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PubMed1990

DNA methylation: evolution of a bacterial immune function into a regulator of gene expression and genome structure in higher eukaryotes.

The amino acid sequence of mammalian DNA methyltransferase has been deduced from the nucleotide sequence of a cloned cDNA. It appears that the mammalian enzyme arose during evolution via fusion of a prokaryotic restriction methyltransferase gene and a second gene of unknown function. Mammalian DNA methyltransferase currently comprises an N-terminal domain of about 1000 amino acids that may have a regulatory role and a C-terminal 570 amino acid domain that retains similarities to bacterial restriction methyltransferases. The sequence similarities among mammalian and bacterial DNA cytosine methyltransferases suggest a common evolutionary origin. DNA methylation is uncommon among those eukaryotes having genomes of less than 10(8) base pairs, but nearly universal among large-genome eukaryotes. This and other considerations make it likely that sequence inactivation by DNA methylation has evolved to compensate for the expansion of the genome that has accompanied the development of higher plants and animals. As methylated sequences are usually propagated in the repressed, nuclease-insensitive state, it is likely that DNA methylation compartmentalizes the genome to facilitate gene regulation by reducing the total amount of DNA sequence that must be scanned by DNA-binding regulatory proteins. DNA methylation is involved in immune recognition in bacteria but appears to regulate the structure and expression of the genome in complex higher eukaryotes. I suggest that the DNA-methylating system of mammals was derived from that of bacteria by way of a hypothetical intermediate that carried out selective de novo methylation of exogenous DNA and propagated the methylated DNA in the repressed state within its own genome.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1987

[Lymphocytes: recent findings].

In the last ten years, considerable progress has been made in our understanding of the physiology of the lymphoid system. These include advances in knowledge of the biochemical nature of the receptors used by B and T lymphocytes in antigen recognition, the origin of the diversity of specificity exhibited by these receptors, and the crucial role played by growth factors in the cellular proliferation elicited during immune response. Moreover, the biological significance of the existence of two subpopulations of T lymphocytes has been reinterpreted in the light of recent studies showing a correlation between expression of the surface markers T4 or T8, and the restriction pattern of the antigenic specificity exhibited by lymphocytes bearing these markers.

Antigens, Surface↗
PubMed2006

Hypermobility disorders in children and adolescents.

It is well recognized that many if not most children and adolescents attending paediatric rheumatology clinics will have a non-inflammatory origin for their complaints or disorder. Mechanical causes are frequently identified, and hypermobility or ligamentous laxity of joints is increasingly recognized as an aetiological factor in the presentation. Such conditions include 'growing pains', recurrent lower-limb arthralgia, anterior knee pain syndromes, and back pain. Studies of significant cohorts of such patients have now been published supporting the link of ligamentous laxity to particular symptom complexes. However, much disagreement remains as to the validity of hypermobility as an aetiogical factor. What seems clear is that not all hypermobile individuals will be symptomatic or indeed possibly have any risk for specific musculoskeletal disorders in later life. Screening tools such as the Beighton score are likely to be inadequate in many paediatric populations. Along with increasing recognition of these disorders in childhood and adolescence has been the development of a multidisciplinary management approach, which usually involves predominantly allied health professionals such as podiatrists, physiotherapists and occupational therapists. The challenge remains to interpret symptoms correctly as being related to the hypermobility and to predict why such children become symptomatic. The answer is likely to involve physiological and psychosocial factors. In addition, early identification and modification of risk factors may have major implications for subsequent prevalence of many adult medical disorders such as low back pain, chronic pain syndromes and degenerative osteoarthritis.

Adolescent↗
PubMed1994

Changing the substrate specificity of penicillin G acylase from Kluyvera citrophila through selective pressure.

Escherichia coli (muT, mutD, Leu-) cells transformed with plasmid pYKD59 harbouring the pac gene encoding penicillin acylase (PA) from Kluyvera citrophila ATCC 21285 were exposed to environmental conditions that made expression of this enzyme essential for growth. Under these conditions, spontaneous mutants were isolated that used adipyl-L-leucine as the sole source of L-leucine. DNA sequencing of the mutant pac genes identified a transversion mutation of thymine to guanine at position 1163. This mutation was located in the beta-subunit of the enzyme and resulted in conversion of Phe-360 to valine. The assignment of this mutation to the shift in substrate specificity was further confirmed by site-directed mutagenesis. Secondary-structure prediction of the region surrounding Phe-360 suggests that this mutation should not produce any significant structural change. The purified mutant acylase was able to hydrolyse adipyl-, glutaryl-, valeryl-, caproyl-, heptanoyl- and phenoxyacetyl-L-leucine at pH 5 with greater efficiency than the wild-type enzyme. However, the mutant enzyme was not able to hydrolyse glutaryl-7-aminocephalosporanic acid and had lost 90% and 50% of activity on penicillin G and phenylacetyl-L-leucine respectively. Nevertheless, mutant PA retained its original activity on 6-nitro-3-phenylacetamidobenzoate and p-nitrophenylphenylacetate, suggesting that the binding specificity of PA by the acyl and amine moieties of the substrate are not independent phenomena. The small differences observed between the c.d. spectra of the mutant enzyme recorded at pH 5 and 8 suggest the existence of different conformational states at the two pH values, but these differences were indistinguishable from those observed in the native enzyme and cannot be correlated with the shift in substrate specificity. Our results demonstrate that it is possible to change the specificity of PA by laboratory evolution and use it to identify the amino acids involved in substrate recognition. However, the synchronous participation of the alpha- and beta-subunits in the complex induced-fit-like mechanism of acylases suggests that, to obtain new enzymes for industrial application, the selection pressure should be specifically designed for the compound of interest.

Amino Acid Sequence↗
PubMed1998

Hans Selye and the development of the stress concept. Special reference to gastroduodenal ulcerogenesis.

Hans Selye has a historic role in the development of the stress concept. Before his short article in Nature in 1936, the neuroendocrine response to nonspecific injury was thought to be restricted to the release of catecholamines, as recognized by Cannon. Selye was the first to appreciate the crucial role of the adrenal cortex/hypophysis axis in the stress response. He also insisted on the nonspecificity of this neuroendocrine response, and he named the stress-causing agent "stressors". His last major contribution was the distinction between negative, that is, distress, and positive, that is, eustress reactions. The "triad of stress" (adrenal hypertrophy, gastrointestinal ulcers, thymolymphatic atrophy) was also first described by Selye, who was fascinated by the fact that in stressed rodents only gastric and not duodenal ulcers would develop. It was not until the recognition of duodenal ulcerogenic properties of propionitrile and cysteamine as well as the subsequent quantitative structure-activity studies predicting the duodenal ulcerogenic action of complex molecules that pathogenetic investigations allowed a molecular and mechanistic approach for studying the etiology and pathogenesis of duodenal ulceration. Recent studies on the role of sulfhydryls, TRH, ET, and growth factors provide new insights into central and peripheral pre-ulcer pathways. We were surprised to learn that an organ-specific ET-1 release may play a role both in ulcer induction and healing, which seems to start with the expression of immediate early genes such as egr-1 and stimulation of the local synthesis of growth factors such as bFGF and PDGF. Thus, a historic review originating with Hans Selye and extending through the next 60 years allows a cellular and molecular approach to the better understanding of stress-related disorders such as gastroduodenal ulceration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

[Does there exist one specific "view of man" in naturopathy / complementary medicine?].

BACKGROUND: Practitioners and users of naturopathic therapies claim that one of the assumptions underlying their work is a holistic "view of man". OBJECTIVE: Does there exist one specific view of man in present naturopathy and what does this mean? MATERIAL AND METHODS: Database and literature research of use and meaning of the term "view of man" and descriptive analysis. RESULTS: The term "view of man" is neither timeless nor related to a specific subject area. Its meaning is connected with the state of knowledge of the respective epoch as well as its reception in science and society. The discourse concerning the term "view of man" in the 2nd half of the 20th century in German literature shows, that in different fields the argumentation about one specific view of man shifts towards a pluralistic understanding of man. This pluralistic view about man exists in medicine as well. On the one hand conventional medicine, a long time under influence of the reductionism of natural science, has widened its worldview due to methods and questions of different disciplines such as psychosomatics, psychotherapy or social medicine towards a more complex perception of man. On the other hand Traditional European Naturopathy (TEN) too, claims to respect aspects of the "body-mind-soul-unity" in its understanding of man; yet, in connection with its hardly ever explained "natural forces". Besides the findings in literature clinical experience with our patients reveals some aspects that are characteristic of today's pluralistic naturopathic understanding of man and could also be useful for conventional medicine: recognition of patients' expectations (e.g. subjective view of illness), participation in the therapy planning (e.g. construction of how to get healthy) and naturopathic modes of therapy (e.g. start of therapy at healthy parts of the body, too). CONCLUSIONS: Despite some characteristics in naturopathy one finds variations of views or images of man, which originate from multiple subjective and socio-cultural perspectives of patients and therapists and which require, next to medical knowledge, on both sides openness and communication regarding aspects of health, illness and therapeutic settings.

Complementary Therapies↗
PubMed2002

Dynamic QSAR techniques: applications in drug design and toxicology.

The basic principles of 3-D quantitative structure-activity relationships (QSARs) analysis are discussed in the light of the fuzzy logic concept. According to that concept, the traditionally one chemical - one structure - one parameter value relationship in QSAR is suggested to be modified into one chemical finite set of structures - range of parameter values principle. In this respect, two recently developed techniques accounting for conformational flexibility in 3-D QSARs are reviewed. A basic assumption underlying both methods is that chemical behavior in complex biological systems is context-dependent. A molecule can exist and interact in a variety of conformations depending on the specificity of the endpoint under investigation and reaction media. It was demonstrated that selection of active conformer(s) in QSAR studies is a task as important as the selection of relevant molecular parameters. Specifically selected active conformers, rather than the lowest-energy states of the chemicals are suggested to be used in the correlative QSARs. The method for recognition the common reactivity pattern (COREPA) of structurally heterogeneous compounds that elicit similar biological behaviour is based on all energetically reasonable conformers of chemicals. The principle assumption of the method is that biologically similar chemicals should possess a commonality in their stereoelectronic (reactivity) pattern. Originally developed algorithms for conformer generation are presented in association with the QSAR methods accounting for conformational flexibility of chemicals. Applicability of the QSAR technique for selection active conformers is illustrated by presenting QSAR models derived for Ah binding affinity of PCBs and antimicrobial activity of rifamicin derivatives. Models for predicting estrogenic activity of structurally diverse chemicals and ACE inhibition exemplified the applicability of the COREPA method. The model performance is analyzed by the 3D screening exercise of large chemical inventories with subsequent experimental validation within the EDAEP project. Besides the impact of conformational flexibility of chemicals in 3D QSAR the role of different molecular descriptors is discussed with respect to their ability to describe molecular interactions with different specificity.

Combinatorial Chemistry Techniques↗
PubMed1990

Protein-protein recognition via short amphiphilic helices; a mutational analysis of the binding site of annexin II for p11.

Annexin II (p36) interacts with its ligand p11 via the short stretch of 12 amino acids (Ac-S-T-V-H-E-I-L-C-K-L-S-L) situated at the N-terminus. We have now synthesized some 37 tetradecapeptides, which differ from the original p11 binding sequence (Ac1-14) by single amino acid substitutions. The relative affinity of each peptide for p11 was determined by fluorescence spectroscopy using a competitive binding assay. The binding behaviour of the different peptides confirms the model of an amphiphilic alpha-helix induced upon binding to p11. The apparent affinities delta delta Gbind of the mutant peptides revealed that the N-acetyl group of serine 1 and the hydrophobic side chains at positions 3, 6, 7 and 10 contribute most to the binding. The observed destabilization of the complex upon removal of signal methyl groups from the hydrophobic side of the helix is comparable with the destabilization of proteins in which methyl groups have been removed from the inner core. We conclude that upon binding to p11 the hydrophobic side of the amphiphatic alpha-helix becomes fully buried.

Amino Acid Sequence↗
PubMed1999

Phylogeny, biogeography, and processes of molecular differentiation in Quercus subgenus Quercus (Fagaceae).

Quercus is one of the most abundant and economically important genera of woody plants in the Northern Hemisphere. To infer phylogenetic relationships within Quercus subgenus Quercus, chloroplast DNA (cpDNA) restriction sites and nucleotide sequences of the internal transcribed spacers (ITS) and the 5.8S coding region of the nuclear ribosomal DNA repeat were obtained for 44 individuals, including 25 species, intraspecific samples, and three outgroups. Separate parsimony analyses of each data set showed that individual gene trees were congruent and often complementary in supporting clades that generally corresponded to previously recognized taxonomic groups. Only one instance of strongly supported gene tree incongruence was detected and this anomalous pattern was explained best by ancient introgression of cpDNA across sectional boundaries. Simultaneous parsimony analysis of the pruned data sets supported the recognition of the strictly Eurasian section Cerris and resolved a novel hypothesis for the major infrageneric groups (Cerris- (Lobatae- (Protobalanus + Quercus sensu stricto))). The biogeographic hypothesis that all major oak lineages evolved locally at middle latitudes within the general distribution of their fossil ancestors was fully supported. This set of relationships also suggested a New World origin for the widespread white oaks of the Northern Hemisphere (section Quercus s. s.). For both data sets, inter- and intraspecific sampling within section Protobalanus showed little correspondence to morphological species. Greater cladistic structure among the samples was obtained by cpDNA restriction sites and two well-delimited plastomes types comprising a total of 15 distinct haplotypes were resolved. Haplotypes of 2 of the peripheral species in this species complex occupy terminal portions of one of the plastome clades, suggesting a more recent origin relative to those of more widespread species. The phylogeography of the two divergent plastome types suggested a north-south pattern, consistent with a Late Tertiary disjunction in the ancestral distribution of section Protobalanus.

Cell Nucleus↗
PubMed1991

Generation of fractal patterns for probing the visual memory.

The effective use of computer-generated pictures as a trial-unique probe for studying the visual memory is described. The shape of the pattern is determined by means of a fractal algorithm with pseudorandom parameters. This method enables us to easily obtain thousands of moderately complex and sufficiently diversified pictures in series from a given number which serves as the seed of a pseudorandom number generator. We can thereby create a new and unique set of pictures if a new seed is given, as well as retrieve exactly the same pictures in the same sequence as when the original seed is given. These properties eliminate the demand for the massive memory space in a computer otherwise needed to store the entire set of stimulus pictures.

Algorithms↗
PubMed1996

Binding of a hairpin polyamide in the minor groove of DNA: sequence-specific enthalpic discrimination.

Hairpin polyamides are synthetic ligands for sequence-specific recognition in the minor groove of double-helical DNA. A thermodynamic characterization of the DNA-binding properties exhibited by a six-ring hairpin polyamide, ImPyPy-gamma-PyPyPy-beta-Dp (where Im = imidazole, Py = pyrrole, gamma = gamma-aminobutyric acid, beta = beta-alanine, and Dp = dimethylaminopropylamide), reveals an approximately 1-2 kcal/mol greater affinity for the designated match site, 5'-TGTTA-3', relative to the single base pair mismatch sites, 5'-TGGTA-3' and 5'-TATTA-3'. The enthalpy and entropy data at 20 degrees C reveal this sequence specificity to be entirely enthalpic in origin. Correlations between the thermodynamic driving forces underlying the sequence specificity exhibited by ImPyPy-gamma-PyPyPy-beta-Dp and the structural properties of the heterodimeric complex of PyPyPy and ImPyPy bound to the minor groove of DNA provide insight into the molecular forces that govern the affinity and specificity of pyrrole-imidazole polyamides.

Amides↗
PubMed1985

Intermodal timing relations and audio-visual speech recognition by normal-hearing adults.

Audio-visual identification of sentences was measured as a function of audio delay in untrained observers with normal hearing; the soundtrack was replaced by rectangular pulses originally synchronized to the closing of the talker's vocal folds and then subjected to delay. When the soundtrack was delayed by 160 ms, identification scores were no better than when no acoustical information at all was provided. Delays of up to 80 ms had little effect on group-mean performance, but a separate analysis of a subgroup of better lipreaders showed a significant trend of reduced scores with increased delay in the range from 0-80 ms. A second experiment tested the interpretation that, although the main disruptive effect of the delay occurred on a syllabic time scale, better lipreaders might be attempting to use intermodal timing cues at a phonemic level. Normal-hearing observers determined whether a 120-Hz complex tone started before or after the opening of a pair of liplike Lissajou figures. Group-mean difference limens (70.7% correct DLs) were - 79 ms (sound leading) and + 138 ms (sound lagging), with no significant correlation between DLs and sentence lipreading scores. It was concluded that most observers, whether good lipreaders or not, possess insufficient sensitivity to intermodal timing cues in audio-visual speech for them to be used analogously to voice onset time in auditory speech perception. The results of both experiments imply that delays of up to about 40 ms introduced by signal-processing algorithms in aids to lipreading should not materially affect audio-visual speech understanding.

Adult↗
PubMed2006

Topological basis of signal integration in the transcriptional-regulatory network of the yeast, Saccharomyces cerevisiae.

BACKGROUND: Signal recognition and information processing is a fundamental cellular function, which in part involves comprehensive transcriptional regulatory (TR) mechanisms carried out in response to complex environmental signals in the context of the cell's own internal state. However, the network topological basis of developing such integrated responses remains poorly understood. RESULTS: By studying the TR network of the yeast Saccharomyces cerevisiae we show that an intermediate layer of transcription factors naturally segregates into distinct subnetworks. In these topological units transcription factors are densely interlinked in a largely hierarchical manner and respond to external signals by utilizing a fraction of these subnets. CONCLUSION: As transcriptional regulation represents the 'slow' component of overall information processing, the identified topology suggests a model in which successive waves of transcriptional regulation originating from distinct fractions of the TR network control robust integrated responses to complex stimuli.

Algorithms↗
PubMedDate not supplied

Endogenous tumor lectins: overview and perspectives.

Lectins are carbohydrate-binding proteins of non-immune origin that can be assayed as agglutinins. They are potential mediators in recognitive processes and cell adhesion by interaction with glycoconjugates. These functions are areas of particular relevance to tumor growth and metastatic spread. The presence of lectins in tumors has first been inferred by histochemical and cytological methods. The biochemical analysis for lectins with various specificities reveals differences in the lectin profile between tumors of different classes (eg, mammary adenocarcinoma, rhabdomyosarcoma, or teratoma) and of the same class (eg, testicular germ cell tumors) and differences in relation to normal tissues. The presence of endogenous lectins in tumors, their relation to lectins of normal tissues, and their interaction with glycoconjugates of tumors and normal tissues may contribute to an understanding of intercellular interactions during the complex process of metastatic spread, and may allow to establish a new tool for diagnosis and a lectin-based therapy.

Humans↗
PubMed1996

A retroviral peptide encoded by mutated env p15E gene is recognized by specific CD8+ T lymphocytes on drug-treated murine mastocytoma P815.

Highly immunogenic ("xenogenized") tumour variants appear after treatment of murine mastocytoma P815 with the triazene derivative DTIC, a phenomenon associated with the appearance of structurally abnormal p15E env proteins in the variant cells. In the present study, we have isolated and sequenced several p15E cDNA gene fragments amplified by means of polymerase chain reaction (PCR) from parental (P815) and xenogenized (P815/DTIC) tumour cells. Compared to known p15E sequences in parental cells, one p15E sequence from xenogenized cells presented three distinct nucleotide changes, one of which was apparently unique to P815/DTIC DNA and cDNA upon single-nucleotide primer extension assay. One major histocompatibility complex (MHC) class I-binding peptide, corresponding to a putative mutation in the p15E sequence, was tested in parallel with the parental peptide for recognition by P815/DTIC-specific cytotoxic T cells in vitro. The results suggested that the amino acid substitution at the relevant position of the p15E protein may produce an antigenic T cell epitope. By skin test assay of mice primed with either the synthetic peptide or P815/DTIC cells, evidence was obtained that the mutated peptide is immunogenic in vivo, and that the neoepitope is expressed by P815/DTIC cells. In accordance with previous data in the L5178Y/DTIC tumour model system, these findings reinforce the notion that xenogenization of tumour cells may result in the expression of class I-binding mutated peptides of retroviral origin.

Amino Acid Sequence↗
PubMed2000

Relationship of seminal traits and insemination time to fertilization rate and embryo quality.

The nature of subfertility due to the male or inseminate is as complex as that of the female. Fertilization failure or failure in embryogenesis are both documented to be of seminal origin. Males also differ in the numbers of sperm required to reach their maximum fertilization rate. Males requiring more sperm would be considered to have compensable seminal deficiencies. These include a number of known (viability and morphology) and unknown factors (functional or molecular traits) precluding sperm access to the ovum or ability to engage the ovum sufficiently to initiate fertilization and the block to polyspermy. Differences in fertility among males or inseminates independent of sperm dosage are considered uncompensable. These deficiencies would be associated with fertilizing sperm that are incompetent to maintain the fertilization process or subsequent embryogenesis once initiated, with most failures occurring prior to maternal recognition of pregnancy. Such sperm would preempt fertilization by competent sperm. Chromatin aberrations in morphologically normal or near normal spermatozoa from abnormal semen samples appear to be the best candidates for the uncompensable deficiency. However, recognition of uncompensable or incompetent fertilizing sperm has not been achieved. Six-day-old non-surgically recovered bovine ova/embryos have been used to evaluate compensable and uncompensable seminal deficiencies as well as to test reproductive strategies. These ova/embryos provide information on fertilization status and embryo quality as well as quantitative and qualitative data regarding associated accessory sperm. Thus, they permit the separation of reproductive failure by fertilization from that by embryonic development. Accessory sperm number is positively associated with both fertilization rate and embryonic quality. Early insemination results in low fertilization rates (low accessory sperm number), but good embryo quality, whereas, late insemination results in high fertilization rates (high accessory sperm number), but poor embryo quality. Additional studies will be necessary to substantiate this model; however, if true, future research designed to improve results to artificial insemination should be tested by breeding early in estrus where sperm viability is most limiting and embryo quality is best.

Animals↗
PubMed2000

Scaling extrafoveal detection of distortion in a face and grating.

Peripheral performance involving simple visual tasks and stimuli can be equated with foveal performance by spatial scaling, whilst more complex tasks and stimuli seem to need additional scaling of image contrast. We therefore determined whether the contrast manipulation needed to compensate for eccentricity-dependent performance changes is due to an increase in stimulus or task difficulty. We measured contrast sensitivities to determine foveal and peripheral ability to discriminate between an original and a distorted version of a polar-circular sinusoidal grating and a face image. Contrast sensitivities as a function of image size were spatially scaleable across eccentricities for both the face and grating. Furthermore, irrespective of stimulus, performance could be scaled with the same individual E2 value. Thus task simplicity overrides the nature of the stimulus in determining scaling requirements, suggesting that it is the complexity of the task, not of the stimulus, that makes contrast scaling necessary in complex tasks.

Contrast Sensitivity↗
PubMed1992

Self-reactive and antigen-specific T cell clones derived from a HLA-DR4+/DR5+ donor: T cell receptors and MHC-restriction patterns.

The relationship of heat shock proteins and rheumatoid arthritis as well as the relevance of autoreactivity in this disease is unclear. T cells of six individuals (four expressing the DRB1*0401 allele, one harboring DRB1*0404 and one the DRB1*0407 allele) were cloned in the presence of 65kD mycobacterial heat shock protein (HSP60) in order to determine T cell receptors (TcR) used and the MHC class II restriction patterns of potentially relevant T cell clones (TcC). All TcC obtained were not specific for HSP60, but six TcC of one donor (HLA-DR4/HLA-DR5) were responsive towards autologous antigen-presenting cells. One TcC displayed authentic autoreactivity whereas five TcC reacted specifically to serum proteins. The amino acids (aa) of the MHC molecule, crucial for immune recognition were mapped to aa #71 or #86 of either maternal or paternal origin. The strictly autoreactive TcC did not recognize transfected L cells implicating specificity for self-peptides not presented by L cells or the involvement of adhesion molecules. Correlations between autoreactivity and TcR V(D)J sequences or N nucleotides of various "autoreactive" TcC were not evident.

Amino Acid Sequence↗