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We have developed a basic concept for studying cell biological phenomena using an interdisciplinary approach starting from organic chemistry. Based on structural information available for a given biological phenomenon, unsolved chemical problems are identified. For their solution, new synthetic pathways and methods are developed, which reflect the state of the art in synthesising lipidated peptide conjugates. These compounds are used as molecular probes for the investigation of biological phenomena that involve both the determination of biophysical properties and cell biological studies. The interplay between organic synthesis, biophysics and cell biology in the study of protein lipidation may open up new and alternative opportunities to gain knowledge about the biological phenomenon that could not be obtained by employing biological techniques alone. This fruitful combination is highlighted using the Ras protein as an outstanding example. Included herein is: the development of methods for the synthesis of Ras-derived peptides and fully functional Ras proteins, the determination of the biophysical properties, in particular the ability to bind to model membranes, and finally the use of synthetic Ras peptides and proteins in cell biological experiments.
PURPOSE: The goals of this study were to survey and summarize the advances in imaging that have potential applications in radiation oncology, and to explore the concept of integrating physical and biological conformality in multidimensional conformal radiotherapy (MD-CRT). METHODS AND MATERIALS: The advances in three-dimensional conformal radiotherapy (3D-CRT) have greatly improved the physical conformality of treatment planning and delivery. The development of intensity-modulated radiotherapy (IMRT) has provided the "dose painting" or "dose sculpting" ability to further customize the delivered dose distribution. The improved capabilities of nuclear magnetic resonance imaging and spectroscopy, and of positron emission tomography, are beginning to provide physiological and functional information about the tumor and its surroundings. In addition, molecular imaging promises to reveal tumor biology at the genotype and phenotype level. These developments converge to provide significant opportunities for enhancing the success of radiotherapy. RESULTS: The ability of IMRT to deliver nonuniform dose patterns by design brings to fore the question of how to "dose paint" and "dose sculpt", leading to the suggestion that "biological" images may be of assistance. In contrast to the conventional radiological images that primarily provide anatomical information, biological images reveal metabolic, functional, physiological, genotypic, and phenotypic data. Important for radiotherapy, the new and noninvasive imaging methods may yield three-dimensional radiobiological information. Studies are urgently needed to identify genotypes and phenotypes that affect radiosensitivity, and to devise methods to image them noninvasively. Incremental to the concept of gross, clinical, and planning target volumes (GTV, CTV, and PTV), we propose the concept of "biological target volume" (BTV) and hypothesize that BTV can be derived from biological images and that their use may incrementally improve target delineation and dose delivery. We emphasize, however, that much basic research and clinical studies are needed before this potential can be realized. CONCLUSIONS: Whereas IMRT may have initiated the beginning of the end relative to physical conformality in radiotherapy, biological imaging may launch the beginning of a new era of biological conformality. In combination, these approaches constitute MD-CRT that may further improve the efficacy of cancer radiotherapy in the new millennium.
To determine the impact of environmental UV radiation, biological dosimeters that weight directly the incident UV components of sunlight have been developed, improved and evaluated in the frame of the BIODOS project. Four DNA-based biological dosimeters ((i) phage T7, (ii) uracil thin layer, (iii) spore dosimeter and (iv) DLR-biofilm) have been assessed from the viewpoint of their biological relevance, spectral response and quantification of their biological effectiveness. The biological dosimeters have been validated by comparing their readings with weighted spectroradiometer data, by comparison with other biological doses, as well as with the determined amounts of DNA UV photoproducts. The data presented here demonstrate that the biological dosimeters are potentially reliable field dosimeters for measuring the integrated biologically effective irradiance for DNA damage.
Establishing quantitative relationships between molecular structure and broad biological effects has been a longstanding challenge in science. Currently, no method exists for forecasting broad biological activity profiles of medicinal agents even within narrow boundaries of structurally similar molecules. Starting from the premise that biological activity results from the capacity of small organic molecules to modulate the activity of the proteome, we set out to investigate whether descriptor sets could be developed for measuring and quantifying this molecular property. Using a 1,567-compound database, we show that percent inhibition values, determined at single high drug concentration in a battery of in vitro assays representing a cross section of the proteome, provide precise molecular property descriptors that identify the structure of molecules. When broad biological activity of molecules is represented in spectra form, organic molecules can be sorted by quantifying differences between biological spectra. Unlike traditional structure-activity relationship methods, sorting of molecules by using biospectra comparisons does not require knowledge of a molecule's putative drug targets. To illustrate this finding, we selected as starting point the biological activity spectra of clotrimazole and tioconazole because their putative target, lanosterol demethylase (CYP51), was not included in the bioassay array. Spectra similarity obtained through profile similarity measurements and hierarchical clustering provided an unbiased means for establishing quantitative relationships between chemical structures and biological activity spectra. This methodology, which we have termed biological spectra analysis, provides the capability not only of sorting molecules on the basis of biospectra similarity but also of predicting simultaneous interactions of new molecules with multiple proteins.
Based on a Rapid Biological Activity Tester (RBAT), a study was taken on the sludge activity which is one of the most important parameters in the operation of aerated biological treating unit in WWTP to measure the effect of the external environmental conditions on the sludge activity, such as acidity and alkalinity, temperature, toxicity, etc. It is observed that the variety of the activity parameters is limited in 20% for a long time. While pH is deviated from the normal value, the biological activity drops to some degree, and furthermore, the ability of the microorganism to endure the acerbic environment is much higher than that to endure the alkaline environment. Temperature increase can result in the enhancement of the biological activity, and if the temperature is higher than 42.5 degrees C, the biological activity is greatly inhibite, but the endogenous respiring rate is less influenced by high temperature. Toxicity can greatly inhibit the biological activity of the activated sludge, and the inhibition is probably selective. Finally, the biological activity of the activated sludge from a real wastewater treatment plant was tested, and the standard deviation of the result is less than 20%. The results indicate that the RBAT is a promising method to measure biological activity, and the characteristics of activated sludge can be well expressed.
The profile of immunologically active human luteinizing hormone (hLH) was determined in aqueous pituitary extracts after electrofocusing using two radioimmunoassay systems and the estimates for each fraction were compared to those obtained by an in vitro bioassay method. Similar biological and immunological profiles were obtained in the pH 7.0-9.0 region, where most of the biological activity was present. Biological to immunological (B/I) ratios ranging from 0.6 to 1.7 (mean ratio 1.01; n = 21) were found in the major biologically active fractions of this pH region when a highly purified human pituitary LH preparation (68/40) was used as standard in both types of assays. The close proximity of these ratios to unity indicates a similar composition of biological and immunological activities in all these fractions in relation to that of the highly purified standard. However, marked discrepancies were observed in the pH region 3.0-7.0 where the B/I ratios ranged from 0.1 to 0.9, indicating the presence of immunological activity associated with relatively little biological activity. When impure human LH preparations of pituitary (69/104) and urinary (hMG 2nd IRP) origin were used as standards for the bioassay and radioimmunoassay of the hLH present in the major fractions of the pH region 7.0-9.0, significantly higher B/I ratios were obtained than with the use of the highly purified standard (68/40). These elevated B/I ratios are attributed to the presence in the impure standard preparations of immunological activity, which is associated with little or no biological activity. These observations may provide an explanation for the differences in B/I ratios which were reported for hLH in plasma, using different standard preparations.
The first IRP of Human Pituitary Gonadotrophins (FSH/LH) for bioassay (69/104) and the 1st IRP of Human Pituitary Luteinizing Hormone (LH) for immunoassay (68/40) were fractionated by an electrofocusing technique in a sucrose density gradient and the profile of biological and immunological activities was determined. The partially purified LH preparation (69/104) gave a broad pattern of biolgical and immunological activities which extended from pH 4 to 10. The biological : immunological (B/I) ratio of the various fractions (using the 68/40 preparation as standard) ranged from 0.04 to 1.05. The low B/I ratios indicate the presence of high levels of immunologically active, biologically inactive material in this preparation. In contrast to the behaviour of the 69/104 preparation, the major proportion (88%) of the biological activity recovered after electrofocusing of the highly purified LH preparation (68/40) was found within the pH range 7--9, with B/I ratios (again using as standard the 68/40 preparation) ranging from 0.4 to 1.5. Multiple dose parallel line design radioimmunoassays revealed a lack of parallelism between the 69/104 and 68/40 International Reference Preparations. This was attributed to the presence of acidic material in the former preparation, which is practically absent from the latter. The biological LH profiles of both the 69/104 and 68/40 preparations differed from those previously reported for aqueous extracts of pituitaries. It is concluded that the dissimilarity in the electrofocusing profiles of the biological and immunological activities of the 69/104 preparation renders this preparation unsuitable as a reference preparation for the quantitation of biologically active LH by radioimmunoassay methods. Using the same criteria, the 68/40 preparation would appear to be a more suitable standard.
We investigated the frequency of remission according to the disease activity score (DAS28) definition, modified American Rheumatology Association (ARA) criteria, and the frequency of an achievement of a functional status above defined thresholds ('functional remission', 'physical independence') in rheumatoid arthritis (RA) patients treated with either biologics or conventional DMARDs. We used the data of a prospective cohort study, the German biologics register RABBIT (German acronym for Rheumatoid Arthritis--Observation of Biologic Therapy) to investigate the outcomes in RA patients with two or more DMARD failures who received new treatment with biologics (BIOL; n = 818) or a conventional DMARD (n = 265). Logistic regression analysis was applied to adjust for differences in baseline risks. Taking risk indicators such as previous DMARD failures or baseline clinical status into account, we found that biologics doubled the chance of remission compared to conventional DMARD therapies (DAS28 remission, adjusted odds ratio (OR) 1.95 (95% confidenece interval (CI) 1.2-3.2)); ARA remission, OR 2.05 (95% CI 1.2-3.5)). High remission rates (DAS28 remission, 30.6%; ARA remission, 16.9%) were observed in BIOL patients with a moderate disease activity (DAS28, 3.2 to 5.1) at the start of treatment. These rates decreased to 8.5% in patients with DAS28 > 6. Sustained remission at 6 and 12 months was achieved in <10% of the patients. Severely disabled patients (< or = 50% of full function) receiving biologic therapies were significantly more likely to achieve a status indicating physical independence (> or = 67% of full function) than controls (OR 3.88 (95% CI 1.7-8.8)). 'Functional remission' (> or = 83% of full function) was more often achieved in BIOL than in controls (OR 2.18 (95% CI 1.04-4.6)). In conclusion, our study shows that biologics increase the chance to achieve clinical remission and a status of functional remission or at least physical independence. However, temporary or even sustained remission remain ambitious aims, which are achieved in a minority of patients only.
The relationship between the biological and immunological activities of human luteinizing hormone (hLH) in plasma collected from female subjects was examined. The biological activity was measured by an in vitro bioassay and the immunological activity by an hLH radioimmunoassay (RIA), using improved reagents, such as the 1st IRP for human pituitary LH for immunoassay (code No. 68/40) as standard, a subunit-free biologically active iodinated hLH preparation as tracer and an anti-hLH serum of relatively high specificity. Similar profiles of biological (B) and immunological (I) activity were obtained in the plasma samples collected daily throughout 40 menstrual cycles (5 cycles from each of 8 subjects). However, the B/I ratios were significantly lower during the period of LH surge (P less than 0.001) than throughout the remainder of the cycle. The within- and between-assay variation in B/I ratios was investigated by the simultaneous assay of biological and immunological activities in plasma pools obtained by combining equal aliquots of plasma from each daily sample of the menstrual cycle from each of 5 cycles of each of 4 subjects. The analysis of these 20 pools revealed highly significant individual differences in B/I ratios, ranging from 0.81 to 1.33. The coefficient of variation was 20% between-subjects and 5% within-subjects. There was no seasonal variation in B/I ratios. That the individual differences in plasma B/I ratios were not attributable to the procedure of pooling was ascertained by the simultaneous assay of both activities in parellel in daily plasma samples and in the pools formed from these samples from three complete cycles. Thus the analysis of the differences in B/I ratios obtained throughout the menstrua- cycle revealed three major sources of variation. The first occurs in the form of generally elevated (higher than unity) B/I ratios, the second consists of a significant drop in B/I ratios during the midcycle LH surge, and the third source is represented by the significant between-subject differences. It is concluded that the first source is attributable to the relatively higher levels of "impurity" (i.e. biologically inactive, immunologically active material) in the standard preparation compared to those present in plasma of biologically inactive, immunologically active material of unknown composition and origin. If so, the latter source limits the quantitative significance of the RIA procedures employed. It is suggested that these three sources of variation account for most of the differences in B/I ratios for plasma lLH reported in the literature.
Systems analysis has historically been performed in many areas of biology, including ecology, developmental biology and immunology. More recently, the genomics revolution has catapulted molecular biology into the realm of systems biology. In unicellular organisms and well-defined cell lines of higher organisms, systems approaches are making definitive strides toward scientific understanding and biotechnological applications. We argue here that two distinct lines of inquiry in molecular biology have converged to form contemporary systems biology.
Synthetic biology is interpreted as the engineering-driven building of increasingly complex biological entities for novel applications. Encouraged by progress in the design of artificial gene networks, de novo DNA synthesis and protein engineering, we review the case for this emerging discipline. Key aspects of an engineering approach are purpose-orientation, deep insight into the underlying scientific principles, a hierarchy of abstraction including suitable interfaces between and within the levels of the hierarchy, standardization and the separation of design and fabrication. Synthetic biology investigates possibilities to implement these requirements into the process of engineering biological systems. This is illustrated on the DNA level by the implementation of engineering-inspired artificial operations such as toggle switching, oscillating or production of spatial patterns. On the protein level, the functionally self-contained domain structure of a number of proteins suggests possibilities for essentially Lego-like recombination which can be exploited for reprogramming DNA binding domain specificities or signaling pathways. Alternatively, computational design emerges to rationally reprogram enzyme function. Finally, the increasing facility of de novo DNA synthesis-synthetic biology's system fabrication process-supplies the possibility to implement novel designs for ever more complex systems. Some of these elements have merged to realize the first tangible synthetic biology applications in the area of manufacturing of pharmaceutical compounds.
This article describes the working principles and working procedures of the Commission on Human Biological Monitoring, which was established in 1993 as a joint commission of the Federal Health Office (Bundesgesundheitsamt) and the Federal Environmental Agency (Umweltbundesamt) in Germany. One of the main tasks of the commission is to develop scientifically based criteria for the application of human biological monitoring and for the evaluation of human monitoring data in environmental medicine. In principle, two different kinds of criteria are recommended: (a) reference values and (b) human biological monitoring values (HBM values). Reference values are intended to indicate the upper margin of the current background exposure of the general population to a given environmental toxin at a given time. Reference values can be used to identify subjects with an increased level of exposure (in relation to background exposure) to a given environmental toxin. However, reference values do not represent health-related criteria for the evaluation of human biological monitoring data. HBM values are derived from human toxicology and epidemiology studies and are intended to be used as a basis for a health-related evaluation of human biological monitoring data. Usually the commission recommends two different HBM values: HBM I, the concentration of an environmental toxin in a human biological material (usually blood, serum, plasma, or urine) below which there is--according to the knowledge and judgement of the commission--no risk for adverse health effects in individuals of the general population: and HBM II, the concentration of an environmental toxin in a human biological material (usually blood, serum, plasma, or urine) above which there is--according to the knowledge and judgement of the commission and with regard to the environmental toxin under consideration--an increased risk for adverse health effects in susceptible individuals of the general population. The HBM I value can be considered a kind of alert value (from the toxicological point of view), whereas the HBM II value represents a kind of action level, at which attempts should be undertaken to reduce the level of exposure immediately and to carry out further medical examinations. Values between HBM I and HBM II should be considered a warning signal of the need to control the analytical measurement and to reduce the level of exposure of the concerned individual as reasonably as is achievable. At present, reference and HBM values are available for lead in blood, for cadmium and mercury in blood and urine, and for pentachlorophenol in plasma/serum and urine. Reference values have been established for some polychlorinated biphenyls in blood and plasma as well as for hexachlorocyclohexane and hexacholorobenzene in blood as well as for some organochlorine in human milk.
Biology cannot accommodate all aspects of culture. Aspects of culture that a biological approach can take into account can be covered by the biological categories of "phenotype" and "environment". There is no need to treat culture as a separate category. Attempts to elaborate biological explanations of "cultural variation" will meet with success only if biologists expand theories of development, and integrate them in evolutionary biology. The alternative--elaborating the idea of so-called "cultural inheritance"--makes little sense from a biological point of view.
Biological control describes situations in which a living antagonist (a predator, parasite, parasitoid or a pathogen) is distributed by man to lower pest (parasite) populations to acceptable sub-clinical densities or to keep the population at a non-harmful level. Ideally, biological control has no negative effects on the environment, whereas chemical control is not always so harmless. Laboratory and field observations have revealed many organisms, such as viruses, bacteria, fungi, protozoans, turbellarians, nematodes, earthworms, tardigrades, insects, copepods and mites as antagonists to parasitic arthropods, protozoans and helminths of domesticated animals. However, only very few of these antagonists have shown promising qualities as biological control agents within veterinary science. The lack of success should be linked to the lack of knowledge about complex natural biological systems and the antagonists that may be found there. This situation has restricted the interest of industry in developing biological products. In the future, however, industry may become more interested in biological control considering the increasing problems with parasite resistance to drugs in combination with the increasing cost of developing new chemical products, and because of increasing public concern about chemical residues in animal products and in the environment.
In this series of papers, a theory of functional organization is proposed for biological systems (formal biological system, FBS), which is based on the concept of 'functional interaction', and on a 'functional self-association hypothesis'. From the specific properties of functional interactions, i.e. non-symmetry, non-locality, and non-instantaneity, it is shown that a biological system can be considered as constituted by two hierarchical systems: (i) the (O-FBS) that describes the topology of the FBS, i.e. the functional organization, with a hierarchical directed graph; (ii) the (D-FBS) that describes the continuous non-linear dynamics of the FBS with a field. In the framework of this theory, the problem of the relation between structure and function is considered to be due to the distinction between structural organization and functional organization. Some advantages of this approach are: (i) the description of the time evolution, during development, of the organization of an FBS with an optimum principle, which leads to a clear comparison with a physical system (paper II); (ii) the description of the space-time dynamics as the variation in space and time of field variables in a hierarchical 'space of structural units'; and, consequently, the relation between topology and geometry, and the existence of non-locality in these hierarchical spaces (paper III). In this paper, the basic concepts of functional interaction, hierarchical functional organization, and physiological function are discussed from a mathematical viewpoint, and arguments for the validity of the self-association hypothesis are given. Specifically, it is shown that, for a particular class of biological systems that are taken as an example, the domain of stability of the (D-FBS) is increased after functional association. This property, which is specifically due to the nature of the biological system, corresponds to an increase in complexity. It will be shown in the second paper that such a self-organization corresponds also to an optimal principle for the (O-FBS). The case of real biological systems (RBSS) is considered in relation with the present theory, which leads to a new hierarchical representation in terms of fields. Such representation could be a base for integrative physiology. As an example, some physiological functions, respiratory and cardio-vascular, are considered and it is shown that the heart shock emerges from the formulation as a cyclic sub-graph.