Antisense and antigene inhibition of gene expression by cell-permeable oligonucleotide-oligospermine conjugates

Oligonucleotides and their derivatives are a proven chemical strategy for modulating gene expression. However, their negative charge remains a challenge for delivery and target recognition inside cells. Here we show that oligonucleotide-oligospermine conjugates (Zip nucleic acids or ZNAs) can help overcome these shortcomings by serving as effective antisense and antigene agents. Conjugates containing DNA and locked nucleic acid (LNA) oligonucleotides are active, and oligospermine conjugation facilitates carrier-free cell uptake at nanomolar concentrations. Conjugates targeting the CAG triplet repeat within huntingtin (HTT) mRNA selectively inhibit expression of the mutant huntingtin protein. Conjugates targeting the promoter of the progesterone receptor (PR) function as antigene agents to block PR expression. These observations support further investigation of ZNA conjugates as gene silencing agents.     

Iodination of anilines and phenols with 18-crown-6 supported ICl2-

A highly crystalline iodinating reagent, {[K·18-C-6]ICl(2)}(n), was synthesized in high yield (93%). The trihalide is supported by an 18-crown-6 macrocycle and forms a coordination polymer in the solid state. This reagent iodinates anilines and phenols efficiently under mild conditions. Controlled mono-iodination with anilines was easily achieved while poly-iodination was observed with phenols.     

Nanostructured polymer assemblies formed at interfaces: applications from immobilization and encapsulation to stimuli-responsive release

In recent years, interfacial properties have been tailored with nanostructured polymer assemblies to generate materials with specific properties and functions for application in diverse fields, including biomaterials, drug delivery, catalysis, sensing, optics and corrosion. This perspective begins with a brief introduction of the assembly techniques that are commonly employed for the synthesis of nanostructured polymer materials, followed by discussions on how the interfaces influence the properties and thus the functionalities of the polymer materials prepared. Applications of the interfacial polymer nanostructures, particularly for the immobilization and encapsulation of cargo, are then reviewed, focusing on stimuli-responsive cargo release from the polymer nanostructured assemblies for controlled delivery applications. Finally, future research directions in these areas are briefly discussed.     

Spectrum of lattice gauge theories with fermions from a 1/d expansion at strong coupling

We study the strong coupling limit of U(N) or SU(N) gauge theories with fermions on a lattice. The integration over the gauge and fermion degrees of freedom is performed by analytic methods, leading to a partition function in terms of localized meson and baryon fields. A method for deriving a systematic expansion in the inverse of the space-time dimension of the corresponding Green functions is developed. It is applied to the study of spontaneous breakdown of chiral symmetry, which occurs for any U(N) or SU(N) theory with fermions in the fundamental representation. Meson and baryon spectra are then computed, and found to be in close agreement with those obtained by numerical methods at finite coupling. The pion decay constant is estimated.     

Broccoli curves and the tropical invariance of Welschinger numbers

In this paper we introduce broccoli curves, certain plane tropical curves of genus zero related to real algebraic curves. The numbers of these broccoli curves through given points are independent of the chosen points — for arbitrary choices of the directions of the ends of the curves, possibly with higher weights, and also if some of the ends are fixed. In the toric Del Pezzo case we show that these broccoli invariants are equal to the Welschinger invariants (with real and complex conjugate point conditions), thus providing a proof of the independence of Welschinger invariants of the point conditions within tropical geometry. The general case gives rise to a tropical Caporaso–Harris formula for broccoli curves which suffices to compute all Welschinger invariants of the plane.     

Milling Down to Nanometers: A General Process for the Direct Dry Synthesis of Supported Metal Catalysts

Supported catalysts are among the most important classes of catalysts. They are typically prepared by wet‐chemical methods, such as impregnation or co‐precipitation. Here we disclose that dry ball milling of macroscopic metal powder in the presence of a support oxide leads in many cases to supported catalysts with particles in the nanometer size range. Various supports, including TiO₂, Al₂O₃, Fe₂O₃, and Co₃O₄, and different metals, such as Au, Pt, Ag, Cu, and Ni, were studied, and for each of the supports and the metals, highly dispersed nanoparticles on supports could be prepared. The supported catalysts were tested in CO oxidation, where they showed activities in the same range as conventionally prepared catalysts. The method thus provides a simple and cost‐effective alternative to the conventionally used impregnation methods.     

Stable,Reactive, and Orthogonal Tetrazines: Dispersion Forces Promote the Cycloaddition with Isonitriles

The isocyano group is a structurally compact bioorthogonal functional group that reacts with tetrazines under physiological conditions. Now it is shown that bulky tetrazine substituents accelerate this cycloaddition. Computational studies suggest that dispersion forces between the isocyano group and the tetrazine substituents in the transition state contribute to the atypical structure–activity relationship. Stable asymmetric tetrazines that react with isonitriles at rate constants as high as 57 L mol^?1 s^?1 were accessible by combining bulky and electron‐withdrawing substituents. Sterically encumbered tetrazines react selectively with isonitriles in the presence of strained alkenes/alkynes, which allows for the orthogonal labeling of three proteins. The established principles will open new opportunities for developing tetrazine reactants with improved characteristics for diverse labeling and release applications with isonitriles.     

Mathematical model to reduce loop mediated isothermal amplification (LAMP) false‐positive diagnosis

Loop mediated isothermal amplification (LAMP) is a nucleic acid amplification technique performed under isothermal conditions. The output of this amplification technique includes multiple different sizes of deoxyribonucleic acid (DNA) structures which are identified by a banding pattern on gel electrophoresis plots. Although this is a specific amplification technique, the complexity of the primer design and amplification still lead to the issue of obtaining false‐positive results, especially when a positive reading is determined solely by whether there is any banding pattern in the gel electrophoresis plot. Here, we first performed extensive LAMP experiments and evaluated the DNA structures using microchip electrophoresis. We then developed a mathematical model derived from the various components that make up an entire LAMP structure to predict the full LAMP structure size in base pairs. This model can be implemented by users to make predictions for specific, DNA size dependent, banding patterns on their gel electrophoresis plots. Each prediction is specific to the target sequence and primers used and therefore reduces incorrect diagnosis errors through identifying true‐positive and false‐positive results. This model was accurately tested with multiple primer sets in house and was also translatable to different DNA and RNA types in previously published literature. The mathematical model can ultimately be used to reduce false‐positive LAMP diagnosis errors for applications ranging from tuberculosis diagnostics to E. coli to numerous other infectious diseases.     

An Improved Rapid Synthesis of Oligo(p‐benzamide) Block Copolymers

We describe a new synthesis that allows the preparation of oligo(p‐benzamide)s up to the heptamer on solid support without the need of semi‐temporary amide N‐protective groups. With increase in length, the solubility of oligo(p‐benzamide)s reduces dramatically. Even the tetra(p‐benzamide) is not soluble in common organic solvents. Therefore, solution syntheses of oligomers beyond the tetramer are not feasible. As will be shown in this paper, solid supported synthesis allows the preparation of even longer oligomers (up to the heptamer) in good yields. The high dilution on the solid support is most likely responsible for their pseudo‐solution‐like reactivity and the prevention of aggregation. This procedure is a significant improvement of previous syntheses and an important tool for the rapid exploration of supramolecular rod–coil copolymers based on oligoaramides.