Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis

Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy.     

Elastic “hard” fibers. I.

Elastic “hard” fibers may be prepared from a number of semicrystalline polymers, notably polypropylene, poly-3-methylbutene-1, and polyoxymethylene. These materials show typically a high degree of length recovery from large extensions, a marked, more-or-less recoverable reduction of apparent density on stretching, and the generation of very large amounts of accessible volume and surface area on stretching. Wide- and low-angle X-ray and electron-microscopic observations indicate that the morphological basis for these properties lies in an array of closely packed lamellae of which the normals lie predominantly parallel to the fiber extrusion direction. It is the tilting and splaying apart of the lamellar network which creates the internal volume and surface area on stretching. The long-range elasticity is believed to be distinctly nonrubberlike, as reflected in an insensitivity of mechanical properties to low temperatures, and to arise from bending of the lamellae. This unusual class of materials provides a significant link between macroscopic properties and a particular morphological structure.     

A calculator‐based computational approach Part 3. The differentiation

This paper extends the themes on the computational approach discussed in Parts 1 and 2 to the differentiation of functions. One theme is that constructing diagrams for programs using a calculator helps students to visualize processes and thus acquire the concepts involved. The ability to construct diagrams for a given problem is identical to that of programming a calculator to solve the problem. However, in this case constructing the diagram for derivatives from the diagram of the function also represents the ability to teach a calculator how to perform formal differentiation. A second theme is that the approach promotes sequential or procedural thinking which is important in both programming and mathematics. A third theme is that the approach permits the generation of many subproblems, thereby encouraging one to pose questions rather than merely to solve those set by others. Consequently, it becomes clear that the approach has wider applications in the learning of mathematics.     

Ab initio studies of methylenecarbene and isoelectronic species

Optimum equilibrium geometries, energetics, harmonic vibrational frequencies, and infared intensities within the double harmonic approximation are computed for methylenecarbene, CCH₂, and isoelectronic species involving silicon and germanium at both the SCF level of theory and the level of second-order perturbation theory using a 6-311G(2df, 2p) basis set or its equivalent. Optimum equilibrium geometries and energetics are also computed at both levels of theory using a smaller 6-311G(d, p) basis set or its equivalent. This investigation of these species is the first to include all of the systems with germanium. In addition, this present work is the first study to includef-type polarization functions in a systematic investigation of the molecular structure and properties of all the molecules in the series. Acetylenic structures are also computed for energy comparisons. Of all the linear isomers, only acetylene is found to be a minimum on the potential energy surface. However, all of the C_2v structures are found to be local minima. Both the C_2v and linear structures will serve as a basis for future work involving mapping the entire hyperenergy surfaces of all of the molecular systems in the series.     

Large transverse momentum particle production in αα and pp collisions at the CERN ISR

The production of charged hadrons with high p_T in αα collisions at √s=126 GeV and pp collisions at √s=31 and 63 GeV is compared, and the structure of the events associated with the high-pT particles is studied. The probability of finding associated particles close to the trigger particle increases strongly between √s=31 and 63 GeV for pp collisions. For p_T>2.5GeV/c the αα/pp cross section ratio at the same energy per nucleon is measured to be 18.7 ± 2.0, to be compared with A² = 16, and a higher associated multiplicity is observed for αα.     

A practical synthesis of bridged diarylacetylenes

An efficient and practical synthesis of bridged diarylacetylenes in multigram quantities has been successfully carried out using high-yielding (classical) synthetic methods and readily available starting materials. The structural analysis of the representative bridged diarylacetylenes by X-ray crystallography strongly suggests that conformations, bending of the linear triple bond, and the angle between the mean planes of aromatic rings in various bridged diarylacetylenes are governed by the p-pi conjugation among the aromatic rings and the ethereal groups. Furthermore, the synthetic scheme also allows the preparation of (appropriately) bromo-substituted bridged diarylacetylenes which hold potential for their future usage for the preparation of polymeric analogues as well as the hexaarylbenzene derivatives for potential applications in the emerging area of molecular electronics and nanotechnology.     

Composition dependence of elasticity in NaxWO3

Single crystal Na_xWO₃ elastic constants have been measured for x = 0.522, 0.628, 0.695, and 0.74 using Brillouin light scattering. The elasticity of Na_xWO₃ is found to be similar to that of ReO₃. Calculations indicate that an observed decrease in c₁₁ with increasing sodium concentration results from perturbation associated with an increasing lattice constant of strong, covalent WO bonds.     

Atomic absorption studies using a hollow-cathode tube as an absorption source

When hollow-cathode tubes are used as the emission source and as the absorption source, atomic absorption studies reveal microgram quantities of several elements; sodium, magnesium, calcium, beryllium, and silicon were detected in the discharge of the absorption tube. Conventional, independent circulating systems and d.c. power supplies, were used with each tube, along with other readily available equipment. An analytical curve plotted for sodium over the range 0—100 μg, obeys Beer's law. Lithium and magnesium suppress the sodium absorption values, thus careful standardization is necessary. The average percent deviation from the mean for a number of sodium samples analyzed was ± 8.0%.