Substitution-Induced Mechanistic Switching in SAr-Warheads for Cysteine Proteases.

The aim of this study was to investigate the transition from non-covalent reversible over covalent reversible to covalent irreversible inhibition of cysteine proteases by making delicate structural changes to the warhead scaffold. To this end, dipeptidic rhodesain inhibitors with different -terminal electrophilic arenes as warheads relying on the SAr mechanism were synthesized and investigated. Strong structure-activity relationships of the inhibition potency, the degree of covalency, and the reversibility of binding on the arene substitution pattern were found.

Regularized relativistic corrections for polyelectronic and polyatomic systems with explicitly correlated Gaussians.

Drachmann's regularization approach is implemented for floating explicitly correlated Gaussians (fECGs) and molecular systems. Earlier applications of drachmannized relativistic corrections for molecular systems were hindered due to the unknown analytic matrix elements of 1/rix1/rjy-type operators with fECGs. In the present work, one of the 1/r factors is approximated by a linear combination of Gaussians, which results in calculable integrals.

The Bethe-Salpeter QED Wave Equation for Bound-State Computations of Atoms and Molecules.

Interactions in atomic and molecular systems are dominated by electromagnetic forces and the theoretical framework must be in the quantum regime. The physical theory for the combination of quantum mechanics and electromagnetism, quantum electrodynamics has been "established" by the mid-twentieth century, primarily as a scattering theory. To describe atoms and molecules, it is important to consider bound states.

Evaluation of the Bethe Logarithm: From Atom to Chemical Reaction.

A general computational scheme for the (nonrelativistic) Bethe logarithm is developed, opening the route to "routine" evaluation of the leading-order quantum electrodynamics correction (QED) relevant for spectroscopic applications for small polyatomic and polyelectronic molecular systems. The implementation relies on the Schwartz method and minimization of a Hylleraas functional. In relation with electronically excited states, a projection technique is considered, which ensures positive definiteness of the functional over the entire parameter (photon momentum) range.

Variational vs perturbative relativistic energies for small and light atomic and molecular systems.

Variational and perturbative relativistic energies are computed and compared for two-electron atoms and molecules with low nuclear charge numbers. In general, good agreement of the two approaches is observed. Remaining deviations can be attributed to higher-order relativistic, also called non-radiative quantum electrodynamics (QED), corrections of the perturbative approach that are automatically included in the variational solution of the no-pair Dirac-Coulomb-Breit (DCB) equation to all orders of the α fine-structure constant.

Variational Dirac-Coulomb explicitly correlated computations for atoms and molecules.

The Dirac-Coulomb equation with positive-energy projection is solved using explicitly correlated Gaussian functions. The algorithm and computational procedure aims for a parts-per-billion convergence of the energy to provide a starting point for further comparison and further developments in relation with high-resolution atomic and molecular spectroscopy. Besides a detailed discussion of the implementation of the fundamental spinor structure, permutation, and point-group symmetries, various options for the positive-energy projection procedure are presented.

On the Breit interaction in an explicitly correlated variational Dirac-Coulomb framework.

The Breit interaction is implemented in the no-pair variational Dirac-Coulomb (DC) framework using an explicitly correlated Gaussian basis reported in the previous paper [P. Jeszenszki, D. Ferenc, and E.

Two Faces of the Two-Phase Thermodynamic Model.

The quantum harmonic model and the two-phase thermodynamic method (2PT) are widely used to obtain quantum-corrected properties such as isobaric heat capacities or molar entropies. 2PT heat capacities were calculated inconsistently in the literature. For water, the classical heat capacity was also considered, but for organic liquids, it was omitted.

All-order explicitly correlated relativistic computations for atoms and molecules.

A variational solution procedure is reported for the many-particle no-pair Dirac-Coulomb and Dirac-Coulomb-Breit Hamiltonians aiming at a parts-per-billion (ppb) convergence of the atomic and molecular energies, described within the fixed nuclei approximation. The procedure is tested for nuclear charge numbers from Z = 1 (hydrogen) to 28 (iron). Already for the lowest Z values, a significant difference is observed from leading-order Foldy-Woythusen perturbation theory, but the observed deviations are smaller than the estimated self-energy and vacuum polarization corrections.

Use of platelet-rich fibrin for the treatment of periodontal intrabony defects: a systematic review and meta-analysis.

Objectives: This study aims to compare the treatment outcomes of periodontal intrabony defects by using platelet-rich fibrin (PRF) with other commonly utilized modalities.

Materials And Methods: The eligibility criteria comprised randomized controlled trials (RCTs) comparing the clinical outcomes of PRF with that of other modalities. Studies were classified into 10 categories as follows: (1) open flap debridement (OFD) alone versus OFD/PRF; (2) OFD/bone graft (OFD/BG) versus OFD/PRF; (3) OFD/BG versus OFD/BG/PRF; (4-6) OFD/barrier membrane (BM), OFD/PRP, or OFD/enamel matrix derivative (EMD) versus OFD/PRF; (7) OFD/EMD versus OFD/EMD/PRF; (8-10) OFD/PRF versus OFD/PRF/metformin, OFD/PRF/bisphosphonates, or OFD/PRF/statins.

Di--butyl Phosphonate Route to the Antiviral Drug Tenofovir.

Di--butyl oxymethyl phosphonates were investigated regarding their suitability for preparing the active pharmaceutical ingredient tenofovir (PMPA). First, an efficient and simple access to the crystalline di--butyl(hydroxymethyl)phosphonate was developed. O-Mesylation gave high yields of the active phosphonomethylation reagent.

Nonadiabatic, Relativistic, and Leading-Order QED Corrections for Rovibrational Intervals of ^{4}He_{2}^{+} (X ^{2}Σ_{u}^{+}).

The rovibrational intervals of the ^{4}He_{2}^{+} molecular ion in its X ^{2}Σ_{u}^{+} ground electronic state are computed by including the nonadiabatic, relativistic, and leading-order quantum-electrodynamics corrections. Good agreement of theory and experiment is observed for the rotational excitation series of the vibrational ground state and the fundamental vibration. The lowest-energy rotational interval is computed to be 70.

Nuclear Quantum Effects from the Analysis of Smoothed Trajectories: Pilot Study for Water.

Nuclear quantum effects have significant contributions to thermodynamic quantities and structural properties; furthermore, very expensive methods are necessary for their accurate computation. In most calculations, these effects, for instance, zero-point energies, are simply neglected or only taken into account within the quantum harmonic oscillator approximation. Herein, we present a new method, Generalized Smoothed Trajectory Analysis, to determine nuclear quantum effects from molecular dynamics simulations.

Non-adiabatic mass correction for excited states of molecular hydrogen: Improvement for the outer-well HH¯ Σ term values.

The mass-correction function is evaluated for selected excited states of the hydrogen molecule within a single-state nonadiabatic treatment. Its qualitative features are studied at the avoided crossing of the EF with the GK state and also for the outer well of the HH¯ state. For the HH¯ state, a negative mass correction is obtained for the vibrational motion near the outer minimum, which accounts for most of the deviation between experiment and earlier theoretical work.

Total Synthesis of (-)-Oxycodone via Anodic Aryl-Aryl Coupling.

A fully regio- and diastereoselective electrochemical 4a-2'-coupling of a 3',4',5'-trioxygenated laudanosine derivative enables the synthesis of the corresponding morphinandienone. This key intermediate is further transformed into (-)-oxycodone through conjugate nucleophilic substitution for E-ring closure and [4 + 2] cycloaddition with photogenerated singlet oxygen to accomplish diastereoselective hydroxylation at C-14. The anodic transformation provides high yields and can be performed under constant current conditions both in a simple undivided cell or in continuous flow.

A Regio- and Diastereoselective Anodic Aryl-Aryl Coupling in the Biomimetic Total Synthesis of (-)-Thebaine.

The biosynthesis of thebaine is based on the regioselective, intramolecular, oxidative coupling of (R)-reticuline. For decades, chemists have sought to mimic this coupling by using stoichiometric oxidants. However, all approaches to date have suffered from low yields or the formation of undesired regioisomers.

Microarchitecture of the Augmented Bone Following Sinus Elevation with an Albumin Impregnated Demineralized Freeze-Dried Bone Allograft (BoneAlbumin) versus Anorganic Bovine Bone Mineral: A Randomized Prospective Clinical, Histomorphometric, and Micro-Computed Tomography Study.

Serum albumin has been identified as an endogenous protein that is integral to early bone regeneration. We hypothesized that albumin addition to allografts may result in better bone remodeling than what can be achieved with anorganic xenografts. Sinus elevations were performed at 32 sites of 18 patients with the lateral window technique.

A Modular Access to (±)-Tubocurine and (±)-Curine - Formal Total Synthesis of Tubocurarine.

Two consecutive Cu-catalyzed Ullmann-type C-O couplings permitted the first successful entry toward the curare alkaloids (±)-tubocurine and (±)-curine. Starting from vanillin, the synthetic sequence comprises 15 linear steps and includes a total of 24 transformations. In addition, the total synthesis of tubocurine represents a formal total synthesis of the famous arrow poison alkaloid tubocurarine.

Chemoenzymatic synthesis of functional sialyl Lewis(x) mimetics with a heteroaromatic core.

Functional mimetics of the sialyl Lewis(X) tetrasaccharide were prepared by the enzymatic sialylation of a 1,3-diglycosylated indole and a glycosyl azide, which was subsequently transformed into a 1,4-diglycosylated 1,2,3-triazole, by using the trans-sialidase of Trypanosoma cruzi. These compounds inhibited the binding of E-, L-, and P-selectin-coated nanoparticles to polyacrylamide-bound sialyl-Lewis(X) -containing neighboring sulfated tyrosine residues (sTyr/sLe(X) -PAA) at low or sub-millimolar concentrations. Except for E-selectin, the mimetics showed higher activities than the natural tetrasaccharide.

Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones.

The cyclocondensation of enones with aminoacetonitrile furnishes 3,4-dihydro-2H-pyrrole-2-carbonitriles which can be readily converted to 2,4-disubstituted pyrroles by microwave-induced dehydrocyanation. Alternatively, oxidation of the intermediates produces 3,5-disubstituted pyrrole-2-carbonitriles.

Radio imaging of the very-high-energy gamma-ray emission region in the central engine of a radio galaxy.

The accretion of matter onto a massive black hole is believed to feed the relativistic plasma jets found in many active galactic nuclei (AGN). Although some AGN accelerate particles to energies exceeding 10(12) electron volts and are bright sources of very-high-energy (VHE) gamma-ray emission, it is not yet known where the VHE emission originates. Here we report on radio and VHE observations of the radio galaxy Messier 87, revealing a period of extremely strong VHE gamma-ray flares accompanied by a strong increase of the radio flux from its nucleus.

(Z)-Amino-(2-methyl-3-oxoisoindolin-1-yl-idene)acetonitrile.

The asymmetric unit of the title compound, C(11)H(9)N(3)O, contains two independent and nearly identical mol-ecules (A and B). Mol-ecule A can be transformed to B using a rotation of approximately 85° around the [111] direction. Each A mol-ecule is connected to three B mol-ecules via N-H⋯N and N-H⋯O hydrogen bonds and vice versa.

Observation of pulsed gamma-rays above 25 GeV from the Crab pulsar with MAGIC.

One fundamental question about pulsars concerns the mechanism of their pulsed electromagnetic emission. Measuring the high-end region of a pulsar's spectrum would shed light on this question. By developing a new electronic trigger, we lowered the threshold of the Major Atmospheric gamma-ray Imaging Cherenkov (MAGIC) telescope to 25 giga-electron volts.

Very-high-energy gamma rays from a distant quasar: how transparent is the universe?

The atmospheric Cherenkov gamma-ray telescope MAGIC, designed for a low-energy threshold, has detected very-high-energy gamma rays from a giant flare of the distant Quasi-Stellar Radio Source (in short: radio quasar) 3C 279, at a distance of more than 5 billion light-years (a redshift of 0.536). No quasar has been observed previously in very-high-energy gamma radiation, and this is also the most distant object detected emitting gamma rays above 50 gigaelectron volts.

Preparation of indoles from alpha-aminonitriles: A short synthesis of FGIN-1-27.

Alpha-Aminonitriles derived from 2-aminocinnamic acid esters and amides can be cyclized under basic conditions to furnish substituted indole-3-acetic acid derivatives in quantitative yield. The reaction provides a simple access to a class of biologically active compounds.