Toward a new generation of vaccines: The anti-cytokine therapeutic vaccines

Pathological conditions, such as cancers, viral infections, and autoimmune diseases, are associated with abnormal cytokine production, and the morbidity associated with many medical disorders is often directly a result of cytokine production. Because of the absence of negative feedback control occurring in some pathophysiologic situations, a given cytokine may flood and accumulate in the extracellular compartment of tissues or tumors thereby impairing the cytokine network homeostasis and contributing to local pathogenesis. To evaluate whether the rise of anti-cytokine Abs by vaccination is an effective way to treat these pathological conditions without being harmful to the organism, we have analyzed each step of the cytokine process (involving cytokine production, target response, and feedback regulation) and have considered them in the local context of effector–target cell microenvironment and in the overall context of the macroenvironment of the immune system of the organism. In pathologic tissues, Abs of high affinity, as raised by anti-cytokine vaccination, should neutralize the pool of cytokines ectopically accumulated in the extracellular compartment, thus counteracting their pathogenic effects. In contrast, the same Abs should not interfere with cytokine processes occurring in normal tissues, because under physiologic conditions cytokine production by effector cells (induced by activation but controlled by negative feedback regulation) does not accumulate in the extracellular compartment. These concepts are consistent with results showing that following animal and human anti-cytokine vaccination, induction of high-affinity Abs has proven to be safe and effective and encourages this approach as a pioneering avenue of therapy.

Diazepam binding inhibitor is a potent cholecystokinin-releasing peptide in the intestine.

Pancreatic proteases in the duodenum inhibit the release of cholecystokinin (CCK) and thus exert feedback control of pancreatic exocrine secretion. Exclusion of proteases from the duodenum either by the diversion of bile-pancreatic juice or by the addition of protease inhibitors stimulates exocrine pancreatic secretion. The mechanism by which pancreatic proteases in the duodenum regulate CCK secretion is unknown. In this study, we isolated a trypsin-sensitive peptide that is secreted intraduodenally, releases CCK, and stimulates pancreatic enzyme secretion in rats. This peptide was found to be identical to the porcine diazepam binding inhibitor by peptide sequencing and mass spectrometry analysis. Intraduodenal infusion of 200 ng of synthetic porcine diazepam binding inhibitor1-86 in rats significantly stimulated pancreatic amylase output. Infusion of the CCK antagonist MK-329 completely blocked the diazepam binding inhibitor-stimulated amylase secretion. Similarly, diazepam binding inhibitor33-52 [corrected] also stimulated CCK release and pancreatic secretion in a dose-dependent manner although it was 100 times less potent than the whole peptide. Using a perfusion system containing isolated mucosal cells from the proximal intestine of rats, porcine diazepam binding inhibitor 10(-12) M) dose dependently stimulated CCK secretion. In separate studies, it was demonstrated that luminal secretion of the diazepam binding inhibitor immunoreactivity (7.5 X 10(11) M) could be detected in rat's intestinal washing following the diversion of bile-pancreatic juice. The secretion of this peptide was inhibited by atropine. In conclusion, we have isolated and characterized a CCK-releasing peptide that has a sequence identical to the porcine diazepam binding inhibitor from pig intestinal mucosa and that stimulates CCK release when administered intraduodenally in rat. This peptide may mediate feedback regulation of pancreatic enzyme secretion.

How photons start vision.

Recent studies have elucidated how the absorption of a photon in a rod or cone cell leads to the generation of the amplified neural signal that is transmitted to higher-order visual neurons. Photoexcited visual pigment activates the GTP-binding protein transducin, which in turn stimulates cGMP phosphodiesterase. This enzyme hydrolyzes cGMP, allowing cGMP-gated cationic channels in the surface membrane to close, hyperpolarize the cell, and modulate transmitter release at the synaptic terminal. The kinetics of reactions in the cGMP cascade limit the temporal resolution of the visual system as a whole, while statistical fluctuations in the reactions limit the reliability of detection of dim light. Much interest now focuses on the processes that terminate the light response and dynamically regulate amplification in the cascade, causing the single photon response to be reproducible and allowing the cell to adapt in background light. A light-induced fall in the internal free Ca2+ concentration coordinates negative feedback control of amplification. The fall in Ca2+ stimulates resynthesis of cGMP, antagonizes rhodopsin's catalytic activity, and increases the affinity of the light-regulated cationic channel for cGMP. We are using physiological methods to study the molecular mechanisms that terminate the flash response and mediate adaptation. One approach is to observe transduction in truncated, dialyzed photoreceptor cells whose internal Ca2+ and nucleotide concentrations are under experimental control and to which exogenous proteins can be added. Another approach is to observe transduction in transgenic mouse rods in which specific proteins within the cascade are altered or deleted.

Speech technology in the year 2001.

This paper introduces the session "Technology in the Year 2001" and is the first of four papers dealing with the future of human-machine communication by voice. In looking to the future it is important to recognize both the difficulties of technological forecasting and the frailties of the technology as it exists today--frailties that are manifestations of our limited scientific understanding of human cognition. The technology to realize truly advanced applications does not yet exist and cannot be supported by our presently incomplete science of speech. To achieve this long-term goal, the authors advocate a fundamental research program using a cybernetic approach substantially different from more conventional synthetic approaches. In a cybernetic approach, feedback control systems will allow a machine to adapt to a linguistically rich environment using reinforcement learning.

A disaccharide that inhibits tumor necrosis factor alpha is formed from the extracellular matrix by the enzyme heparanase.

The activation of T cells by antigens or mitogens leads to the secretion of cytokines and enzymes that shape the inflammatory response. Among these molecular mediators of inflammation is a heparanase enzyme that degrades the heparan sulfate scaffold of the extracellular matrix (ECM). Activated T cells use heparanase to penetrate the ECM and gain access to the tissues. We now report that among the breakdown products of the ECM generated by heparanase is a trisulfated disaccharide that can inhibit delayed-type hypersensitivity (DTH) in mice. This inhibition of T-cell mediated inflammation in vivo was associated with an inhibitory effect of the disaccharide on the production of biologically active tumor necrosis factor alpha (TNF-alpha) by activated T cells in vitro; the trisulfated disaccharide did not affect T-cell viability or responsiveness generally. Both the in vivo and in vitro effects of the disaccharide manifested a bell-shaped dose-response curve. The inhibitory effects of the trisulfated disaccharide were lost if the sulfate groups were removed. Thus, the disaccharide, which may be a natural product of inflammation, can regulate the functional nature of the response by the T cell to activation. Such a feedback control mechanism could enable the T cell to assess the extent of tissue degradation and adjust its behavior accordingly.

Fabrication, installation, test and evaluation of motorcycle controls and displays; gear position, indicator, non-linear throttle, tactile indicator of neutral position. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

SSB(N) quiet steering system study (Phase I).

Mode of access: Internet.

Executive-controlled adaptive systems,

At head of title: Microwave Research Institute, Polytechnic Institute of Brooklyn, Systems and Controls Group, R-688-58, PIB-616, contract no. DA-30-069-ORD-1560.

Digital processes for sampled data systems.

Includes bibliography.

Adaptive phase measurements in linear optical quantum computation

Photon counting induces an effective non-linear optical phase shift in certain states derived by linear optics from single photons. Although this non-linearity is non-deterministic, it is sufficient in principle to allow scalable linear optics quantum computation (LOQC). The most obvious way to encode a qubit optically is as a superposition of the vacuum and a single photon in one mode-so-called 'single-rail' logic. Until now this approach was thought to be prohibitively expensive (in resources) compared to 'dual-rail' logic where a qubit is stored by a photon across two modes. Here we attack this problem with real-time feedback control, which can realize a quantum-limited phase measurement on a single mode, as has been recently demonstrated experimentally. We show that with this added measurement resource, the resource requirements for single-rail LOQC are not substantially different from those of dual-rail LOQC. In particular, with adaptive phase measurements an arbitrary qubit state a alpha/0 > + beta/1 > can be prepared deterministically.

Suppressing chaos via Lyapunov-Krasovskii's method

An algorithm for suppressing the chaotic oscillations in non-linear dynamical systems with singular Jacobian matrices is developed using a linear feedback control law based upon the Lyapunov-Krasovskii (LK) method. It appears that the LK method can serve effectively as a generalised method for the suppression of chaotic oscillations for a wide range of systems. Based on this method, the resulting conditions for undisturbed motions to be locally or globally stable are sufficient and conservative. The generalized Lorenz system and disturbed gyrostat equations are exemplified for the validation of the proposed feedback control rule. (c) 2005 Elsevier Ltd. All rights reserved.

Psychometric properties of the Chinese version of the diabetes empowerment scale

Metabolic control is central to positive clinical outcome in patients with diabetes. Empowerment has been linked to metabolic control in this clinical group. The current study sought to determine key psychometric properties of the Chinese version of the Diabetes Empowerment Scale (C-DES) and to explore the relationship of the C-DES sub-scales to metabolic control in 189 patients with a diagnosis of diabetes. Confirmatory factor analysis established that the five sub-scales of the C-DES offered a highly satisfactory fit to the data. Furthermore, C-DES sub-scales were found to have generally acceptable internal consistency and divergent reliability. However, convergent reliability of C-DES sub-scales could not be established against metabolic control. It is concluded that future research needs to address ambiguities in the relationship between empowerment and metabolic control in order to afford patients an evidenced-based treatment package to assure optimal metabolic control.

Interactions within heterogeneous systems of uncontrolled rectifiers for aircraft electrical power systems

There is an increase in the use of multi-pulse, rectifier-fed motor-drive equipment on board more-electric aircraft. Motor drives with feedback control appear as constant power loads to the rectifiers, which can cause instability of the DC filter capacitor voltage at the output of the rectifier. This problem can be exacerbated by interactions between rectifiers that share a common source impedance. In order that such a system can be analysed, there is a need for average, dynamic models of systems of rectifiers. In this study, an efficient, compact method for deriving the approximate, linear, large-signal, average models of two heterogeneous systems of rectifiers, which are fed from a common source impedance, is presented. The models give insight into significant interaction effects that occur between the converters, and that arise through the shared source impedance. First, a 6-pulse and doubly wound, transformer-fed, 12-pulse rectifier system is considered, followed by a 6-pulse and autotransformer-fed, 12-pulse rectifier system. The system models are validated against detailed simulations and laboratory prototypes, and key characteristics of the two system types are compared.

Fibre-based devices for next generation photonics communication systems

The future broadband information network will undoubtedly integrate the mobility and flexibility of wireless access systems with the huge bandwidth capacity of photonics solutions to enable a communication system capable of handling the anticipated demand for interactive services. Towards wide coverage and low cost implementations of such broadband wireless photonics communication networks, various aspects of the enabling technologies are continuingly generating intense research interest. Among the core technologies, the optical generation and distribution of radio frequency signals over fibres, and the fibre optic signal processing of optical and radio frequency signals, have been the subjects for study in this thesis. Based on the intrinsic properties of single-mode optical fibres, and in conjunction with the concepts of optical fibre delay line filters and fibre Bragg gratings, a number of novel fibre-based devices, potentially suitable for applications in the future wireless photonics communication systems, have been realised. Special single-mode fibres, namely, the high birefringence (Hi-Bi) fibre and the Er/Yb doped fibre have been employed so as to exploit their merits to achieve practical and cost-effective all-fibre architectures. A number of fibre-based complex signal processors for optical and radio frequencies using novel Hi-Bi fibre delay line filter architectures have been illustrated. In particular, operations such as multichannel flattop bandpass filtering, simultaneous complementary outputs and bidirectional nonreciprocal wavelength interleaving, have been demonstrated. The proposed configurations featured greatly reduced environmental sensitivity typical of coherent fibre delay line filter schemes, reconfigurable transfer functions, negligible chromatic dispersions, and ease of implementation, not easily achievable based on other techniques. A number of unique fibre grating devices for signal filtering and fibre laser applications have been realised. The concept of the superimposed fibre Bragg gratings has been extended to non-uniform grating structures and into Hi-Bi fibres to achieve highly useful grating devices such as overwritten phase-shifted fibre grating structure and widely/narrowly spaced polarization-discriminating filters that are not limited by the intrinsic fibre properties. In terms of the-fibre-based optical millimetre wave transmitters, unique approaches based on fibre laser configurations have been proposed and demonstrated. The ability of the dual-mode distributed feedback (DFB) fibre lasers to generate high spectral purity, narrow linewidth heterodyne signals without complex feedback mechanisms has been illustrated. A novel co-located dual DFB fibre laser configuration, based on the proposed superimposed phase-shifted fibre grating structure, has been further realised with highly desired operation characteristics without the need for costly high frequency synthesizers and complex feedback controls. Lastly, a novel cavity mode condition monitoring and optimisation scheme for short length, linear-cavity fibre lasers has been proposed and achieved. Based on the concept and simplicity of the superimposed fibre laser cavities structure, in conjunction with feedback controls, enhanced output performances from the fibre lasers have been achieved. The importance of such cavity mode assessment and feedback control for optimised fibre laser output performance has been illustrated.

An experimental analysis of operating conditions in cold roll-forming

A detailed literature survey confirmed cold roll-forming to be a complex and little understood process. In spite of its growing value, the process remains largely un-automated with few principles used in set-up of the rolling mill. This work concentrates on experimental investigations of operating conditions in order to gain a scientific understanding of the process. The operating conditions are; inter-pass distance, roll load, roll speed, horizontal roll alignment. Fifty tests have been carried out under varied operating conditions, measuring section quality and longitudinal straining to give a picture of bending. A channel section was chosen for its simplicity and compatibility with previous work. Quality measurements were measured in terms of vertical bow, twist and cross-sectional geometric accuracy, and a complete method of classifying quality has been devised. The longitudinal strain profile was recorded, by the use of strain gauges attached to the strip surface at five locations. Parameter control is shown to be important in allowing consistency in section quality. At present rolling mills are constructed with large tolerances on operating conditions. By reduction of the variability in parameters, section consistency is maintained and mill down-time is reduced. Roll load, alignment and differential roll speed are all shown to affect quality, and can be used to control quality. Set-up time is reduced by improving the design of the mill so that parameter values can be measured and set, without the need for judgment by eye. Values of parameters can be guided by models of the process, although elements of experience are still unavoidable. Despite increased parameter control, section quality is variable, if only due to variability in strip material properties. Parameters must therefore be changed during rolling. Ideally this can take place by closed-loop feedback control. Future work lies in overcoming the problems connected with this control.