Ionic liquids as active pharmaceutical ingredients

Ionic liquids (ILs) are ionic compounds that possess a melting temperature below 100 °C. Their physical and chemical properties are attractive for various applications. Several organic materials that are now classified as ionic liquids were described as far back as the mid-19th century. The search for new and different ILs has led to the progressive development and application of three generations of ILs: 1) The focus of the first generation was mainly on their unique intrinsic physical and chemical properties, such as density, viscosity, conductivity, solubility, and high thermal and chemical stability. 2) The second generation of ILs offered the potential to tune some of these physical and chemical properties, allowing the formation of "task-specific ionic liquids" which can have application as lubricants, energetic materials (in the case of selective separation and extraction processes), and as more environmentally friendly (greener) reaction solvents, among others. 3) The third and most recent generation of ILs involve active pharmaceutical ingredients (API), which are being used to produce ILs with biological activity. Herein we summarize recent developments in the area of third-generation ionic liquids that are being used as APIs, with a particular focus on efforts to overcome current hurdles encountered by APIs. We also offer some innovative solutions in new medical treatment and delivery options.     

Immobilization of laccase from Myceliophthora thermophila on functionalized silica nanoparticles: Optimization and application in lindane degradation

This work is focused on immobilization of laccase from Myceliophthora thermophila expressed in Aspergillus oryzae(Novozym 51003? laccase) on amino modified fumed nano-silica(AFNS) and the possible use in bioremediation. Hereby, for the first time, factors affecting the immobilization of Novozym 51003? laccase on AFNS were investigated for defining the immobilization mechanism and optimizing the utilization of AFNS as support for laccase immobilization. The highest specific activity(13.1 IU·mg~(-1) proteins) was achieved at offered 160 mg per g of AFNS and for the same offered protein concentration the highest activity immobilization yield, reaching68.3% after the equilibrium time, at optimum pH 5.0, was obtained. Laccase immobilization occurs by adsorption as monolayer enzyme binding in 40 min, following pseudo-first-order kinetics. The possible use of obtained immobilized preparation was investigated in degradation of pesticide lindane. Within 24 h, lindane concentration was reduced to 56.8% of initial concentration and after seven repeated reuses it retained 70% of the original activity.     

Nanopore/electrode structures for single-molecule biosensing

Biological and solid-state nanopores have recently attracted much interest as ultrafast DNA fragment sizing and sequencing devices. Their potential however goes far beyond DNA sequencing. In particular, nanopores offer perspectives of single-molecule (bio)sensing at physiologically relevant concentrations, which is key for studying protein/protein or protein/DNA interactions. Integration of electrode structures into solid-state nanopore devices moreover enables control and fast switching of the pore properties, e.g. for active control of biopolymer transport through the nanopore. We present some of recent work in this area, namely the fabrication and characterization of nanopore/electrode architectures for single-(bio)molecule sensing. Specifically, we introduce a new technique to fabricate ultra-small metal nanopores with diameters smaller than 20 nm based on ion current feedback (ICF) controlled electrodeposition. It offers precise control of the pore conductance, is easily multiplexed, and can be extended to a wide range of different metals.     

Acceleration of Anti‐Markovnikov Hydroamination in the Synthesis of an Active Pharmaceutical Ingredient

Slow chemical reactions are a big challenge in the modern pharmaceutical industry. Their accelerations together with the introduction of continuous manufacturing modes are major drivers for future development. One example reaction is hydroamination, a reaction between unsaturated hydrocarbons and amines. Such a reaction type is the main focus of this work. More precisely, the anti‐Markovnikov hydroamination reaction between cis/trans 9H‐thioxanthene‐2‐chloro‐9‐(2‐propenylidene)‐(9CI) and 1‐(2‐hydroxyethyl)piperazine (HEP) is investigated in detail. It has been traditionally performed in toluene with a huge excess of HEP and reaction times of up to 24 h. Acceleration of the reaction from 24 down to 4 h is achieved by switching from batch operation mode in toluene to either solvent‐free batch mode or microwave‐assisted hydroamination with tetrahydrofuran as a solvent.     

Thiol‐ene photofunctionalization of 1,4‐polymyrcene

1,4‐Polymyrcene was synthesized by anionic polymerization of β‐myrcene and was subjected to photochemical functionalization with various thiols (i.e. methyl thioglycolate, methyl 3‐mercaptopropionate, butyl 3‐mercaptopropionate, ethyl 2‐mercaptopropionate and 2‐methyl‐2‐propanethiol) using benzophenone/UV light as the radical source. The yield of thiol addition to the trisubstituted double bonds of 1,4‐polymyrcene decreased in the order 1° thiol (ca 95%) > 2° thiol (ca 80%) > 3° thiol (<5%), due to the reversibility of the thiol‐ene reaction. Remarkably, thiol addition to the side‐chain double bonds was 8 ? 10 times (1° thiol) or 24 times (2° thiol) faster than to the main‐chain double bonds, which can be explained by the different accessibility of the double bonds and steric hindrance. Despite the use of a 10‐fold excess of thiol with respect to myrcene units, the thiol‐ene addition was accompanied by chain coupling reactions, which in the extreme case of 3° thiol (or in the absence of thiol) resulted in the formation of insoluble crosslinked material. As an example, a methyl‐thioglycolate‐functionalized 1,4‐polymyrcene was saponified/crosslinked to give submicron polyelectrolyte particles in dilute alkaline solution. © 2018 Society of Chemical Industry     

The number of spanning trees of a graph with given matching number

The number of spanning trees of a graph G is the total number of distinct spanning subgraphs of G that are trees. In this paper, we present sharp upper bounds for the number of spanning trees of a graph with given matching number.     

Adaptive control of a class of nonlinear systems with convex/concave parameterization

This paper deals with adaptive control of a class of second-order nonlinear systems with a triangular structure and convex/concave parameterization. In Annaswamy et al. (Automatica 33(11) (1998) 1975–1995) it was shown that nonlinearly parameterized systems that satisfy certain matching conditions can be adaptively controlled in a stable manner. In this paper, we relax these matching conditions and include additional dynamics between the nonlinearities and the control input. Global boundedness and convergence to within a desired precision is established. No overparameterization of the adaptive controller is required.     

Annotating patient clinical records with syntactic chunks and named entities: the Harvey Corpus

The free text notes typed by physicians during patient consultations contain valuable information for the study of disease and treatment. These notes are difficult to process by existing natural language analysis tools since they are highly telegraphic (omitting many words), and contain many spelling mistakes, inconsistencies in punctuation, and non-standard word order. To support information extraction and classification tasks over such text, we describe a de-identified corpus of free text notes, a shallow syntactic and named entity annotation scheme for this kind of text, and an approach to training domain specialists with no linguistic background to annotate the text. Finally, we present a statistical chunking system for such clinical text with a stable learning rate and good accuracy, indicating that the manual annotation is consistent and that the annotation scheme is tractable for machine learning.     

Trees with minimal Laplacian coefficients

Let $G$ be a simple undirected graph with the characteristic polynomial of its Laplacian matrix $L\left(G\right)$, $P(G,\mu )={\sum }_{k=0}^n{(?1)}^k{c}_k{\mu }^{n?k}$. It is well known that for trees the Laplacian coefficient $c_{n?2}$ is equal to the Wiener index of $G$, while $c_{n?3}$ is equal to the modified hyper-Wiener index of the graph. In this paper, we characterize $n$-vertex trees with given matching number $m$ which simultaneously minimize all Laplacian coefficients. The extremal tree $A(n,m)$ is a spur, obtained from the star graph $S_{n?m+1}$ with $n?m+1$ vertices by attaching a pendant edge to each of certain $m?1$ non-central vertices of $S_{n?m+1}$. In particular, $A(n,m)$ minimizes the Wiener index, the modified hyper-Wiener index and the recently introduced Incidence energy of trees, defined as $IE\left(G\right)={\sum }_{k=0}^n\sqrt{{\mu }_k}$, where ${\mu }_k$ are the eigenvalues of signless Laplacian matrix $Q\left(G\right)=D\left(G\right)+A\left(G\right)$. We introduced a general $\rho$ transformation which decreases all Laplacian coefficients simultaneously. In conclusion, we illustrate on examples of Wiener index and Incidence energy that the opposite problem of simultaneously maximizing all Laplacian coefficients has no solution.     

Compositional software verification based on game semantics and process algebra

We present an approach to software model checking based on game semantics and the CSP process algebra. Open program fragments (i.e. terms-in-context) are compositionally modelled as CSP processes which represent their game semantics. This translation is performed by a prototype compiler. Observational equivalence and regular properties are checked by traces refinement using the FDR tool. We also present theorems for parameterised verification of polymorphic terms and properties. The effectiveness of the approach is evaluated on several examples. We acknowledge support by the EPSRC (GR/S52759/01). The second author was also supported by the Intel Corporation, and is also affiliated to the Mathematical Institute, Serbian Academy of Sciences and Arts, Belgrade