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PubMed1977

The area-code hypothesis: the immune system provides clues to understanding the genetic and molecular basis of cell recognition during development.

Numberous studies of embryogenesis have provided evidence for highly specific cell-surface recognition phenomena. These include both the interactions of neighboring cells and the specific cellular migrations which occur as the developmental program of the embryo progresses. The area-code hypothesis elaborate here is an attempt to provide a framework for understanding cell-recognition phenomena in development. This hypothesis is based on extensive genetic, molecular, and cellular studies of the immune system. These studies suggest that the following events occur during the differentiation of antibody-producing cells. 1) Somatic cell lines of antibody-producing cells undergo a modification of their DNA as they become committed to synthesize a particular type of antibody molecule. This chromosomal modification event is probably a DNA translocation which leads to a somatic rearrangement of certain antibody genes. 2) In each of the specific cell lineages the new arrangement of DNA is inherited by all subsequent generations of cells. 3) The developmental programs which control these genetic alterations may be employed in a programmed and reproducible fashion. This programming of antibody development is suggested because different embryos appear to become committed to the production of identical antibody molecules in the same developmental sequence. 4) Antibody molecules are initially displayed on the cell surface where they serve as highly specifici receptors to trigger the cell to proliferate and differentiate upon interacting with appropriate external molecular signals. 5) Antibody-producing cells display combinations of different molecules on their surfaces which cause each of a very large number of different cells to interact differently with their environment. 6) The genes which code for many of these cell-surface molecules are organized into multigene families. These observations as well as information from other developmental systems have led us to propose the area-code hypothesis. This hypothesis is concerned with the structure, function, and regulation of cell-surface molecules that mediate recognition phenomena during embryogenesis. Area-code molecules are cell-surface molecules which are involved in the specific recognition phenomena during growth and development. These molecules provide cells with distinct cell-surface addresses or phenotypes, and provide the basis for the specificity in cell-cell recognition during cell migrations and cell-cell interactions, as well as serving as receptors for diffusible differentiation signals. The area-code hypothesis has 3 main postulates. i) There is a progressive display of specific combinations of area-code molecules on the surfaces of cells during development. ii) The genetic programs which determine the specific expression of area-code molecules are in part controlled by DNA modifications. These chromosomal modifications are believed to channel cells into specific lineages uith progressively restricted developmental options...

Animals↗

PubMed1989

Production of human adrenocorticotropin by cleavage of alkaline-phosphatase-derived fusion proteins containing repetitive recognition sequences for collagenases.

Recombinant plasmids coding for fusion proteins which consist of human adrenocorticotropin joined to N-terminal sequences of Escherichia coli alkaline phosphatase via collagenase-sensitive linkers were constructed and used for the production of these proteins by transformed E. coli cells. It was shown that repetitive linkers of the form -Gly-(Pro-Xaa-Gly)n-Pro- with n greater than or equal to 2 were cleaved by clostridiopeptidase A (Clostridium histolyticum) by orders of magnitude faster than corresponding nonrepetitive sequences (n = 1). The C-terminal cleavage product was Gly-Pro-adrenocorticotropin which could be converted to the authentic hormone by dipeptidyl peptidase IV. On the basis of these enzymatic reactions a procedure for the preparation of pure adrenocorticotropin was developed. Derivatives of alkaline phosphatase containing similar repetitive linker sequences were cleaved by clostridiopeptidase A as efficiently as the adrenocorticotropin fusion proteins.

Adrenocorticotropic Hormone↗

PubMed1998

Headache coding and diagnostic-related groups: a survey of one year's admissions to a neurological department.

In 1995, the introduction of Diagnostic Related Groups (DRGs) within the Italian National Health Service (NHS) significantly changed the mode of payment for hospital admissions. The ICD-IX system is the fundamental instrument by which to identify various clinical entities; however, its codes still refer to an old international classification of diseases. Headache disorders are now diagnosed according to the new classification of the International Headache Society, and their recognition using ICD-IX codes appears to be increasingly inadequate. We evaluated 1-year admissions for "headache" in our Department of Neurology according to the new DRG system, and paid particular attention to the problems related to compilation of the patient discharge schedule. The most common mistakes affecting the definition of DRGs and the admission costs for the NHS were also examined.

Data Collection↗

PubMedDate not supplied

[Mechanism determining the variability of the immunologic specificity spectrum of antibodies and other immunoglobulins (theory)].

An analysis of the theories of immunity-the germ line theory, the translocations and recombinations theory, the somatic mutation theory, and the reverse translation theory advanced earlier shows that their postulates afford no answer to any of the central questions of immunology, such as: 1) The origin of genetic information which codes the entire multimillion totality of immunologically different antibodies and antigen-recognizing receptors of the immunological system B and T cells. 2) The causes of sharp differences in both, the resolving power and mechanisms of recognition of antigenic determinant by antibodies and B cell receptors, on the one hand, and of macromolecular antigens as such by antigen-recognizing receptors of T cells, on the other 3) The essence of the mechanisms by means of which the T cell receptors recognize and distinguish the macro-molecular antigens as such. A new theory is advanced which in terms of the principle of cross stereocomplementarycity determining the regularities of mutual specific recognition by polynucleotides and polypeptides coded by them and also on the basis of some biophysical, virological phenomena explains the physico-chemical and genetic basis of immunological phenomena mentioned above.

Antibody Specificity↗

PubMed1995

Control of mating and development in Ustilago maydis.

In the fungus Ustilago maydis, the ability to distinguish between partners that are of the same or of different mating type is controlled by two mating-type loci. One locus allows extracellular recognition though a pheromone-based system. After cell fusion, the other mating-type locus, which exists in multiple alleles, determines intracellular recognition. Each allele encodes a pair of homeodomain proteins that are active only in pairwise combinations in which the two partners originate from different alleles of the locus. Recent discoveries suggest that the underlying molecular recognition mechanism is the ability to form heterodimers. Whereas the proteins in all different allelic combinations interact, it is a specific feature of proteins from the same allele not to interact. This suggests the existence of a code for protein-protein recognition.

Alleles↗

PubMed2000

Initial events in the degradation of the polycistronic puf mRNA in Rhodobacter capsulatus and consequences for further processing steps.

Individual segments of the polycistronic puf mRNA of Rhodobacter capsulatus exhibit extremely different half-lives contributing to the stoichiometry of light-harvesting and reaction centre complexes of this facultative phototrophic bacterium. While earlier investigations shed light on the processes leading to the degradation of the 2.7 kb pufBALMX mRNA and, consequently, to the formation of the highly stable 0.5 kb pufBA mRNA processing product, we have now investigated the initial events in the degradation of the highly unstable 3.2 kb pufQBALMX primary transcript. Sequence modifications of two putative RNase E recognition sites within the pufQ coding region provide strong evidence that RNase E-mediated cleavage of a sequence at the 3' end of pufQ is involved in rate-limiting cleavage of the primary pufQBALMX transcript in vivo. The putative RNase E recognition sequence at the 5' end of pufQ is cleaved in vitro but does not contribute to rate-limiting cleavage in vivo. Analysis of the decay of puf mRNA segments transcribed from wild-type and mutated puf DNA sequences in R. capsulatus and Escherichia coli reveal that RNase E-mediated cleavage within the pufQ mRNA sequence also affects the stability of the 0.5 kb pufBA processing product. These findings demonstrate that the stability of a certain mRNA segment depends on the pathway of processing of its precursor molecule.

Bacterial Proteins↗

PubMed1997

Structure of the acceptor stem of Escherichia coli tRNA Ala: role of the G3.U70 base pair in synthetase recognition.

The fidelity of translation of the genetic code depends on accurate tRNA aminoacylation by cognate aminoacyl-tRNA synthetases. Thus, each tRNA has specificity not only for codon recognition, but also for amino acid identity; this aminoacylation specificity is referred to as tRNA identity. The primary determinant of the acceptor identity of Escherichia coli tRNAAlais a wobble G3.U70 pair within the acceptor stem. Despite extensive biochemical and genetic data, the mechanism by which the G3.U70 pair marks the acceptor end of tRNAAla for aminoacylation with alanine has not been clarified at the molecular level. The solution structure of a microhelix derived from the tRNAAla acceptor end has been determined at high precision using a very extensive set of experimental constraints (approximately 32 per nt) obtained by heteronuclear multidimensional NMR methods. The tRNAAla acceptor end is overall similar to A-form RNA, but important differences are observed. The G3.U70 wobble pair distorts the conformation of the phosphodiester backbone and presents the functional groups of U70 in an unusual spatial location. The discriminator base A73 has extensive stacking overlap with G1 within the G1.C72 base pair at the end of the double helical stem and the -CCA end is significantly less ordered than the rest of the molecule.

Alanine-tRNA Ligase↗

PubMed2003

An estrogen-dependent four-gene micronet regulating social recognition: a study with oxytocin and estrogen receptor-alpha and -beta knockout mice.

Estrogens control many physiological and behavioral processes, some of which are connected to reproduction. These include sexual and other social behaviors. Here we implicate four gene products in a micronet required for mammalian social recognition, through which an individual learns to recognize other individuals. Female mice whose genes for the neuropeptide oxytocin (OT) or the estrogen receptor (ER)-beta or ER-alpha had been selectively "knocked out" were deficient specifically in social recognition and social anxiety. There was a remarkable parallelism among results from three separate gene knockouts. The data strongly suggest the involvement in social recognition of the four genes coding for ER-alpha, ER-beta, OT, and the OT receptor. We thus propose here a four-gene micronet, which links hypothalamic and limbic forebrain neurons in the estrogen control over the OT regulation of social recognition. In our model, estrogens act on the OT system at two levels: through ER-beta, they regulate the production of OT in the hypothalamic paraventricular nucleus, and through ER-alpha, they drive the transcription of the OT receptor in the amygdala. The proper operation of a social recognition mechanism allows for the expression of appropriate social behaviors, aggressive or affiliative.

Animals↗

PubMed1999

[The evolution of ethical standards in the practice of psychology: a reflection on the APA Code of Ethics].

After briefly describing the need for ethics in the development of professional regulation and analyzing the historical emergence of codes of ethics, the goal of this paper is to scrutinize the process by which the American Psychological Association developed its own Code of Ethics and proceeded to revise it periodically. Different lessons can be derived from these efforts and from the criticisms that were formulated. The need for international standards in professional and research ethics is then considered, and the results of a recent study on this subject are presented. Five major conclusions can be derived from the preceding analysis: (1) Codes of ethics can help professional recognition by stressing the importance given to the protection of the public, (2) the development of a code of ethics is usually related to the advancement of professional practice, (3) ethical standards should be in tune with the cultural values and the belief system of a given community, (4) a well-balanced code should incorporate both general aspirational principles and enforceable standards, and (5) the method used to define principles and standards should be empirically based.

Ethics, Professional↗

PubMed1995

Effect of dichotic presentation on the recognition of telegraphy signs.

The recognition of telegraphy signs (Morse code) masked by noise was studied at different interaural phase conditions at 250, 500, 1000 and 2000 Hz tone frequency in eight normal-hearing men. The possible effect of a left-right ear of dominance was considered. Best recognition was obtained at 500 Hz tone frequency with the telegraphy signs 180 degrees out of phase but with the noise in phase. When the telegraphy signs and noise were presented in one ear, recognition improved when the same masking noise without any phase difference was added to the other ear. The effect was most marked at 500 Hz. No significant difference was found between the left and right ear.

Adult↗

PubMed1990

Simultaneous manipulation of propositional and analog codes in picture memory.

Revealing a picture as a whole or as momentarily displayed strips presumably manipulated the propositional coding of the picture. Analog manipulation employed superimposition of a grid pattern. Effectiveness of simultaneous manipulations was tested via recognition with three foil categories, each of which presumably tapped the analog or propositional codes mainly, or both of them in detection. While figural units' perspective reversals should presumably be detected via the analog code, their locational displacements should be detected via the propositional code. Foils with novel item substitution should be detected by both codes. On the basis of such presumptions about encoding and recognition manipulations, certain predictions were made for scan and grid effects in "reversal," "displacement," and "novelty" foil categories. Full confirmation of these predictions was then taken as evidence that both analog and propositional codes do exist. Once such evidence was established, other issues were tackled, showing that target detection involves the propositional code only, while foil detection involves both codes. Further, recognition hypermnesia, where performance improves with repeated testing, was obtained only when both codes were attenuated. Data suggested that subjects might be switching from analog to propositional codes when both codes were strong, thereby preventing hypermnesia.

Adult↗

PubMed1999

Activation of CD4 T cells by somatic transgenesis induces generalized immunity of uncommitted T cells and immunologic memory.

Cellular immune responses were analyzed in vivo after a single intraspleen inoculation of DNA coding for a 12-residue Th cell determinant associated with a 12-residue B cell epitope, a process termed somatic transgene immunization. We show that CD4 T cells are readily activated and produce IL-2, IFN-gamma and IL-4, characteristics of an uncommitted phenotype. Linked recognition of the two epitopes coded in the same transgene promoted IgM-IgG1 switch and enhanced the total Ab response but had no effect on IgG2a Abs. Although originating in the spleen, T cell responsiveness was found to spread immediately and with similar characteristics to all lymph nodes in the body. A single inoculation was also effective in establishing long term immunologic memory as determined by limiting dilution analysis, with memory T cells displaying a cytokine profile different from that of primary effector T cells. These studies provide evidence that by initiating immunity directly in secondary lymphoid organs, an immune response is generated with characteristics that differ from those using vaccines of conventional DNA or protein in adjuvant administered in peripheral sites. Somatic transgene immunization can therefore be used to probe T cell responsiveness in vivo and represents a tool to further understanding of the nature of the adaptive immune response.

Animals↗

PubMed1987

Molecular cloning and sequencing of a cDNA encoding the acyl carrier protein and its flanking domains in the mammalian fatty acid synthetase.

Cloned cDNAs containing coding sequences for domains proximal to the carboxy terminus of the rat fatty acid synthetase have been isolated using an expression vector and domain-specific antibodies. The coding regions were assigned to specific domains of the multifunctional complex by identification of sequences coding for characterized peptide fragments and by recognition of sequences homologous to other monofunctional enzymes. Two clones contain the entire coding region for the acyl carrier protein domain. The sequence is flanked at the 3'-end by a region coding for the thioesterase domain and at the 5'-end by a sequence coding for a reductase, most likely the ketoreductase domain. Thus the ordering of these domain-coding regions in the fatty acid synthetase mRNA is established. The acyl carrier protein domain exhibits about 25% homology with that of the discrete monofunctional acyl carrier proteins of Escherichia coli, spinach and barley, the ketoreductase domain exhibits about 25% homology with bacterial dihydrofolate reductases and the active site of the thioesterase domain exhibits both primary and secondary structural features common to the serine proteases. These findings lend support to the hypothesis that the polyfunctional fatty acid synthetase probably arose by a complex evolutionary process involving fusion of genes coding for seven individual enzymes.

Acyl Carrier Protein↗

PubMed2002

Recognizing shorter coding regions of human genes based on the statistics of stop codons.

With the quick progress of the Human Genome Project, a great amount of uncharacterized DNA sequences needs to be annotated copiously by better algorithms. Recognizing shorter coding sequences of human genes is one of the most important problems in gene recognition, which is not yet completely solved. This paper is devoted to solving the issue using a new method. The distributions of the three stop codons, i.e., TAA, TAG and TGA, in three phases along coding, noncoding, and intergenic sequences are studied in detail. Using the obtained distributions and other coding measures, a new algorithm for the recognition of shorter coding sequences of human genes is developed. The accuracy of the algorithm is tested based on a larger database of human genes. It is found that the average accuracy achieved is as high as 92.1% for the sequences with length of 192 base pairs, which is confirmed by sixfold cross-validation tests. It is hoped that by incorporating the present method with some existing algorithms, the accuracy for identifying human genes from unannotated sequences would be increased.

Algorithms↗

PubMed1975

A possible model for cell-cell recognition via surface macromolecules.

Alternative possibilities for the establishment of the proper cell distribution during embryogenesis are summarized at the beginning, followed by an assessment of the examples known so far where cell-cell recognition is known to be mediated via cell surface components. In the second part the species-specific recognition process which occurs during the sorting-out of dissociated sponge cells is analysed since it may serve as a possible model for cell-cell recognition in higher animals. Three possible mechanisms for the establishment of proper cell distribution are considered. These include, first, chemotaxis: secondly, guidance of cell or cell sheet movement by extracellular matrix or by surrounding cells and thirdly, random movement followed by recognition at the final point of destination. Recognition is necessary for both of the two latter processes, i.e. for cell guidance as well as for locking the cells into their final position after random movement. Two basically different recognition mechanisms should be distinguished from each other. On the one hand cells may recognize each other with the help of macromolecules situated in or just outside of the plasmamembrane which fit to each other like enzymes and substrates or antibodies and antigens. On the other hand, cells may exchange information by exchanging cytoplasmatic components via vesicles or gap junctions. The species-specific aggregation of dissociated sponge cells is considered to be a possible model for cell-cell recognition in higher animals. A proteoglycan-like intercellular macromolecule called aggregation factor seems to mediate recognition of a given species of cells in the reaggregation process of dissociated cells. The data available at the present time suggest that a monovalent surface macromolecule (baseplate) may mediate the recognition process probably by recognizing the carbohydrate side chains of the multivalent proteoglycan aggregation factor. A cell-free system was devised to mimic this aggregation process. Addition of aggregation factor to baseplate-coated sepharose beads of approximately the size of the original sponge cells has essentially the same characteristics as the cellular system. Macromolecule-coded surface information for the recognition between cells has not been established during the embryogenesis of higher animals and remains an interesting challenge.

Animals↗

PubMed1993

Coding coenzyme handles: a hypothesis for the origin of the genetic code.

The coding coenzyme handle hypothesis suggests that useful coding preceded translation. Early adapters, the ancestors of present-day anticodons, were charged with amino acids acting as coenzymes of ribozymes in a metabolically complex RNA world. The ancestral aminoacyl-adapter synthetases could have been similar to present-day self-splicing tRNA introns. A codon-anticodon-discriminator base complex embedded in these synthetases could have played an important role in amino acid recognition. Extension of the genetic code proceeded through the take-over of nonsense codons by novel amino acids, related to already coded ones either through precursor-product relationship or physicochemical similarity. The hypothesis is open for experimental tests.

Amino Acyl-tRNA Synthetases↗

PubMed1999

Evolution of the genetic code: the nonsense, antisense, and antinonsense codes make no sense.

According to the molecular recognition theory, the complementarity of the sense and nonsense DNA strands is reflected in a complementarity of polypeptides and the corresponding nonsense polypeptides. A comparison of the sense and nonsense code matrices, and of the antisense and antinonsense code matrices, either by visual inspection or by comparing the corresponding hydrophobicity matrices (e.g. by simply adding them together), revealed no complementarity of these pairs of matrices in terms of possible attractive physical forces. Instead, it was evident that the codes divide the amino acids into two major groups: hydrophilic and hydrophobic, a division which is directly correlated with the folding property of proteins. A simple primordial genetic code distinguishing between these two types of amino acids would have been capable of generating three-dimensionally folded peptides, which could stabilize coding RNAs by forming ribonucleoprotein complexes. This evolutionary scheme is reflected in the present organisation of information processing and storage in essentially all organisms. RNAs are processed and translated into proteins by ribonucleoproteins, while other steps in information retrieval and processing, such as DNA replication, transcription, protein folding and posttranslational processing, are catalyzed by proteins. This shows that the evolution of DNA as an information storage medium was a secondary event, unrelated to the evolution of the genetic code. From the primordial hydrophilic/hydrophobic (f.ex. Leu/Arg) code, evolution proceeded by introduction of a catalytic amino acid (Ser). The further evolution of the code has mainly served to increase the number of functional hydrophilic amino acids, since there has not been a great advantage in increasing the number of structural, hydrophobic amino acids. At some stage during the evolution of the genetic code, double-stranded DNA was introduced as a maximally safe genetic copy of RNA. This required the action of highly specific enzymes, and was therefore preceded by the refinement of the genetic code. As a conclusion of this evolutionary scheme, it can be inferred that, in general only the sense strand encodes proteins.

Codon, Nonsense↗

PubMed1995

Use of document image processing in cancer registration: how and why?

The aims of the study are to test and evaluate a system for document image processing (DIP) in cancer registration and coding. The results from use of optical character recognition (OCR) and image character recognition (ICR) in the data entry process are of particular interest. Cases of cancer must be reported both by clinicians and pathologists. Annually the Registry receives 80,000 reports concerning new cases and supplementary information on patients who are registered earlier [1]. Clinicians report new cancer cases to the Cancer Registry on a special designed form. Optionally, they can use a software-based application delivered from the Registry free of charge. As a part of the DIP-system, an optical digital image processing text (ODIT) system is used in recognition of machine- and hand-printed characters. The traditional registration and coding system is run parallel to the new system. After a period of testing the DIP-system nationwide, the new system will be evaluated and compared to the traditional system. The first part of the study compared the results from three character readers (CGK, XDR, and Nestor), which have been tested on our own application-specific data in a realistic setting [2]. The test shows that over 90% of the digits and about 70% of the letters can be correctly recognized by the system [3]. Feedback is communicated to clinicians to improve the quality of hand-print in the forms. It is to be hoped that this action among others will give a better recognition result for the next part of the study. The XDR Network Reader will serve as a reader in the ODIT-system chosen for the rest of the study. The software system Open Image Link shall serve as the image manager. De facto standard software like MS-Access is used as a part of the DIP-system. The next part of the study is the main project and started at the end of June 1994. Results from the project will be presented. Does the new system produce the expected high percentage of the clinicians will optionally use the software application instead of of paper forms in reporting cancer? And at what quality of data? Will the new DIP-system be cost-effective? The results from the study and the reasons for running such a project will be discussed.

Medical Oncology↗