Basic Signaling Research Articles

Information coding in the cortex by independent or coordinated populations.

The cerebral cortex is the primary seat of our sensory experiences, our plans, and the control of our actions. As such, it has been carefully examined since the inception of brain science and has been studied intensively at the level of individual neurons for over 40 years (1, 2). Nonetheless, it appears a fair assessment to say that the single most essential question about cortical physiology—“What is the basic cortical population signalling mechanism?”—has not yet been definitively answered and is still the subject of vigorous debate (3–9). Does the cortex function by pooling together essentially independent neural signals, as in an election, or does the signal come through the coordination of the elements, as in a symphony (3, 10, 11)? An article by Hatsopoulos et al., appearing in this issue of the Proceedings (12), provides interesting new examples of pairs of neurons in the primary motor cortex of monkeys conveying information by the relative timing of their action potentials during an eight-choice reaching task. Forming clear distinctions between independent and coordinated coding is challenging, because cortical neurons have overlapping functions and work together by distributing signals across many elements. These authors present a straightforward, measurable distinction between information transmission in independent and coordinated coding and use their data to evaluate these two hypotheses.

Cell signaling: an overview.

Cell signaling: an overview.

Signal transduction during NK cell activation: balancing opposing forces.

Significant progress has been made in our understanding of the basic signaling mechanisms regulating NK cell activation. Advances have been fueled in part by the molecular characterization of specific activating receptors (e.g., the Fc gamma RIII multi-subunit complex) and inhibitory receptors (e.g., novel MHC-recognizing inhibitory receptors). However, certain aspects of these analyses are complicated by the heterogeneous nature of the receptor-ligand interactions utilized during the development of a cytotoxic response. Future advances will depend in part on the further molecular characterization of the involved receptors and second messengers and on the development of experimental models for genetically manipulating the signaling elements. It will remain important to understand both activating and inhibitory signaling pathways as the emerging theme is that the balance of these two opposing forces determines the functional outcome of an NK cells interaction with its target.

The fundamental solutions for the fractional diffusion-wave equation

The time fractional diffusion-wave equation is obtained from the classical diffusion or wave equation by replacing the first- or second-order time derivative by a fractional derivative of order 2β with 0 < β ≤ 1 2 or 1 2 < β ≤ 1 , respectively. Using the method of the Laplace transform, it is shown that the fundamental solutions of the basic Cauchy and Signalling problems can be expressed in terms of an auxiliary function M( z; β), where z = |x| t β is the similarity variable. Such function is proved to be an entire function of Wright type.

Comparative statics of a signaling game: An experimental study

In this paper a simple and basic signaling game is studied in an experimental environment. First, we check whether we can replicate some of the findings in the literature concerning equilibrium selection and the use and impact of costly signals. Second, and foremost, the comparative statics implications of the game are studied. The experimental results are related to the predictions of two competing behavioral models: a game model, in which subjects are assumed to behave in line with (refined) sequential equilibrium theory, and a decision model, in which subjects are assumed to behave as non-strategic decision makers. The experimental outcomes replicate the finding in the literature that costly messages are sent more frequently by ‘higher’ sender types (whose information is such that persuasion is also profitable to the responder), and that such messages have an impact on the behavior of the responder. These results are consistent with (versions of) both the game model and the decision model. The comparative statics results, however, clearly point in the direction of the decision model. Play is most strongly affected by ‘own’ payoff parameters, as predicted by the decision model, and less so by opponent's payoff parameters, as predicted by the mixed strategies of the refined sequential equilibrium. Particularly, a decision model in which players are assumed to adapt beliefs about opponents' choice probabilities in response to experience in previous play, appears to succeed best in organizing the data.

The time fractional diffusion-wave equation

The time fractional diffusion-wave equation is obtained from the classical diffusion or wave equation by replacing the first- or second-order time derivative by a fractional derivative of order 2β with 0<β≤1/2 or 1/2<β≤1, respectively. Using the method of the Laplace transform, it is shown that the fundamental solutions of the basic Cauchy and signalling problems can be expressed in terms of an auxiliary function M (z; β), where z is the similarity variable. Such function, which reduces to the well-known Gaussian function for β=1/2 (ordinary diffusion), is proved to be an entire function of Wright type.

Apoptosis in L929 Cells Expressing a CD40/Fas Chimeric Receptor: Dissociation of Stimulatory from Inhibitory Death Signaling Functions

A chimeric transmembrane receptor was constructed by fusing the extracellular domain of human CD40 to the transmembrane/intracellular domain of human Fas. When stably overexpressed in L929, the chimera retained the ligand binding specificity of CD40 and the basic signalling properties of Fas since an apoptotic response could be induced in a dose-dependent manner upon administration of recombinant, soluble CD40 ligand trimer or immobilized antiCD40 antibodies. However, this apoptotic response was independent of actinomycin D which is in contrast to results previously reported for L929 cells stably expressing wildtype human Fas. A labile protein factor was postulated to be responsible for inhibition of Fas-induced apoptosis in these cells. The apoptotic Fas signal tranduced by the chimeric CD40/Fas receptor is not regulated by this putative inhibitor. Our data suggest that the extracellular domains of CD40 and Fas form functionally similar mono- and multimeric structures and that the extracellular domain of Fas participates in the regulation of Fas-specific signal transduction.

Choline and human nutrition.

Choline is crucial for sustaining life. It modulates the basic signaling processes within cells, is a structural element in membranes, and is vital during critical periods in brain development. Choline metabolism is closely interrelated with the metabolism of methionine and folate. We believe that the normal human diet provides sufficient choline to sustain healthy organ function. However, vulnerable populations may become choline deficient, including the growing infant, the pregnant or lactating woman, the cirrhotic, and the patient fed intravenously. Further studies of choline requirements in these groups are required.

Intercellular signalling. The pros and cons of c-ret.

Recent studies of the proto-oncogene c-ret illuminate the basic developmental signalling pathways mediated by receptor tyrosine kinases, as well as the aberrant signalling processes that can lead to cancer.

The SH2 domain protein GRB-7 is co-amplified, overexpressed and in a tight complex with HER2 in breast cancer.

SH2 domain proteins are important components of the signal transduction pathways activated by growth factor receptor tyrosine kinases. We have been cloning SH2 domain proteins by bacterial expression cloning using the tyrosine phosphorylated C-terminus of the epidermal growth factor receptor as a probe. One of these newly cloned SH2 domain proteins, GRB-7, was mapped on mouse chromosome 11 to a region which also contains the tyrosine kinase receptor, HER2/erbB-2. The analogous chromosomal locus in man is often amplified in human breast cancer leading to overexpression of HER2. We find that GRB-7 is amplified in concert with HER2 in several breast cancer cell lines and that GRB-7 is overexpressed in both cell lines and breast tumors. GRB-7, through its SH2 domain, binds tightly to HER2 such that a large fraction of the tyrosine phosphorylated HER2 in SKBR-3 cells is bound to GRB-7. GRB-7 can also bind tyrosine phosphorylated SHC, albeit at a lower affinity than GRB2 binds SHC. We also find that GRB-7 has a strong similarity over > 300 amino acids to a newly identified gene in Caenorhabditis elegans. This region of similarity, which lies outside the SH2 domain, also contains a pleckstrin homology domain. The presence of evolutionarily conserved domains indicates that GRB-7 is likely to perform a basic signaling function. The fact that GRB-7 and HER2 are both overexpressed and bound tightly together suggests that this basic signaling pathway is greatly amplified in certain breast cancers.

Expression of proto-oncogenes in mouse eggs and preimplantation embryos.

The expression of several protooncogenes has been investigated in mouse eggs and preimplantation embryos using reverse transcription coupled to amplification of cDNAs by the polymerase chain reaction (RT-PCR). The genes chosen for analysis included both cytoplasmic (c-raf-1, rasH, rasK, and rasN) and nuclear (c-fos and c-myc) proto-oncogenes encoding proteins involved in the transduction of signals from protein-tyrosine kinase growth factor receptors. Transcripts of the cytoplasmic proto-oncogenes were detected both as maternal and embryonic mRNAs at levels (ca. 1,000 copies per egg or embryo) approximately comparable to their levels of transcription in somatic cells. Transcripts of c-fos and c-myc were also detected in both eggs and embryos, although at more variable levels: Maternal transcripts were present at very low levels (ca. 1-10 copies per egg) in growing oocytes and ovulated eggs; embryonic transcription of c-myc increased, reaching mRNA levels of approximately 100-1,000 copies per embryo in four-cell embryos, morula, and blastocysts; in contrast the transcription of c-fos remained at low, barely detectable levels throughout preimplantation development. Although the significance of the low levels of c-fos mRNA is unclear, these results indicate that preimplantation embryos possess the basic intracellular signaling apparatus required to respond to polypeptide growth factors.

The contribution of remote monitoring to the development of IBC

The paper describes an application pilot experiment being carried out under the European Communities&apos; RACE programme. The experiment centres on the electronic security industry, in particular the remote monitoring of alarm signals. The aim of the project is to reduce the waste of resources caused by the high number of ‘false’ alarm calls and to introduce the users of remote signalling systems to the benefits of improving communications technology. The paper summarises the problem and presents a scenario for introducing the users of basic signalling systems to a wider variety of potential services that can be provided in an integrated broadband communications environment.

Mechanisms of receptor-mediated transmembrane signalling

Although this paper has dealt with general mechanisms whereby a hormonal signal is transmitted across the cell membrane, advances in work with a number of receptors should permit a precision of description of these mechanisms that would have delighted both Langley and Ehrlich. For instance, the detailed sequences now known for the separate subunits of the nicotinic cholinergic receptor and the cellular manipulations made possible by the cloning of the separate subunit genes will make it possible to determine the precise receptor sequence involved either in acetylcholine binding or in ion channel function. The complete sequences and biochemical properties now known for the insulin and EGF-URO receptors to be dealt with in part by a subsequent article (van Obberghen and Gammeltoft, this series) should lay the groundwork for elucidating the transmembrane signalling mechanisms used by the kinase family of growth factor receptors. Continuing work on the structure of the beta-adrenergic receptor, and on the interaction of such receptors with guanine nucleotide regulatory complexes and on the detailed properties of the family of so-called G-proteins and their associated regulatory subunits should unravel the details for a variety of transmembrane signalling reactions. Thus, at least for three basic transmembrane signalling mechanisms: ligand modulated ion transport; ligand-modulated receptor enzyme activity (e.g. tyrosine kinase); and ligand-modulated liberation of cryptic mediators (like the alpha- and beta-subunits of the guanine nucleotide regulatory complexes) one can look forward with excitement to the elucidation in the not-too-distant future of a number of specific biochemical reaction pathways that lead to cell activation.

Exhibit honors Spanish Nobelist on 50th anniversary of death

This year marks the 50th anniversary of the death of neuroscientist Santiago Ramon y Cajal (1852-1934). To honor Cajal, the American Academy of Neurology presented an exhibit of his works— including histology drawings, photographs, and slide preparations—at its annual meeting in Boston. Cajal, who in 1906 shared the Nobel Prize for Physiology or Medicine with Camillo Golgi, is best known for the improvement and application of Golgi's silver nitrate stain, which provided him with evidence that neurons are the basic signaling unit of the nervous system. This neuron doctrine, as it came to be called, refuted the earlier reticular theory that envisioned neuronal processes (axons and dentrites) ending in a network of enmeshed fibers rather than in distinct synapses. Cajal's accomplishments were commemorated on two Spanish postage stamps—one in 1934, the year of his death, and the other in 1952, the centennial of his birth—and on a Swedish stamp in

A Novel TV Add-On Data Communication System

This paper presents a description of the theory and operation of a new television add-on data communication system which does not utilize the vertical interval. The basic add-on signalling technique allows more efficient utilization of the television spectrum. Added information, producing no perceptible interference with either the picture, or ancillary and test signals, is sent through a television channel along with the standard video signal. Novel techniques to significantly reduce errors in the data channel will be described. Several interesting systems utilizing this new signalling method have been built and will be described in this paper.

An Optimal Nonlinear Detector for Digital Data Transmission Through Non-Gaussian Channels

The problem of binary synchronous communication in additive non-Gaussian noise is considered. It is shown that, for a class of additive noises, an optimal detector consists of a two-input nonlinear device followed by an integrator and decision box. This system suppresses large excursions from the signal level in an optimal manner before integration of the received signal, so that the effects of large amplitude noise waveforms on the signal decision are minimized. Asymptotic performance characteristics are obtained indicating the relationships between the basic system parameters, signaling waveforms, signal energy, system bandwidth, decision time, noise dispersion, and error probability. Explicit expressions and curves for system performance in large variance (Cauchy distributed) noise are given for various basic signaling waveforms.

Some problems encountered in the design of marine transmitters

The paper gives a brief survey of the development of the marine transmitter since 1919, and points out that, although the basic signalling requirement has remained practically unchanged, many refinements have become necessary to ensure that the original purpose of the apparatus shall be realized as the radio frequency spectrum becomes more and more congested. Modern requirements regarding frequency stability, bandwidth, power output and keying are reviewed and some of the problems presented to the designer are discussed. Mention is also made of the G.P.O. type-approval tests.