Identification and Directed Development of Non‐Organic Catalysts with Apparent Pan‐Enzymatic Mimicry into Nanozymes for Efficient Prodrug Conversion

Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a narrow range of mammalian enzymes, near‐exclusively performing redox reactions. We present an unexpected discovery of non‐proteinaceous enzymes based on metals, metal oxides, 1D/2D‐materials, and non‐metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan‐glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme‐prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti‐inflammatory and antibacterial agents, as well as “nanozyme prodrug therapy” to mediate antibacterial measures.     

Base-Pairing Properties of Double-Headed Nucleotides

Nucleotides that contain two nucleobases (double-headed nucleotides) have the potential to condense the information of two separate nucleotides into one. This presupposes that both bases must successfully pair with a cognate strand. Here, double-headed nucleotides that feature cytosine, guanine, thymine, adenine, hypoxanthine, and diaminopurine linked to the C2′-position of an arabinose scaffold were developed and examined in full detail. These monomeric units were efficiently prepared by convergent synthesis and incorporated into DNA oligonucleotides by means of the automated phosphoramidite method. Their pairing efficiency was assessed by UV-based melting-temperature analysis in several contexts and extensive molecular dynamics studies. Altogether, the results show that these double-headed nucleotides have a well-defined structure and invariably behave as functional dinucleotide mimics in DNA duplexes.     

Rate coefficients for reactions of OH radicals with CH3D,CH2D2, CHD3, and CD4

Fourier transform infrared (FTIR) smog chamber techniques were used to investigate the atmospheric chemistry of the isotopologues of methane. Relative rate measurements were performed to determine the kinetics of the reaction of the isotopologues of methane with OH radicals in cm³ molecule⁻¹ s⁻¹ units: k(CH₃D + OH) = (5.19 ± 0.90) × 10⁻¹⁵, k(CH₂D₂ + OH) = (4.11 ± 0.74) × 10⁻¹⁵, k(CHD₃ + OH) = (2.14 ± 0.43) × 10⁻¹⁵, and k(CD₄ + OH) = (1.17 ± 0.19) × 10⁻¹⁵ in 700 Torr of air diluent at 296 ± 2 K. Using the determined OH rate coefficients, the atmospheric lifetimes for CH_4–xD_x (x = 1–4) were estimated to be 6.1, 7.7, 14.8, and 27.0 years, respectively. The results are discussed in relation to previous measurements of these rate coefficients.     

Luminescence Spectroscopy of Rhodamine Homodimer Dications in Vacuo Reveals Strong Dye-Dye Interactions

Being alone or together makes a difference for the photophysics of dyes but for ionic dyes it is difficult to quantify the interactions due to solvent screening and nearby counter ions. Gas-phase luminescence experiments are desirable and now possible based on recent developments in mass spectrometry. Here we present results on tailor-made rhodamine homodimers where two dye cations are separated by methylene linkers, (CH₂)_n. In solution the fluorescence is almost identical to that from the monomer whereas the emission from bare cation dimers redshifts with decreasing n. In the absence of screening, the electric field from the charge on one dye is strong enough to polarize the other dye, both in the ground state and in the excited state. An electrostatic model based on symmetric dye responses (equal induced-dipole moments in ground state) captures the underlying physics and demonstrates interaction even at large distances. Our results have possible implications for gas-phase Förster Resonance Energy Transfer.     

Towards a Comprehensive Stability Theory for Feynman’s Operational Calculus: The Time-Dependent Setting

We obtain lower bounds on blow-up of solutions for the 3D magneto-micropolar equations. More precisely, we establish some estimates for the solution \((\mathbf{u},\mathbf{w},\mathbf{b}) (t)\) in its maximal interval \([0,T^{*})\) provided that \(T^{*}<\infty\), which show for \(\delta\in(0,1)\) that \(\|(\mathbf{u},\mathbf{w},\mathbf{b})(t)\|_{\dot{H}^{s}}\) is at least of the order \((T^{*}-t)^{-(\delta s)/(1+2\delta)}\) for \(s\geq1/2+\delta\). In particular, by choosing a suitable \(\delta\), one concludes that \(\|(\mathbf{u},\mathbf{w},\mathbf{b})(t)\|_{\dot{H}^{s}}\) is at least of the order \((T^{*}-t)^{-s/4}\), and \((T^{*}-t)^{1/4-s/2}\) for \(s\geq1\), and \(1/2< s<3/2\), respectively. We also show that \((T^{*}-t)^{-s/3}\) is a lower rate for \(\|(\mathbf{u},\mathbf{w},\mathbf{b})(t)\|_{\dot{H}^{s}}\) if \(s>3/2\).     

Anisotropic Mixed-Norm Hardy Spaces

We introduce and explore Hardy spaces defined by mixed Lebesgue norms and anisotropic dilations. We prove that the definitions of these spaces in terms of smooth, non-tangential, auxiliary, grand, and Poisson maximal operators coincide. We also study the relation between anisotropic mixed-norm Hardy spaces and mixed-norm Lebesgue spaces.     

Substrates and Cyclic Peptide Inhibitors of the Oligonucleotide-Activated Sirtuin 7**

The sirtuins are NAD⁺-dependent lysine deacylases, comprising seven isoforms (SIRT1–7) in humans, which are involved in the regulation of a plethora of biological processes, including gene expression and metabolism. The sirtuins share a common hydrolytic mechanism but display preferences for different ϵ-N-acyllysine substrates. SIRT7 deacetylates targets in nuclei and nucleoli but remains one of the lesser studied of the seven isoforms, in part due to a lack of chemical tools to specifically probe SIRT7 activity. Here we expressed SIRT7 and, using small-angle X-ray scattering, reveal SIRT7 to be a monomeric enzyme with a low degree of globular flexibility in solution. We developed a fluorogenic assay for investigation of the substrate preferences of SIRT7 and to evaluate compounds that modulate its activity. We report several mechanism-based SIRT7 inhibitors as well as de novo cyclic peptide inhibitors selected from mRNA-display library screening that exhibit selectivity for SIRT7 over other sirtuin isoforms, stabilize SIRT7 in cells, and cause an increase in the acetylation of H3 K18.     

Non-linear stochastic response of a shallow cable

The paper considers the stochastic response of geometrical non-linear shallow cables. Large rain-wind induced cable oscillations with non-linear interactions have been observed in many large cable stayed bridges during the last decades. The response of the cable is investigated for a reduced two-degrees-of-freedom system with one modal coordinate for the in-plane displacement and one for the out-of-plane displacement. At first harmonic varying chord elongation at excitation frequencies close to the corresponding eigenfrequencies of the cable is considered in order to identify stable modes of vibration. Depending on the initial conditions the system may enter one of two states of vibration in the static equilibrium plane with the out-of-plane displacement equal to zero, or a whirling state with the out-of-plane displacement different from zero. Possible solutions are found both analytically and numerically. Next, the chord elongation is modelled as a narrow-banded Gaussian stochastic process, and it is shown that all the indicated harmonic solutions now become instable with probability one. Instead, the cable jumps randomly back and forth between the two in-plane and the whirling mode of vibration. A theory for determining the probability of occupying either of these modes at a certain time is derived based on a homogeneous, continuous time three states Markov chain model. It is shown that the transitional probability rates can be determined by first-passage crossing rates of the envelope process of the chord wise component of the support point motion relative to a safe domain determined from the harmonic analysis of the problem.