Small-signal analysis of wavelength conversion in semiconductorlaser amplifiers via gain saturation

Wavelength conversion due to gain saturation in a travelling wave semiconductor laser amplifier is analyzed using a small-signal model. An analytic expression is developed showing that the small-signal bandwidth of wavelength conversion is not limited simply to the carrier modulation bandwidth, but also depends on the single-pass gain of the device     

Herpes simplex virus type 1 alkaline nuclease is required for efficient processing of viral DNA replication intermediates

Mutations in the alkaline nuclease gene of herpes simplex type 1 (HSV-1) (nuc mutations) induce almost wild-type levels of viral DNA; however, mutant viral yields are 0.1 to 1% of wild-type yields (L. Shao, L. Rapp, and S. Weller, Virology 195:146-162, 1993; R. Martinez, L. Shao, J.C. Bronstein, P.C. Weber, and S. Weller, Virology 215:152-164, 1996). nuc mutants are defective in one or more stages of genome maturation and appear to package DNA into aberrant or defective capsids which fail to egress from the nucleus of infected cells. In this study, we used pulsed-field gel electrophoresis to test the hypothesis that the defects in nuc mutants are due to the failure of the newly replicated viral DNA to be processed properly during DNA replication and/or recombination. Replicative intermediates of HSV-1 DNA from both wild-type- and mutant-infected cells remain in the wells of pulsed-field gels, while free linear monomers are readily resolved. Digestion of this well DNA with restriction enzymes that cleave once in the viral genome releases discrete monomer DNA from wild-type virus-infected cells but not from nuc mutant-infected cells. We conclude that both wild-type and mutant DNAs exist in a complex, nonlinear form (possibly branched) during replication. The fact that discrete monomer-length DNA cannot be released from nuc DNA by a single-cutting enzyme suggests that this DNA is more branched than DNA which accumulates in cells infected with wild-type virus. The well DNA from cells infected with wild-type and nuc mutants contains XbaI fragments which result from genomic inversions, indicating that alkaline nuclease is not required for mediating recombination events within HSV DNA. Furthermore, nuc mutants are able to carry out DNA replication-mediated homologous recombination events between inverted repeats on plasmids as evaluated by using a quantitative transient recombination assay. Well DNA from both wild-type- and mutant-infected cells contains free U(L) termini but not free U(S) termini. Various models to explain the structure of replicating DNA are considered.     

Mechanical response properties of nociceptors innervating feline hairy skin

1. The responses of feline cutaneous nociceptors were examined in vivo by systematically manipulating the intensive and spatial dimensions of mechanical stimulation. A computer-controlled motor was used to apply prescribed forces (5-90 g) to a nociceptor's receptive field, with flat-tipped, cylindrical probes of various sizes (contact areas: 0.1-5.0 mm2). The stimulating device and protocols were similar to those previously used to evaluate human perception, thus allowing for comparisons of the two data sets. 2. With a ramp-and-hold stimulus of controlled force, most nociceptors showed a slowly adapting (SA) response throughout the stimulus. In this way, nociceptors resembled low-threshold SA mechanoreceptors. However, in contrast to SA mechanoreceptors, nociceptors failed to exhibit an onset burst of activity associated with the stimulus ramp. Nineteen percent (6 of 31) of the nociceptors often showed the opposite trend during the stimulus, e.g., a gradually increasing firing rate. Most of these nociceptors (5 of 6) had particularly high mechanical thresholds. 3. With 30 stimuli repeated at short intervals (6-8 s), response rates tended to decrease across trials. This phenomenon was most evident with more intense stimuli. When two series of stimuli were separated by 4-5 min, there was no apparent trend of reduced responsiveness between series. 4. Overall, nociceptors responded in an orderly way to variations in force and probe size. For a given probe size, larger forces produced greater responses; for a given force, smaller probes produced greater responses. The relationship between probe size and force was best described as an even tradeoff between force and a linear dimension of the probe (i.e., probe perimeter), rather than the area of the probe. Thus a given pressure (force/area) did not evoke the same response from nociceptors as probe size was varied. 5. There were two significant differences in the mechanical responsiveness between A fiber and C fiber nociceptors. First, for a given set of stimuli, A fiber nociceptors exhibited a greater response rate than the C fiber nociceptors. Second, the A fiber nociceptors exhibited a greater differential response related to probe size than the C fiber nociceptors. On the basis of these two features, the A fiber nociceptors' response profiles showed a closer parallel with previously reported human pain thresholds than the C fiber nociceptors did. 6. When the nociceptors were subdivided as to their mechanical threshold, those with lower thresholds [mechanically sensitive afferents (MSAs)] showed a response saturation with the more intense stimuli. On average, the stimulus levels at which saturation occurred were close to human pain threshold. Those nociceptors with higher thresholds [mechanically insensitive afferents (MIAs)] did not show such saturation. Thus only the MIAs appeared to have the capacity to unambiguously encode mechanical stimulus intensities above pain threshold. The MSAs, on the other hand, exhibited their greatest dynamic response range near the threshold for nonpainful sharpness. Thus the group of afferents commonly defined as nociceptors exhibit a heterogeneity of mechanical response properties, which may serve functionally different roles for perception.     

Pharmacological characterisation of excitatory synaptic transmission in the cat red nucleus in vivo

Extracellular recordings were made from the magnocellular neurones of the red nucleus (mRN) in anaesthetised cats. A study was made of the effects of selective excitatory amino acid receptor antagonists on excitatory monosynaptic responses evoked from the sensorimotor cortex (SMC) and cerebellar interpositus nucleus (IPN). Iontophoretically applied CNQX and NBQX antagonised both SMC and IPN responses whereas, D-AP5 inhibited the SMC response but was ineffective to the IPN. At currents that selectively antagonised NMDA responses, CPPene had no effect on either SMC or IPN responses. 7-chlorokynurenate inhibited both SMC and IPN responses but required currents that antagonised both AMPA and NMDA responses and was therefore acting in a non-selective manner. Iontophoretically applied glycine was inhibitory to both agonist and synaptic responses, whilst D-serine potentiated NMDA responses but did not enhance monosynaptic responses of the SMC. However in the presence of either 7-chlorokynurenate or high currents of CNQX that reduced the SMC synaptic activation of the mRN neurones, D-serine attenuated the inhibitory action of these antagonists. It is concluded that monosynaptic responses from the SMC are mediated by both NMDA and non-NMDA receptors whereas the monosynaptic responses evoked from the IPN are mediated only by non-NMDA receptors. The lack of effect of CPPene is consistent with the postulate that two NMDA receptor subtypes are present on mRN neurones.     

Elevational spatial compounding

Spatial compounding has long been explored to reduce coherent speckle noise in medical ultrasound. By laterally translating a one-dimensional array, partially correlated measurements made at different look directions can be obtained and incoherently averaged. The lateral resolution, however, is limited by the sub-array length used for each independent measurement. To reduce speckle contrast without compromising lateral resolution, a new spatial compounding technique using two-dimensional, anisotropic arrays is proposed. This technique obtains partially correlated measurements by steering the image plane elevationally with small inclinations. Incoherent averaging is then performed by adding image magnitudes. Therefore, contrast resolution is improved only at the price of a slightly wider elevational beam. Note that although anisotropic arrays have limited steering capability in elevation, grating lobes are not considered influential since only small inclinations are needed between measurements. Simulations have been performed to show both the change in spatial resolution and the improvement in contrast resolution. Results indicated minimal increase in the correlation length both laterally and axially. It was also shown that detectability can be significantly enhanced by increasing the number of measurements or increasing the differential inclination between measurements. This technique is therefore effective for reducing speckle noise while maintaining in-plane spatial resolution. Furthermore, it demonstrates a new application of two-dimensional anisotropic arrays in spite of their limited elevational steering capability.     

IL-10 impacts autoimmune diabetes via a CD8+ T cell pathway circumventing the requirement for CD4+ T and B lymphocytes

IL-10 is essential for an early phase of diabetes in nonobese diabetic (NOD) mice, but later becomes protective against its development. The mechanism by which IL-10 mediates the pathway to diabetes in these mice is unknown. Herein, we dissected the cellular and costimulation requirements for diabetes in transgenic (tg) NOD mice that expressed IL-10 in their pancreatic islets (IL-10-NOD mice). We found that IL-10 alone did not cause diabetes because the offspring (IL-10-NOD-scid mice) from back-crosses of IL-10-NOD mice with NOD-scid mice had no diabetes. Moreover, these IL-10-NOD-scid mice were free of lymphocytic infiltration. Treatment of IL-10-NOD mice with depleting anti-CD4 mAb or control mAb had no effect on diabetes. Surprisingly, depletion of CD8+ T cells by treatment with the corresponding mAb inhibited diabetes without attenuating insulitis, demonstrating a critical role for CD8+ T cells in the disease process. Interestingly, B cell-deficient IL-10-NOD mice readily developed diabetes with kinetics and incidence similar to those observed in wild-type mice, demonstrating that B lymphocytes as APCs were not required in the disease process. Administration of anti-CD40 ligand (CD40L) mAb did not prevent disease, indicating that CD40/CD40L costimulation is not required for diabetes in IL-10-NOD mice. Immunization of IL-10-NOD mice with CFA or heat-shock protein 65, known to block diabetes in NOD mice, had no effect on their diabetes. We demonstrate that IL-10 contributes early to the pathology of diabetes via a CD8+ T cell pathway, eliminating the requirement for B lymphocytes and CD40-CD40L costimulation. Our findings provide a mechanism for the participation of IL-10 in the early development of diabetes.     

Transgenic models of Huntington's disease

CAG/polyglutamine expansion has been shown to form the molecular basis of an increasing number of inherited neurodegenerative diseases. The mutation is likely to act by a dominant gain of function but the mechanism by which it leads to neuronal dysfunction and cell death is unknown. The proteins harbouring these polyglutamine tracts are unrelated and without exception are widely expressed with extensively overlapping expression patterns. The factors governing the cell specific nature of the neurodegeneration have yet to be understood. Upon a certain size threshold, expanded CAG repeats become unstable on transmission and a modest degree of somatic mosaicism is apparent. Similarly, the molecular basis of the instability and its tissue specificity has yet to be unravelled. Recent reports describing the first mouse models of CAG/polyglutamine disorders indicate that it will be possible to model both the pathogenic mechanism and the CAG repeat instability in the mouse. This has great potential and promise for uncovering the molecular basis of these diseases and developing therapeutic interventions.