Targeting of cancer cells using click-functionalized polymer capsules

Targeted delivery of drugs to specific cells allows a high therapeutic dose to be delivered to the target site with minimal harmful side effects. Combining targeting molecules with nanoengineered drug carriers, such as polymer capsules, micelles and polymersomes, has significant potential to improve the therapeutic delivery and index of a range of drugs. We present a general approach for functionalization of low-fouling, nanoengineered polymer capsules with antibodies using click chemistry. We demonstrate that antibody (Ab)-functionalized capsules specifically bind to colorectal cancer cells even when the target cells constitute less than 0.1% of the total cell population. This precise targeting offers promise for drug delivery applications.     

Targeted LC–MS derivatization for aldehydes and carboxylic acids with a new derivatization agent 4-APEBA

Based on the template of a recently introduced derivatization reagent for aldehydes, 4-(2-(trimethylammonio)ethoxy)benzeneaminium dibromide (4-APC), a new derivatization agent was designed with additional features for the analysis and screening of biomarkers of lipid peroxidation. The new derivatization reagent, 4-(2-((4-bromophenethyl)dimethylammonio)ethoxy)benzenaminium dibromide (4-APEBA) contains a bromophenethyl group to incorporate an isotopic signature to the derivatives and to add additional fragmentation identifiers, collectively enhancing the abilities for detection and screening of unknown aldehydes. Derivatization can be achieved under mild conditions (pH 5.7, 10 °C). By changing the secondary reagent (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide instead of sodium cyanoborohydride), 4-APEBA is also applicable to the selective derivatization of carboxylic acids. Synthesis of the new label, exploration of the derivatization conditions, characterization of the fragmentation of the aldehyde and carboxylic acid derivatives in MS/MS, and preliminary applications of the labeling strategy for the analysis of aldehydes in urine and plasma are described.     

Development of a microfluidic confocal fluorescence detection system for the hyphenation of nano-LC to on-line biochemical assays

One way to profile complex mixtures for receptor affinity is to couple liquid chromatography (LC) on-line to biochemical detection (BCD). A drawback of this hyphenated screening approach is the relatively high consumption of sample, receptor protein and (fluorescently labeled) tracer ligand. Here, we worked toward minimization of sample and reagent consumption, by coupling nano-LC on-line to a light-emitting diode (LED) based capillary confocal fluorescence detection system capable of on-line BCD with low-flow rates. In this fluorescence detection system, a capillary with an extended light path (bubble cell) was used as a detection cell in order to enhance sensitivity. The technology was applied to a fluorescent enhancement bioassay for the acetylcholine binding protein, a structural analog of the extracellular ligand-binding domain of neuronal nicotinic acetylcholine receptors. In the miniaturized setup, the sensitive and low void volume LED-induced confocal fluorescence detection system operated in flow injection analysis mode allowing the measurement of IC₅₀ values, which were comparable with those measured by a conventional plate reader bioassay. The current setup uses 50 nL as injection volume with a carrier flow rate of 400 nL/min. Finally, coupling of the detection system to gradient reversed-phase nano-LC allowed analysis of mixtures in order to identify the bioactive compounds present by injecting 10 nL of each mixture.     

Trends in aircraft noise annoyance: the role of study and sample characteristics

Recently, it has been suggested that the annoyance of residents at a given aircraft noise exposure level increases over the years. The objective of the present study was to verify the hypothesized trend and to identify its possible causes. To this end, the large database used to establish earlier exposure-response relationships on aircraft noise was updated with original data from several recent surveys, yielding a database with data from 34 separate airports. Multilevel grouped regression was used to determine the annoyance response per airport, after which meta-regression was used to investigate whether study characteristics could explain the heterogeneity in annoyance response between airports. A significant increase over the years was observed in annoyance at a given level of aircraft noise exposure. Furthermore, the type of annoyance scale, the type of contact, and the response percentage were found to be sources of heterogeneity. Of these, only the scale factor could statistically account for the trend, although other findings rule it out as a satisfactory explanation. No evidence was found for increased self-reported noise sensitivity. The results are of importance to the applicability of current exposure-annoyance relationships for aircraft noise and provide a basis for decisions on whether these need to be updated.     

Inhibited spontaneous emission of quantum dots observed in a 3D photonic band gap

We present time-resolved emission experiments of semiconductor quantum dots in silicon 3D inverse-woodpile photonic band gap crystals. A systematic study is made of crystals with a range of pore radii to tune the band gap relative to the emission frequency. The decay rates averaged over all dipole orientations are inhibited by a factor of 10 in the photonic band gap and enhanced up to 2× outside the gap, in agreement with theory. We discuss the effects of spatial inhomogeneity, nonradiative decay, and transition dipole orientations on the observed inhibition in the band gap.     

In vitro evaluation of cytotoxic and inflammatory properties of silica nanoparticles of different sizes in murine RAW 264.7 macrophages

The biological response to four well-characterized amorphous silica nanoparticles was investigated in RAW 264.7 macrophages in view of their potential application as drug carriers to sites of inflammation. All silica nanoparticles-induced cell membrane damage, reduced metabolic activity, generated ROS and released various cytokines, but to different extents. Two silica nanoparticles of 34 nm (A and B) with different zetapotentials were more cytotoxic than (aggregated) 11 and 248 nm nanoparticles, while cytokines were mostly induced by the (aggregated) 11 nm and only one of the 34 nm nanoparticles (34A). The results indicate that specific silica nanoparticles may have counterproductive effects, for example when used as carriers of anti-inflammatory drugs. The physicochemical properties determining the response of nanoparticles vary for different responses, implying that a screening approach for the safe development of nanoparticles needs to consider the role of combinations of (dynamic) physicochemical properties and needs to include multiple toxicity endpoints.     

Approximate queueing models for capacitated multi-stage inventory systems under base-stock control

A queueing analysis is presented for base-stock controlled multi-stage production-inventory systems with capacity constraints. The exact queueing model is approximated by replacing some state-dependent conditional probabilities (that are used to express the transition rates) by constants. Two recursive algorithms (each with several variants) are developed for analysis of the steady-state performance. It is analytically shown that one of these algorithms is equivalent to the existing approximations given in the literature. The system studied here is more general than the systems studied in the literature. The numerical investigation for three-stage systems shows that the proposed approximations work well to estimate the relevant performance measures.     

Global and local behavior of zeros of nonpositive type

A generalized Nevanlinna function Q(z)$Q(z)$ with one negative square has precisely one generalized zero of nonpositive type in the closed extended upper halfplane. The fractional linear transformation defined by _Qτ(z)=(Q(z)−τ)/(1+τQ(z))$Q_{\tau }(z)=(Q(z)-\tau )/(1+\tau Q(z))$, τ∈R∪{∞}$\tau \in \mathbb{R}\cup \{\infty \}$, is a generalized Nevanlinna function with one negative square. Its generalized zero of nonpositive type α(τ)$\alpha (\tau )$ as a function of τ is being studied. In particular, it is shown that it is continuous and its behavior in the points where the function extends through the real line is investigated.     

Using genetic programming to evolve action selection rules in traversal-based automated software testing: results obtained with the TESTAR tool

Traversal-based automated software testing involves testing an application via its graphical user interface (GUI) and thereby taking the user’s point of view and executing actions in a human-like manner. These actions are decided on the fly, as the software under test (SUT) is being run, as opposed to being set up in the form of a sequence prior to the testing, a sequence that is then used to exercise the SUT. In practice, random choice is commonly used to decide which action to execute at each state (a procedure commonly referred to as monkey testing), but a number of alternative mechanisms have also been proposed in the literature. Here we propose using genetic programming (GP) to evolve such an action selection strategy, defined as a list of IF-THEN rules. Genetic programming has proved to be suited for evolving all sorts of programs, and rules in particular, provided adequate primitives (functions and terminals) are defined. These primitives must aim to extract the most relevant information from the SUT and the dynamics of the testing process. We introduce a number of such primitives suited to the problem at hand and evaluate their usefulness based on various metrics. We carry out experiments and compare the results with those obtained by random selection and also by Q-learning, a reinforcement learning technique. Three applications are used as Software Under Test (SUT) in the experiments. The analysis shows the potential of GP to evolve action selection strategies.