The 11th edition of Harrison's Principles of Internal Medicine welcomes Anthony Fauci to its editorial staff, in addition to more than 85 new contributors. While the organization of the book is similar to previous editions, major emphasis has been placed on disorders that affect multiple organ systems. Important advances in genetics, immunology, and oncology are emphasized. Many chapters of the book have been rewritten and describe major advances in internal medicine. Subjects that received only a paragraph or two of attention in previous editions are now covered in entire chapters. Among the chapters that have been extensively revised are the chapters on infections in the compromised host, on skin rashes in infections, on many of the viral infections, including cytomegalovirus and Epstein-Barr virus, on sexually transmitted diseases, on diabetes mellitus, on disorders of bone and mineral metabolism, and on lymphadenopathy and splenomegaly. The major revisions in these chapters and many

Harrison's Principles of Internal Medicine

Copper is an essential trace element in living systems, present in the parts per million concentration range. It is a key cofactor in a diverse array of biological oxidation-reduction reactions. These involve either outer-sphere electron transfer, as in the blue copper proteins and the Cu{sub A} site of cytochrome oxidase and nitrous oxide redutase, or inner-sphere electron transfer in the binding, activation, and reduction of dioxygen, superoxide, nitrite, and nitrous oxide. Copper sites have historically been divided into three classes based on their spectroscopic features, which reflect the geometric and electronic structure of the active site: type 1 (T1) or blue copper, type 2 (T2) or normal copper, and type 3 (T3) or coupled binuclear copper centers. 428 refs.

Multicopper Oxidases and Oxygenases

Denitrification is a distinct means of energy conservation, making use of N oxides as terminal electron acceptors for cellular bioenergetics under anaerobic, microaerophilic, and occasionally aerobic conditions. The process is an essential branch of the global N cycle, reversing dinitrogen fixation, and is associated with chemolithotrophic, phototrophic, diazotrophic, or organotrophic metabolism but generally not with obligately anaerobic life. Discovered more than a century ago and believed to be exclusively a bacterial trait, denitrification has now been found in halophilic and hyperthermophilic archaea and in the mitochondria of fungi, raising evolutionarily intriguing vistas. Important advances in the biochemical characterization of denitrification and the underlying genetics have been achieved with Pseudomonas stutzeri, Pseudomonas aeruginosa, Paracoccus denitrificans, Ralstonia eutropha, and Rhodobacter sphaeroides. Pseudomonads represent one of the largest assemblies of the denitrifying bacteria within a single genus, favoring their use as model organisms. Around 50 genes are required within a single bacterium to encode the core structures of the denitrification apparatus. Much of the denitrification process of gram-negative bacteria has been found confined to the periplasm, whereas the topology and enzymology of the gram-positive bacteria are less well established. The activation and enzymatic transformation of N oxides is based on the redox chemistry of Fe, Cu, and Mo. Biochemical breakthroughs have included the X-ray structures of the two types of respiratory nitrite reductases and the isolation of the novel enzymes nitric oxide reductase and nitrous oxide reductase, as well as their structural characterization by indirect spectroscopic means. This revealed unexpected relationships among denitrification enzymes and respiratory oxygen reductases. Denitrification is intimately related to fundamental cellular processes that include primary and secondary transport, protein translocation, cytochrome c biogenesis, anaerobic gene regulation, metalloprotein assembly, and the biosynthesis of the cofactors molybdopterin and heme D1. An important class of regulators for the anaerobic expression of the denitrification apparatus are transcription factors of the greater FNR family. Nitrate and nitric oxide, in addition to being respiratory substrates, have been identified as signaling molecules for the induction of distinct N oxide-metabolizing enzymes.

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Cell biology and molecular basis of denitrification.

Graphene, a single monolayer of graphite, has recently attracted considerable interest owing to its novel magneto-transport properties, high carrier mobility and ballistic transport up to room temperature. It has the potential for technological applications as a successor of silicon in the post Moore's law era, as a single-molecule gas sensor, in spintronics, in quantum computing or as a terahertz oscillator. For such applications, uniform ordered growth of graphene on an insulating substrate is necessary. The growth of graphene on insulating silicon carbide (SiC) surfaces by high-temperature annealing in vacuum was previously proposed to open a route for large-scale production of graphene-based devices. However, vacuum decomposition of SiC yields graphene layers with small grains (30-200 nm; refs 14-16). Here, we show that the ex situ graphitization of Si-terminated SiC(0001) in an argon atmosphere of about 1 bar produces monolayer graphene films with much larger domain sizes than previously attainable. Raman spectroscopy and Hall measurements confirm the improved quality of the films thus obtained. High electronic mobilities were found, which reach mu=2,000 cm (2) V(-1) s(-1) at T=27 K. The new growth process introduced here establishes a method for the synthesis of graphene films on a technologically viable basis.

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Towards wafer-size graphene layers by atmospheric pressure graphitization of silicon carbide

For present purposes, a protein-bound metal site consists of one or more metal ions and all protein side chain and exogenous bridging and terminal ligands that define the first coordination sphere of each metal ion. Such sites can be classified into five basic types with the indicated functions: (1) structural -- configuration (in part) of protein tertiary and/or quaternary structure; (2) storage -- uptake, binding, and release of metals in soluble form: (3) electron transfer -- uptake, release, and storage of electrons; (4) dioxygen binding -- metal-O{sub 2} coordination and decoordination; and (5) catalytic -- substrate binding, activation, and turnover. The authors present here a classification and structure/function analysis of native metal sites based on these functions, where 5 is an extensive class subdivided by the type of reaction catalyzed. Within this purview, coverage of the various site types is extensive, but not exhaustive. The purpose of this exposition is to present examples of all types of sites and to relate, insofar as is currently feasible, the structure and function of selected types. The authors largely confine their considerations to the sites themselves, with due recognition that these site features are coupled to protein structure at all levels. In themore » next section, the coordination chemistry of metalloprotein sites and the unique properties of a protein as a ligand are briefly summarized. Structure/function relationships are systematically explored and tabulations of structurally defined sites presented. Finally, future directions in bioinorganic research in the context of metal site chemistry are considered. 620 refs.« less

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Structural and Functional Aspects of Metal Sites in Biology

The phase transitions between $(2\ifmmode\times\else\texttimes\fi{}4)/c(2\ifmmode\times\else\texttimes\fi{}8)$ and $c(4\ifmmode\times\else\texttimes\fi{}4)$ on GaAs(001) surfaces are studied by ultrahigh-vacuum scanning tunneling microscopy. It is evident that the Ga diffusion is remarkable for length up to the micrometer range at the beginning of the transition, but the diffusion is prevented by nucleation at the final stage of the transition. We found that the size of the minimum nucleus depends on reconstruction. The structural stability is discussed, taking the surface electronic properties into account.

Extremely long surface diffusion of Ga and critical nucleation on As-rich GaAs(001) surfaces caused by phase transitions

Effectiveness of probucol in preventing restenosis after percutaneous transluminal coronary angioplasty: Probucol angioplasty restenosis trial (PART)

The catalytic mechanism of glutathione synthetase is proposed to proceed via phosphorylation of the dipeptide substrate to yield an acyl phosphate intermediate; this intermediate is subsequently attacked by glycine, followed by loss of inorganic phosphate, leading to glutathione formation A flexible loop (Ile226-Gly242) in Escherichia coli B glutathione synthetase is proposed to stabilize the acyl phosphate intermediate by preventing its decomposition by hydrolysis with water [Tanaka, T, Kato, H, Nishioka, T, & Oda, J (1992) Biochemistry 31, 2259-2265; Tanaka, T, Yamaguchi, H, Kato, H, Nishioka, T, Katsube, Y, & Oda, J (1993) Biochemistry 32, 12398-12404] To investigate the function of the loop in the E coli enzyme definitely, a loopless mutant in which the loop (Ile226-Arg241) was replaced with three residues of glycine was constructed The crystal structure of the loopless mutant enzyme was essentially identical with that of the wild-type enzyme Kinetic measurements showed that the replacement of the loop led to increases in the Km values, especially for the glycine, and a 930-fold decrease in the k0 value Hence, the loopless mutant was 3 x 10(4) less active in terms of its specificity constant (k0/Km) for glycine than the wild-type enzyme Moreover, the loopless mutant showed gamma-L-glutamyl-L-cysteine-dependent ATP hydrolase activity to almost the same extent as its glutathione synthetase activity These studies support the fact that the loop enhances the recognition of glycine as well as stabilizes the acyl phosphate intermediate so that the intermediate rapidly reacts with glycine

Flexible loop that is novel catalytic machinery in a ligase. Atomic structure and function of the loopless glutathione synthetase.

We fabricated semiconducting free-standing-beam and Hall-bar structures with a high slenderness ratio, a minimum thickness of 50 nm, and a typical length of several tens of microns using InAs membranes processed from InAs/GaAs heterostructures. These structures showed clear electric conductivity without any intentional doping. We obtained the carrier concentration and mobility by means of standard Hall measurements, thus confirming that both parameters were much larger than those of as-grown heterostructure samples. These results indicate that this material system is promising for micro/nanoelectromechanical system applications.

Excellent electric properties of free-standing InAs membranes

We fabricated self-sensing microelectromechanical displacement sensors from InAs/AlGaSb heterostructures. The sensitivity increased with reduced InAs thickness showing that the piezoresistivity was strongly enhanced when the quantum level approached to the pinning position of surface Fermi level. The high-sensitivity allowed us to detect a subangstrom displacement induced by thermal vibration of cantilevers.

Hiroshi Yamaguchi

Papers

Extremely long surface diffusion of Ga and critical nucleation on As-rich GaAs(001) surfaces caused by phase transitions

Effectiveness of probucol in preventing restenosis after percutaneous transluminal coronary angioplasty: Probucol angioplasty restenosis trial (PART)

Flexible loop that is novel catalytic machinery in a ligase. Atomic structure and function of the loopless glutathione synthetase.

Excellent electric properties of free-standing InAs membranes

Microelectromechanical displacement sensing using InAs/AlGaSb heterostructures