Phenothiazine-Biaryl-Containing Fluorescent RGD Peptides

Cyclic RGD peptides are well-known ligands of integrins. The integrins α_Vβ₃ and α₅β₁ are involved in angiogenesis, and integrin α_Vβ₃ is abundantly present on cancer cells, thus representing a therapeutic target. Hence, synthetic and biophysical studies continuously are being directed towards the understanding of ligand-integrin interaction. In this context, the development of versatile synthetic strategies to obtain fluorescent building blocks that can add molecular diversity and modular spectral characteristics while not compromising binding affinity or selectivity is a relevant task. An on-resin intramolecular Suzuki–Miyaura cross-coupling (SMC) between l - or d -7-bromotryptophan (7BrTrp) and a phenothiazine (Ptz) boronic acid affords fluorescent cyclic RGD pseudopeptides, c(RGD(W/w)Ptz). Ring closure by SMC establishes a phenothiazine–indole moiety with axial chirality. An array of eight novel compounds has been synthesized, among them one fluorescent compound with good affinity to integrin α_Vβ₃. The fluorescence properties of the analogues can be efficiently tuned depending on the substituents in Ptz moiety even for fluorescence emission in the visible (red) spectral range.     

Homogenization of a nonlinear multiscale model of calcium dynamics in biological cells

Calcium is one of the most important intracellular messengers, which occurs in the cytosol and the endoplasmic reticulum of animal cells. While most calcium dynamics models either do not account properly for the fact that the endoplasmic reticulum constitutes a microstructure of the cell or are infeasible by resolving the fine structure very explicitly, Goel et al. [15] derived an effective macroscopic model by formal homogenization. In this paper, this approach is made rigorous using periodic homogenization techniques to upscale the nonlinear coupled system of reaction–diffusion equations and, moreover, the appropriate scaling of the interfacial exchange term is taken into consideration.     

Direct measurement of the angular dependence of the single-photon ionization of aligned N2 and CO2

By combining a state-of-the-art high-harmonic ultrafast soft X-ray source with field-free dynamic alignment, we map the angular dependence of molecular photoionization yields for the first time for a nondissociative molecule. The observed modulation in ion yield as a function of molecular alignment is attributed to the molecular frame transition dipole moment of single-photon ionization to the X, A and B states of N2(+) and CO2(+). Our data show that the transition dipoles for single-photon ionization of N2 and CO2 at 43 eV have larger perpendicular components than parallel ones. A direct comparison with published theoretical partial wave ionization cross-sections confirms these experimental observations, which are the first results to allow such comparison with theory for bound cation states. The results provide the first step toward a novel method for measuring molecular frame transition dipole matrix elements.     

Quantification of brain lipids by FTIR spectroscopy and partial least squares regression

Brain tissue is characterized by high lipid content. Its content decreases and the lipid composition changes during transformation from normal brain tissue to tumors. Therefore, the analysis of brain lipids might complement the existing diagnostic tools to determine the tumor type and tumor grade. Objective of this work is to extract lipids from gray matter and white matter of porcine brain tissue, record infrared (IR) spectra of these extracts and develop a quantification model for the main lipids based on partial least squares (PLS) regression. IR spectra of the pure lipids cholesterol, cholesterol ester, phosphatidic acid, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, sphingomyelin, galactocerebroside and sulfatide were used as references. Two lipid mixtures were prepared for training and validation of the quantification model. The composition of lipid extracts that were predicted by the PLS regression of IR spectra was compared with lipid quantification by thin layer chromatography.     

Compact boson stars

We consider compact boson stars that arise for a V-shaped scalar field potential. They represent a one parameter family of solutions of the scaled Einstein–signum–Gordon equations. We analyze the physical properties of these solutions and determine their domain of existence. Along their physically relevant branch emerging from the compact Q-ball solution, their mass increases with increasing radius. Employing arguments from catastrophe theory we argue that this branch is stable, until the maximal value of the mass is reached. There the mass and size are on the order of magnitude of the Schwarzschild limit, and thus the spiraling respectively oscillating behaviour, well known for compact stars, sets in.     

Mathematical cognition: individual differences in resource allocation

Individuals scoring higher in tests of general cognitive abilities tend to perform better on novel and familiar mathematical tasks. It has been scarcely investigated how this superior mathematical performance relates to the amount of cognitive resources that is invested to solve a given task. In this study we propose that, on novel tasks, individuals with high cognitive abilities outperform less able individuals, because they allocate a higher amount of resources. On familiar tasks, however, individuals with higher abilities profit from more efficient processes compared to individuals of lower cognitive abilities. We tested this hypothesis by administering to 11th graders a geometric analogy task not practiced at school and an algebraic transformation task comprising operations that are routinely required during mathematical courses. General cognitive abilities were measured with Ravens Advanced Progressive matrices (fluid intelligence), the d2 (focused attention) and KAI-N (working memory capacity). Resource allocation was measured by assessing pupil diameter during the problem-solving process. Performance on both the analogy and the algebra task was correlated with general cognitive abilities, especially fluid intelligence. In line with our assumptions, a positive correlation between fluid intelligence and resource allocation was observed in the novel geometric analogy task, whereas the correlation was not significant in the more familiar algebra task.     

Broadband phase-coherent optical frequency synthesis with actively linked Ti:sapphire and Cr:forsterite femtosecond lasers

We link the output spectra of a Ti:sapphire and a Cr:forsterite femtosecond laser phase coherently to form a continuous frequency comb with a wavelength coverage of 0.57-1.45 microm at power levels of 1 nW to 40 microW per frequency mode. To achieve this, the laser repetition rates and the carrier-envelope offset frequencies are phase locked to each other. The coherence time between the individual components of the two combs is 40 micros. The timing jitter between the lasers is 20 fs. The combined frequency comb is self-referenced for access to its overall offset frequency. We report the first demonstration to our knowledge of an extremely broadband and continuous, high-powered and phase-coherent frequency comb from two femtosecond lasers with different gain media.     

Tracing the Photoaddition of Pharmaceutical Psoralens to DNA

The psoralens 8-methoxypsoralen (8-MOP), 4,5′,8-trimethylpsoralen (TMP) and 5-methoxypsoralen (5-MOP) find clinical application in PUVA (psoralen + UVA) therapy. PUVA treats skin diseases like psoriasis and atopic eczema. Psoralens target the DNA of cells. Upon photo-excitation psoralens bind to the DNA base thymine. This photo-binding was studied using steady-state UV/Vis and IR spectroscopy as well as nanosecond transient UV/Vis absorption. The experiments show that the photo-addition of 8-MOP and TMP involve the psoralen triplet state and a biradical intermediate. 5-MOP forms a structurally different photo-product. Its formation could not be traced by the present spectroscopic technique.     

Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified α_vβ₃ and α₅β₁ receptors using biotinylated vitronectin (α_vβ₃) and fibronectin (α₅β₁) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for α_vβ₃ over α₅β₁. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin α_vβ₃). The two RGD ligands showed IC₅₀ values in the same micromolar range as the reference compound (cyclo[RGDfV]), while for the isoDGR derivative an IC₅₀ value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the α_Vβ₃ integrin active site, provided a rationale for the behavior of these ligands toward the receptor.