balb/c mice received 50mM D-tryptophan (Sigma Aldrich, Germany) dissolved in the filtered drinking water or filtered drinking water as control (n=8 per group) starting at least 3 days before the first sensitization until sacrificing on day 25. An ovalbumin model with 3 intraperitoneal sensitizations (d0, d7, 14) and 3 intranasal challenges (d21, 22, 23) was applied to induce allergic airway inflammation. Results: Oral supplementation of mice with D-tryptophan significantly increased D-tryptophan serum levels indicating enteric uptake and systemic distribution. Pre-treatment of mice with D-tryptophan for 3 days and throughout experimental “asthma” induction lowered total BALF cells (from 9.1±1.9x10 5 to 4.4±0.5x10 5 cells), which was mainly caused by reduced eosinophils. Furthermore, D-Tryptophan treated mice exhibited less airway hyperreactivity than controls. Analysis of splenocytes revealed that D-tryptophan significantly reduced IL-13 and trendwise IL-4 (p=0.07) producing CD3 + CD4 + T cells, while IFNg + , Foxp3 + and IL-10 + T cells remained unchanged. In addition, the percentages of CD40 + and CD86 + DCs were reduced by half. Conclusion: Oral D-tryptophan supplementation reduces allergic airway inflammation in mice. Further studies are needed to provide insights into the mechanism of action.

It has been suggested that male achievement in sports and athletics is correlated with a putative measure of prenatal testosterone the 2nd to 4th digit ratio (2D:4D). It is not known whether this association also extends to females, or whether the association results from an effect of testosterone on behavior (such as exercise frequency) or on physical fitness. Here, we report for the first time data from two studies which consider associations between 2D:4D and physical fitness in females in addition to males: Study I--in a sample of teenage boys (n = 114) and girls (n = 175), their 'physical education grade' was negatively associated with 2D:4D of the right hand (boys), and right and left hand (girls), and Study II-among a sample of young men (n = 102) and women (n = 77), a composite measure of physical fitness was negatively related to right hand 2D:4D in men and left hand 2D:4D in women. We conclude that 2D:4D is negatively related to physical fitness in both men and women. In Study II, there was evidence that the relationship between physical fitness and 2D:4D in men was mediated through an association with exercise frequency. Thus, 2D:4D in males may be a negative correlate of frequent exercise which then relates to achievement in sports and athletics.

In vivo phosphorylation of FTY720 (1) in rats and humans resulted exclusively in the biologically active (S)-configured enantiomer, which was proven by an ex vivo o-phthaldialdehyde derivatization protocol especially elaborated for phosphates of 1. Starting from the prochiral amino alcohol 1, racemic and enantiomerically pure phosphates of 1 were synthesized. Pure enantiomers were obtained after purification of a partially protected key intermediate on an enantioselective support. The absolute stereochemistry was determined by X-ray diffraction.

International audience; Chlamydia trachomatis is an obligate intracellular pathogen responsible for loss of eyesight through trachoma and for millions of cases annually of sexually transmitted diseases. The bacteria develop within a membrane-bounded inclusion. They lack enzymes for several biosynthetic pathways, including those to make some phospholipids, and exploit their host to compensate. Three-dimensional fluorescence microscopy demonstrates that small organelles of the host, peroxisomes, are translocated into the Chlamydia inclusion and are found adjacent to the bacteria. In cells deficient for peroxisome biogenesis the bacteria are able to multiply and give rise to infectious progeny, demonstrating that peroxisomes are not essential for bacterial development in vitro. Mass spectrometry-based lipidomics reveal the presence in C. trachomatis of plasmalogens, ether phospholipids whose synthesis begins in peroxisomes and have never been described in aerobic bacteria before. Some of the bacterial plasmalogens are novel structures containing bacteria-specific odd-chain fatty acids; they are not made in uninfected cells nor in peroxisome-deficient cells. Their biosynthesis is thus accomplished by the metabolic collaboration of peroxisomes and bacteria.

Global HIV-1 treatment would benefit greatly from safe herbal medicines with scientifically validated novel anti-HIV-1 activities. The root extract from the medicinal plant Pelargonium sidoides (PS) is licensed in Germany as the herbal medicine EPs®7630, with numerous clinical trials supporting its safety in humans. Here we provide evidence from multiple cell culture experiments that PS extract displays potent anti-HIV-1 activity. We show that PS extract protects peripheral blood mononuclear cells and macrophages from infection with various X4 and R5 tropic HIV-1 strains, including clinical isolates. Functional studies revealed that the extract from PS has a novel mode-of-action. It interferes directly with viral infectivity and blocks the attachment of HIV-1 particles to target cells, protecting them from virus entry. Analysis of the chemical footprint of anti-HIV activity indicates that HIV-1 inhibition is mediated by multiple polyphenolic compounds with low cytotoxicity and can be separated from other extract components with higher cytotoxicity. Based on our data and its excellent safety profile, we propose that PS extract represents a lead candidate for the development of a scientifically validated herbal medicine for anti-HIV-1 therapy with a mode-of-action different from and complementary to current single-molecule drugs.

The ionization of neutral diacylglycerols (DAGs) by electrospray ionization mass spectrometry (ESI-MS) is challenging compared with other lipid classes which possess ionic head group conjugations. Although ESI-MS is the method of choice in lipidomic analysis, it is questionable whether all lipid classes can be efficiently ionized by this method. Actually, various lipids were not efficiently detected (due to poor ionization) in many studies which claimed to comprehensively describe lipid profiles. Since neutral lipids are precursors for the biosynthesis of most other lipid classes, the necessity for improved or alternative ionization and identification schemes becomes obvious.We identified the 1,2-diacylglycerol (DAG) dimer ion formation in the gas phase by ultra-high-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) in negative electrospray ionization ((-)ESI) mode. The geometry of the dimer ion was investigated by accurate density functional theory (DFT) calculations at the B3LYP/6-311+G(d)//B3LYP/LANL2DZ level of theory. Fragmentation of the dimer ions of many investigated DAGs has been achieved via collision-induced dissociation (CID) experiments with several elevated collision energies (0-12 eV).We revealed the possibility to ionize neutral DAGs as dimer ions in the negative ESI mode. Quantum mechanical calculations revealed a polar head-to-head intermolecular interaction between one charged DAG and one DAG neutral. This represents an energy minimum structure for the DAG dimer ions. We could furthermore detect CID fragmentation product ions that can only result from intermolecular reactions in this head-to-head conformation (SN2 nucleophilic substitution reactions inside the dimer DAG ion).Here, we present for the first time the opportunity to ionize and identify DAGs as dimer ions. This new finding provides a new alternative for investigations of important diacylglycerol lipids and provides the opportunity to obtain complementary and more comprehensive results in future lipidomic studies.

The growing scientific attention in the biological function of D-amino acids leads to an increasing analytical interest for enantiomeric amino acid separation, which is still very challenging due to the lack of sufficiently sensitive, high-throughput analytical methods that can cope with often occurring matrix interferences and very low D-amino acid concentrations. Here, enantioseparation can benefit from improved resolution and chromatographic speed offered by modern UHPLC techniques and the precision of MS detection. We developed a RP-UHPLC-QqToF-MS method using pre-column OPA/IBLC derivatization for very precise discrimination of amino acids enantiomers. The method shows a superb sensitivity with limits of detection in the range of several pmol/l. It has neither shown matrix inferences in the tested very complex biological matrices (serum, plasma, urine and gut) nor stability or racemization problems.

Infections with Chlamydia pneumoniae cause several respiratory diseases, such as community-acquired pneumonia, bronchitis or sinusitis. Here, we present an integrated non-targeted metabolomics analysis applying ultra-high-resolution mass spectrometry and ultra-performance liquid chromatography mass spectrometry to determine metabolite alterations in C. pneumoniae-infected HEp-2 cells. Most important permutations are elaborated using uni- and multivariate statistical analysis, logD retention time regression and mass defect-based network analysis. Classes of metabolites showing high variations upon infection are lipids, carbohydrates and amino acids. Moreover, we observed several non-annotated compounds as predominantly abundant after infection, which are promising biomarker candidates for drug-target and diagnostic research.

Auf welche Weise konnen neue Patienten fur die Praxis gewonnen werden? Und wie bindet man Stammpatienten ? Neben diesen Fragen widmet sich dieses Kapitel vorrangig dem externen Marketing . Fur das interne Marketing, also Belange innerhalb der Praxis zu Team oder Patientenansprache, sei auf die umfangreiche Fachliteratur und auf entsprechende Seminare verwiesen.