Totalsynthese von Lagunamid A und Chloromyxamid A

This PhD-Work describes the total synthesis of the natural products Lagunamide A and Chloromyxamide A. The Lagunamides are potent cyclic depsipeptides, which were isolated from the cyano bacteria Lyngbya Majuscula in 2007. Lagunamide A consists of a pentapeptide, a α-hydroxy carboxylic acid and a polyketide part with four stereogenic centers. A novel synthesis for Lagunamide A with the construction of all stereogenic centers of the polyketide part by using iterative Matteson-homologations is described. This synthesis also serves as a proof of concept for the synthesis of related natural products like Odoamide or derivatives of these compounds. The Chloromyxamides were isolated at the Helmholtz-institute for pharmaceutical research Saarland from myxobacteria. Herein an efficient total synthesis of Chloromyxamide A is disclosed. The synthesis of the unusual N-terminal amino acid with three stereogenic centers represtens the primary focus of this synthesis. The synthetic compound was used to determine the absolute configuration of the natural product.Diese Doktorarbeit behandelt die Totalsynthese der Naturstoffe Lagunamid A und Chloromyxamid A. Die Lagunamide sind potente cyclische Depsipeptide, die aus dem Cyanobakterium Lyngbya Majuscula im Jahr 2007 isoliert wurden. Lagunamid A besteht aus einem Pentapeptid, einer α-Hydroxycarbonsäure und einem Polyketidteil mit vier Stereozentren. Eine neuartige Synthese des Naturstoffs mit iterativen Matteson-Homologisierungen zum stereoselektiven Aufbau des Polyketidteils wird beschrieben. Ausgehend von einem chiralen Boronsäureester konnten alle vier Stereozentren des Polyketidteils erzeugt werden. Die Synthese von Lagunamid A über diese Route dient auch als konzeptioneller Beweis, um später verwandte Naturstoffe wie Odoamid oder Derivate dieser Verbindungen aufbauen zu können. Die Chloromyxamide wurden am Helmholtz-Institut für Pharmazeutische Forschung Saarland aus Myxobakterien isoliert. Im Rahmen dieser Doktorarbeit gelang die Synthese von Chloromyxamid A. Hauptaugenmerk lag hierbei auf der Synthese der nicht-proteinogenen, N-terminalen Aminosäure mit drei Stereozentren. Durch die Totalsynthese konnte die absolute Konfiguration des Naturstoffs bestimmt und damit die Struktur verifiziert werden

Saccadic intrusions in amyotrophic lateral sclerosis (ALS)

The attempt to steadily fixate at a small visual object is continuously interrupted by a variety of fixational eye movements comprising, among others, a continuum of saccadic intrusions (SI) which ranges in size from microsaccades with amplitudes ≤0.25° to larger refixation saccades of up to about 2°. The size and frequency of SI varies considerably among individuals and is known to increase in neurodegenerative diseases such as neurodegenerative parkinsonism and amyotrophic lateral sclerosis (ALS). However, studies of ALS disagree whether also the frequency of SI increases. We undertook an analysis of SI in 119 ALS patients and 47 age-matched healthy controls whose eye movements during fixation and tests of executive functions (e.g antisaccades) had been recorded by video-oculography according to standardised procedures. SI were categorised according to their spatio-temporal patterns as stair case, back-and-forth and square wave jerks (a subcategory of back-and-forth). The SI of patients and controls were qualitatively similar (same direction preferences, similar differences between patterns), but were enlarged in ALS. Notably however, no increase of SI frequency could be demonstrated. Yet, there were clear correlations with parameters such as eye blink rate or errors in a delayed saccade task that suggest an impairment of inhibitory mechanisms, in keeping with the notion of a frontal dysfunction in ALS. However, it remains unclear how the impairment of inhibitory mechanisms in ALS could selectively increase the amplitude of intrusions without changing their frequency of occurrence

Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity.

BACKGROUND: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. METHODS: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. RESULTS: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. CONCLUSIONS: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders

Detection and attribution of aerosol-cloud interactions in large-domain large-eddy simulations with the ICOsahedral Non-hydrostatic model

Clouds and aerosols contribute the largest uncertainty to current estimates and interpretations of the Earth’s changing energy budget. Here we use a new-generation large-domain large-eddy model, ICON-LEM (ICOsahedral Non-hydrostatic Large Eddy Model), to simulate the response of clouds to realistic anthropogenic perturbations in aerosols serving as cloud condensation nuclei (CCN). The novelty compared to previous studies is that (i) the LEM is run in weather prediction mode and with fully interactive land surface over a large domain and (ii) a large range of data from various sources are used for the detection and attribution. The aerosol perturbation was chosen as peak-aerosol conditions over Europe in 1985, with more than fivefold more sulfate than in 2013. Observational data from various satellite and ground-based remote sensing instruments are used, aiming at the detection and attribution of this response. The simulation was run for a selected day (2 May 2013) in which a large variety of cloud regimes was present over the selected domain of central Europe. It is first demonstrated that the aerosol fields used in the model are consistent with corresponding satellite aerosol optical depth retrievals for both 1985 (perturbed) and 2013 (reference) conditions. In comparison to retrievals from ground-based lidar for 2013, CCN profiles for the reference conditions were consistent with the observations, while the ones for the 1985 conditions were not. Similarly, the detection and attribution process was successful for droplet number concentrations: the ones simulated for the 2013 conditions were consistent with satellite as well as new ground-based lidar retrievals, while the ones for the 1985 conditions were outside the observational range. For other cloud quantities, including cloud fraction, liquid water path, cloud base altitude and cloud lifetime, the aerosol response was small compared to their natural variability. Also, large uncertainties in satellite and ground-based observations make the detection and attribution difficult for these quantities. An exception to this is the fact that at a large liquid water path value (LWP > 200 g m−2), the control simulation matches the observations, while the perturbed one shows an LWP which is too large. The model simulations allowed for quantifying the radiative forcing due to aerosol–cloud interactions, as well as the adjustments to this forcing. The latter were small compared to the variability and showed overall a small positive radiative effect. The overall effective radiative forcing (ERF) due to aerosol–cloud interactions (ERFaci) in the simulation was dominated thus by the Twomey effect and yielded for this day, region and aerosol perturbation −2.6 W m$^{-2}$. Using general circulation models to scale this to a global-mean present-day vs. pre-industrial ERFaci yields a global ERFaci of −0.8 W m$^{-2}$

10Kin1day: A Bottom-Up Neuroimaging Initiative.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain