Apoptosis and its role in human disease

In a landmark paper published over two decades ago, Kerr et al. proposed the term apoptosis "for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations". In the ensuing years, this natural cell death process was studied at the basic science level, primarily with a view to understanding its roles in cancer and in the development and maintenance of the immune system. More recently, however, evidence has suggested a role for the failure of normal apoptosis control in many of the major diseases of the industrialized world. Though complex, apoptosis appears amenable to therapeutic intervention. The range of modern pharmaceutical strategies available to treat such disregulated gene-directed processes offers promise for advances in the control of cancer, immune system and neurodegenerative disorders, heart disease, and perhaps even the aging process itself.     

Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids

CD22 beta is a B cell-restricted phosphoprotein expressed on the surface of mature resting B cells. It mediates interactions with other cells partly or exclusively via recognition of alpha 2-6-linked sialic acids on glycoconjugates. The sialylated N-linked oligosaccharides recognized best by CD22 beta are common to many glycoproteins, suggesting that additional regulatory mechanisms may exist. Since the exocyclic side chain of sialic acid is required for recognition, we explored the effects of a naturally occurring modification of the side chain, 9-O-acetylation. Semisynthetic N-linked oligosaccharides terminating with 9-O-acetylated, alpha 2-6-linked sialic acids showed markedly reduced binding to CD22 beta relative to their non-O-acetylated counterparts. Murine lymphoid cells were probed for natural CD22 beta ligands that might be O-acetylated using recombinant soluble forms of CD22 beta (CD22 beta Rg) and influenza C esterase (CHE-Fc, which specifically removes 9-O-acetyl esters from sialic acids). By flow cytometry analysis, CD22 beta Rg binding to splenic B cells and a subset of T cells was increased by pretreatment with CHE-Fc, indicating that some potential CD22 beta ligands are naturally "masked" by 9-O-acetylation. Unmasking of these CD22 beta ligands by removal of 9-O-acetyl esters from intact splenocytes substantially increases their CD22 beta-dependent adhesion in an in vitro adhesion assay. Probing of murine lymphoid tissue sections by CD22 beta Rg and CHE-Fc treatment demonstrates regionally restricted and differentially expressed patterns of distribution between masked and unmasked ligands. For example, lymph node-associated follicular B cells express high levels of CD22 beta ligands, none of which are masked by 9-O-acetylation. In contrast, the ligands on lymph node-associated dendritic cells are almost completely masked by 9-O-acetylation, suggesting that masking may regulate interactions between CD22 beta-positive B cells and dendritic cells. In the thymus, only medullary cells express CD22 beta ligands, and a significant portion of these are masked by 9-O-acetylation, particularly at the cortical-medullary junction. Thus, 9-O-acetylation of sialic acids on immune cells is in a position to negatively regulate CD22 beta adhesion events in a manner depending on both cell type and tissue localization.     

Isolation and characterization of a monoclonal anti-quadruplex DNA antibody from autoimmune "viable motheaten" mice

A cell line that produces an autoantibody specific for DNA quadruplex structures has been isolated and cloned from a hybridoma library derived from 3-month-old nonimmunized autoimmune, immunodeficient "viable motheaten" mice. This antibody has been tested extensively in vitro and found to bind specifically to DNA quadruplex structures formed by two biologically relevant sequence motifs. Scatchard and nonlinear regression analyses using both one- and two-site models were used to derive association constants for the antibody-DNA binding reactions. In both cases, quadruplexes had higher association constants than triplex and duplex molecules. The anti-quadruplex antibody binds to the quadruplex formed by the promoter-region-derived oligonucleotide d(CGCG4GCG) (Ka = 3.3 x 10(6) M-1), and has enhanced affinity for telomere-derived quadruplexes formed by the oligonucleotides d(TG4) and d(T2G4T2G4T2G4T2G4) (Ka = 5.38 x 10(6) and 1.66 x 10(7) M-1, respectively). The antibody binds both types of quadruplexes but has preferential affinity for the parallel four-stranded structure. In vitro radioimmunofilter binding experiments demonstrated that purified anti-DNA quadruplex antibodies from anti-quadruplex antibody-producing tissue culture supernatants have at least 10-fold higher affinity for quadruplexes than for triplex and duplex DNA structures of similar base composition and length. The antibody binds intramolecular DNA triplexes formed by d(G4T3G4T3C4) and d(C4T3G4T3G4), and the duplex d(CGCGCGCGCG)2 with an affinities of 6. 76 x 10(5), 5.59 x 10(5), and 8.26 x 10(5) M-1, respectively. Competition experiments showed that melted quadruplexes are not effective competitors for antibody binding when compared to native structures, confirming that the quadruplex is bound structure-specifically. To our knowledge, this is the first immunological reagent known to specifically recognize quadruplex structures. Subsequent sequence analysis demonstrates homologies between the antibody complementarity determining regions and sequences from Myb family telomere binding proteins, which are hypothesized to control cell aging via telomeric DNA interactions. The presence of this antibody in the autoimmune repertoire suggests a possible linkage between autoimmunity, telomeric DNA binding proteins, and aging.     

H] Tryptamine and 3H-water as diffusible internal standards for measuring brain extraction of radio-labeled substances following carotid injection

Urinary amino acid excretion was determined in 31 leukemic patients and 29 normal individuals by rapid gas chromatographic analysis of 16 amino acids as their N-acetyl-n-propyl esters. The leukemic patients were concurrently undergoing, or had recently completed, chemotherapy. It was found that aspartic acid, threonine, and serine were of significance in distinguishing between patients "on" therapy and those "off" therapy. Patients with advanced disease have the greatest aminoaciduria, although both the normal and leukemic populations have wide individual ranges. Within both populations, men excrete a greater variety and quantity of amino acids than women. It is concluded that analysis of urinary amino acids represents a history of complex metabolic events, which is potentially useful for evaluating patient response to chemotherapy in leukemia.     

A continuous-wave hybrid AlGaInAs-silicon evanescent laser

We report a novel laser architecture, the hybrid silicon evanescent laser (SEL), that utilizes offset AlGaInAs quantum wells (QWs) bonded to a silicon waveguide. The silicon waveguide is fabricated on a silicon-on-insulator wafer using a complimentary metal-oxide-semiconductor-compatible process, and is subsequently bonded with the AlGaInAs QW structure using low temperature O/sub 2/ plasma-assisted wafer bonding. The optical mode in the SEL is predominantly confined in the passive silicon waveguide and evanescently couples into the III-V active region providing optical gain. The SEL lases continuous wave (CW) at 1568 nm with a threshold of 23 mW. The maximum temperature for CW operation is 60/spl deg/C. The maximum single-sided fiber-coupled CW output power at room temperature is 4.5 mW.     

Optimization of GaAs amplification photodetectors for 700% quantum efficiency

We investigate the device physics of novel GaAs waveguide photodetectors with integrated photon multiplication. Such detectors have the potential to achieve simultaneously high saturation power, high speed, high responsivity, and quantum efficiencies above 100%. Our device design vertically combines a bulk photodetector ridge waveguide region with laterally confined quantum wells for amplification. Measurements on the first device generation show quantum efficiencies of only 56%. Advanced device simulation is employed to analyze these devices and to reveal performance limitations. Excellent agreement between simulations and measurements is obtained. Device design optimization is proposed, promising more than 700% efficiency.     

What Does a Pigeon (Columba livia) Brain Look Like During Homing? Selective Examination of ZENK Expression.

Lesion studies have shown that the avian hippocampus plays a crucial role in homing pigeon (Columba livia) navigation. Using the expression of the immediate early gene protein ZENK in intact pigeons, the authors found regional variation in hippocampal activation as a consequence of homing and, necessarily, the behavior and internal states that accompany it. Specifically, pigeons that homed displayed a significant increase in the number of ZENK-labeled cells in the lateral hippocampal formation compared with pigeons that did not home, whereas no difference was seen in the medial hippocampus. Significant changes in ZENK expression were also found in the medial striatum, which resembles the mammalian ventral striatum. The results identify portions of the hippocampal formation and the medial striatum as sites of plasticity associated with homing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Millimetre-waveguide-mounted InGaAs photodetectors

We describe the design and characteristics of InGaAs PIN photodetectors mounted in microwave waveguides for use in transmission of millimetre-wave modulation signals on optical carriers. For an experimental device operating to 60 GHz (5 mm wavelength), we show the wavelength dependence of responsivity, the spatial uniformity of response and the bias dependence of modulation bandwidth.     

High Output Saturation and High-Linearity Uni-Traveling-Carrier Waveguide Photodiodes

Waveguide uni-traveling-carrier photodiodes (UTC-PDs) have been fabricated and tested. Output saturation currents greater than 40 mA at 1 GHz are demonstrated for a 10 mumtimes150mum photodiode (PD). The third-order intermodulation distortion is also measured and exhibits a third-order output intercept point of 43 dBm at 20 mA and 34 dBm at 40 mA for this same PD. UTC-PDs with geometries of 5 mumtimes100 mum and 10 mumtimes100 mum are also compared and it is shown that a wider waveguide PD has improved saturation characteristics due to the lower optical power density which reduces the saturation at the front end of the device