New Delhi metallo-β-lactamase: structural insights into β-lactam recognition and inhibition

The β-lactam antibiotics have long been a cornerstone for the treatment of bacterial disease. Recently, a readily transferable antibiotic resistance factor called the New Delhi metallo-β-lactamase-1 (NDM-1) has been found to confer enteric bacteria resistance to nearly all β-lactams, including the heralded carbapenems, posing a serious threat to human health. The crystal structure of NDM-1 bound to meropenem shows for the first time the molecular details of how carbapenem antibiotics are recognized by dizinc-containing metallo-β-lactamases. Additionally, product complex structures of hydrolyzed benzylpenicillin-, methicillin-, and oxacillin-bound NDM-1 have been solved to 1.8, 1.2, and 1.2 ?, respectively, and represent the highest-resolution structural data for any metallo-β-lactamase reported to date. Finally, we present the crystal structure of NDM-1 bound to the potent competitive inhibitor l-captopril, which reveals a unique binding mechanism. An analysis of the NDM-1 active site in these structures reveals key features important for the informed design of novel inhibitors of NDM-1 and other metallo-β-lactamases.     

Total-variation-diminishing implicit–explicit Runge–Kutta methods for the simulation of double-diffusive convection in astrophysics

We put forward the use of total-variation-diminishing (or more generally, strong stability preserving) implicit–explicit Runge–Kutta methods for the time integration of the equations of motion associated with the semiconvection problem in the simulation of stellar convection. The fully compressible Navier–Stokes equation, augmented by continuity and total energy equations, and an equation of state describing the relation between the thermodynamic quantities, is semi-discretized in space by essentially non-oscillatory schemes and dissipative finite difference methods. It is subsequently integrated in time by Runge–Kutta methods which are constructed such as to preserve the total variation diminishing (or strong stability) property satisfied by the spatial discretization coupled with the forward Euler method. We analyse the stability, accuracy and dissipativity of the time integrators and demonstrate that the most successful methods yield a substantial gain in computational efficiency as compared to classical explicit Runge–Kutta methods.     

Enhancement of the radiation yield, in plasma flow switchexperiments

The Shiva Star fast capacitor bank, an inductive store, and a plasma flow switch were used to deliver multimegaampere currents with submicrosecond rise times to cylindrical foil loads. A series of numerical simulations of the plasma flow switch/imploding load system were performed with the goal of discovering a way to boost the total power radiated by the imploding plasma as it stagnates on the axis of symmetry. The changes to the experimental design that were investigated include variations of the shape of the electrodes, size and mass of the load foil, structure of the axial view vanes, shape and mass of the switching plasma, material from which the load is constructed, the degree to which the load is bowed, and the energy of the capacitor bank. Radiation yields in the range 6-9 TW are predicted for future experiments on Shiva Star     

Solid-phase synthesis of substituted alkynes using the Nicholas reaction

The first example of a Nicholas reaction on solid phase is reported, involving the reaction of cobalt complexes of polymer-bound alkynols with different nucleophiles in the presence of a Lewis acid, to form carbon-oxygen or carbon-carbon bonds.     

Co-aggregation of fullerene C60 and thiophene in the non-aromatic solvent cyclohexene

Co-aggregation of fullerene C₆₀ and thiophene has been studied calorimetrically in cyclohexene at 25 °C. The total aggregation heat is found to depend on initial concentration of thiophene and fall between −1.9 and −5.8 kJ mol⁻¹. The corresponding thiophene/fullerene molar ratio (“co-aggregation number”) ranges from 7 to 12. The data are rationalized by formation of heteromolecular nanoaggregates with intermolecular contacts of both fullerene–thiophene and fullerene–fullerene types. A physical model describing interaction between fullerenes and π-donors in solution is substantiated and used to explain heterogeneity of composites containing fullerenes.     

An isomerization-ring-closing metathesis strategy for the synthesis of substituted benzofurans

Twelve substituted benzofurans were synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using ruthenium-mediated C- and O-allyl isomerization followed by ring-closing metathesis.     

Conversion between triplet pair states is controlled by molecular coupling in pentadithiophene thin films

In singlet fission (SF) the initially formed correlated triplet pair state, ¹(TT), may evolve toward independent triplet excitons or higher spin states of the (TT) species. The latter result is often considered undesirable from a light harvesting perspective but may be attractive for quantum information sciences (QIS) applications, as the final exciton pair can be spin-entangled and magnetically active with relatively long room temperature decoherence times. In this study we use ultrafast transient absorption (TA) and time-resolved electron paramagnetic resonance (TR-EPR) spectroscopy to monitor SF and triplet pair evolution in a series of alkyl silyl-functionalized pentadithiophene (PDT) thin films designed with systematically varying pairwise and long-range molecular interactions between PDT chromophores. The lifetime of the (TT) species varies from 40 ns to 1.5 μs, the latter of which is associated with extremely weak intermolecular coupling, sharp optical spectroscopic features, and complex TR-EPR spectra that are composed of a mixture of triplet and quintet-like features. On the other hand, more tightly coupled films produce broader transient optical spectra but simpler TR-EPR spectra consistent with significant population in ⁵(TT)₀. These distinctions are rationalized through the role of exciton diffusion and predictions of TT state mixing with low exchange coupling J versus pure spin substate population with larger J. The connection between population evolution using electronic and spin spectroscopies enables assignments that provide a more detailed picture of triplet pair evolution than previously presented and provides critical guidance for designing molecular QIS systems based on light-induced spin coherence.

Pentadithiophene derivatives produce triplet pairs efficiently with secondary spin state evolution that depends on their unique intermolecular juxtapositions.     

Aryl annulation of cyclic ketones via a magnesium carbometalation-6-pi- electrocyclization protocol

A new strategy for the aryl annulation of cyclic ketones is described. Palladium(0) coupling of a propargyl alcohol with the enol triflate of a ketone and addition of vinylmagnesium chloride generates a triene as a magnesium chelate that may be quenched with an electrophile. In some cases, the triene cyclizes under the reaction conditions. Aromatization is accomplished by exposure to manganese dioxide or dichlorodicyanoquinone (DDQ). [reaction: see text]