MaSTerClass: a case-based reasoning system for the classification of biomedical terms

MOTIVATION: The sheer volume of textually described biomedical knowledge exerts the need for natural language processing (NLP) applications in order to allow flexible and efficient access to relevant information. Specialized semantic networks (such as biomedical ontologies, terminologies or semantic lexicons) can significantly enhance these applications by supplying the necessary terminological information in a machine-readable form. With the explosive growth of bio-literature, new terms (representing newly identified concepts or variations of the existing terms) may not be explicitly described within the network and hence cannot be fully exploited by NLP applications. Linguistic and statistical clues can be used to extract many new terms from free text. The extracted terms still need to be correctly positioned relative to other terms in the network. Classification as a means of semantic typing represents the first step in updating a semantic network with new terms. RESULTS: The MaSTerClass system implements the case-based reasoning methodology for the classification of biomedical terms.     

Importance of complete DNA digestion in minimizing variability of 8-oxo-dG analyses.

Estimates of 8-oxo-2'-deoxyguanosine (8-oxo-dG) in DNA vary at least one order of magnitude using different quantitative methods or even the same method. Our hypothesis is that an incomplete DNA hydrolysis to nucleosides by the conventional nuclease P1 (NP1) and alkaline phosphatase (AP) digestion system plays an important role in contributing to the variability of measurements using HPLC coupled with UV and electrochemical (EC) detection. We show here that factors, such as the amount of DNA, choice of enzymes, their activities, and incubation time, can affect DNA digestion and, thus, cause variability in 8-oxo-dG levels. The addition of DNase I and phosphodiesterases I and II to the NP1 + AP system improves the DNA digestion by completely releasing normal nucleosides and 8-oxo-dG, thereby reducing the interday variations of 8-oxo-dG levels. Diethylenetriamine pentaacetic acid (DTPA), an iron chelator, prevented background increases of 8-oxo-dG during DNA digestion, as well as during the waiting period in the autosampler when a batch of DNA samples is analyzed by HPLC. After optimization of the DNA digestion conditions, the interday variability of 8-oxo-dG measurements using commercially available salmon testes DNA (ST DNA) were 26% over a period of 2 years. Under these optimal conditions, our laboratory variability may contribute as little as 13% to the overall variability as shown by assessment of oxidative DNA damage in a population of smokers. Based on our results, we believe that the modified DNA digestion conditions will provide much more accurate 8-oxo-dG determinations and, thus, more reliable estimates of cancer risk.     

Learning about protein hydrogen bonding by minimizing contrastive divergence

Defining the strength and geometry of hydrogen bonds in protein structures has been a challenging task since early days of structural biology. In this article, we apply a novel statistical machine learning technique, known as contrastive divergence, to efficiently estimate both the hydrogen bond strength and the geometric characteristics of strong interpeptide backbone hydrogen bonds, from a dataset of structures representing a variety of different protein folds. Despite the simplifying assumptions of the interatomic energy terms used, we determine the strength of these hydrogen bonds to be between 1.1 and 1.5 kcal/mol, in good agreement with earlier experimental estimates. The geometry of these strong backbone hydrogen bonds features an almost linear arrangement of all four atoms involved in hydrogen bond formation. We estimate that about a quarter of all hydrogen bond donors and acceptors participate in these strong interpeptide hydrogen bonds.     

Evolution by phenotype: a biomedical perspective

Genes are widely assumed to play a major role in the epidemiology of complex chronic diseases, yet attempts to characterize the genetic architecture of such traits have been frustrating. Understanding that evolution works by screening phenotypes rather than genotypes can help explain the source of this frustration. Complex traits are usually the result of long-term, often subtle, gene-environment interactions, such that individual life histories may be as important as population histories in predicting and explaining these traits. Recognizing that the problem is not due to technological limitations can help temper expectations and guide the design of future work in biomedical genetics, by allowing us to focus on better approaches where they exist and on those problems most likely to yield a genetic solution. We may even be forced to re-conceive complex biological causation.     

Structural ambiguity and limits to coping

How well a person can cope with any situation is determined, among other factors, by his ability to resolve the ambiguity of that situation, which in turn depends on its structural complexity. We attempted to analyze a whole range of situations in terms of three dimesions: differentiations, the number of alternatives perceived; articulation, the differentiation and rankability of these alternatives; and loading, the emotional loading (positive or negative) associated with the situation. The efficiency of mapping with these dimensions was investigated by analyzing the effects of 75 situations on coping, as reported in the literature. These were divided into three groups, 25 situations in each, associated with good coping, reduced coping, and failure to come (in terms of performance relative to a baseline or to the population's norm). The interaction between the demands imposed by the complexity of the situation and the success of coping was analyzed by the Multidimensional Scalogram Analysis (MSA). Results show effectiveness of coping to be inversely related to the structural complexity of a situation, mapped in terms of articulation, loading and differentiation. The relative importance of these dimensions is as ordered above; this offers a possible way to construct an "ambiguity score" which may be the primary factor determining the coping limit set by any situation.     

Normalizing temporal patterns to analyze sit-to-stand movements by using registration of functional data

Functional data analysis techniques provide an alternative way of representing movement and movement variability as a function of time. In particular, the registration of functional data provides a local normalization of time functions. This normalization transforms a set of curves, records of repeated trials, yielding a new set of curves that only vary in terms of amplitude. Therefore, main events occur at the "same time" for all transformed curves and interesting features of individual recordings remain after averaging processes. This paper presents an application of the registration process to the analysis of the vertical forces exerted on the ground by both feet during the sit-to-stand movement. This movement is particularly interesting in functional evaluations related to balance control, lower extremity dysfunction or low-back pain.     

Biochemiluminescence and biomedical applications

Although used for analytical purposes for more than 40 years it is only recently that biochemiluminescence (BCL) has found widespread acceptance. Methods employing BCL reactions now play an important role in biomedical research and laboratory medicine. The main attractions for the assay technology include exquisite sensitivity (attomole-zeptomole), high selectivity, speed and simplicity. In biomedical research, the most important applications of BCL are: (1) to estimate microbial numbers and to assess cellular states (e.g., after exposure to antibiotic or cytotoxic agents) and in reporter gene studies (firefly luciferase gene); (2) NAD(P)H involved in redox/dehydrogenase studies usingVibrio luciferase complex; (3) BCL labels and CL detection of enzyme labels in immunoassays are the most widespread routine application for this technology. BCL enzyme immunoassays represent the most active area of development, e.g., enhanced BCL method for peroxidase and BCL assays for alkaline phosphatase labels using adamantyl 1,2-dioxetane.Abbreviations BCL biochemiluminescence - CL chemiluminescence - RLU relative light unit - ROS reactive oxygen species     

Fine-tuning of protein domain boundary by minimizing potential coiled coil regions

Structural determination of individual protein domains isolated from multidomain proteins is a common approach in the post-genomic era. Novel and thus uncharacterized domains liberated from intact proteins often self-associate due to incorrectly defined domain boundaries. Self-association results in missing signals, poor signal dispersion and a low signal-to-noise ratio in ¹H–¹⁵N HSQC spectra. We have found that a putative, non-canonical coiled coil region close to a domain boundary can cause transient hydrophobic self-association and monomer–dimer equilibrium in solution. Here we propose a rational method to predict putative coiled coil regions adjacent to the globular core domain using the program COILS. Except for the amino acid sequence, no preexisting knowledge concerning the domain is required. A small number of mutant proteins with a minimized coiled coil region have been rationally designed and tested. The engineered domains exhibit decreased self-association as assessed by ¹H–¹⁵N HSQC spectra with improved peak dispersion and sharper cross peaks. Two successful examples of isolating novel N-terminal domains from AAA-ATPases are demonstrated. Our method is useful for the experimental determination of domain boundaries suited for structural genomics studies. Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .     

Ethics and biomedical research

Ethics in biomedical research took off from the 1947 Nuremberg Code to its own right in the wake of the Declaration of Helsinki in 1964. Since then, (inter)national regulations and guidelines providing a framework for clinical studies and protection for study participants have been drafted and implemented, while ethics committees and drug evaluation agencies have sprung up throughout the world. These two developments were crucial in bringing about the protection of rights and safety of the participants and harmonization of the conduct of biomedical research. Ethics committees and drug evaluation agencies deliver ethical and scientific assessments on the quality and safety of the projects submitted to them and issue respectively approvals and authorizations to carry out clinical trials, while ensuring that they comply with regulatory requirements, ethical principles, and scientific guidelines. The advent of biomedical ethics, together with the responsible commitment of clinical investigators and of the pharmaceutical industry, has guaranteed respect for the patient, for whom and with whom research is conducted. Just as importantly, it has also ensured that patients reap the benefit of what is the primary objective of biomedical research: greater life expectancy, well-being, and quality of life.     

Sexual ambiguity and a non-fluorescent Y chromosome

The personal experience in three patients with ambiguous external genitalia and 45,X/46,XYnf karyotype is reported. The different clinical and cytogenetic aspects of this entity are described and discussed.     

SNPtoGO: characterizing SNPs by enriched GO terms

For the analysis of complex polygenic diseases, one does not expect all patients to share the same disease-associated alleles. Not even will disease-causing variations be assigned to the identical sets of genes between patients. However, one does expect overlaps in the sets of genes that are involved and even more so in their assigned molecular processes. Furthermore, the assignment of single nucleotide polymorphisms (SNPs) to genes is highly ambiguous for intergenic SNPs. The tool presented here hence adds external information, i.e. GeneOntology (GO) terms (Gene Ontology Consortium), to the analysis of SNP data. AVAILABILITY: A web interface and source code are offered at https://webtools.imbs.uni-luebeck.de/snptogo     

Normalizing Off-Label Experiments and the Pharmaceuticalization of Homebirths in Pakistan

Abstract

The off-label use of the drug misoprostol has effectively turned homebirths in ‘resource-poor’ nations into unmarked and un-enunciated zones of experimentation. Misoprostol has become the public health solution in response to medico-humanitarian discourses that construct homebirths as responsible for high maternal mortality. In the absence of proper safety tests, advocating its routine administration against postpartum haemorrhage in homes around Pakistan functions to erase the distinction between service delivery projects and experimentation. Drawing on ethnographic research in Balochistan, I argue that promoting misoprostol in contexts of structural inequality, particularly where excessive artificial labour induction prevails, constitutes the enactment of a kind of ‘medical relativism’. This medical relativism entails an experimental practice that burdens poor women with undue risk as misoprostol becomes a substitute for required structural and economic transformation of Pakistan's healthcare system. Overall, the paper concludes, the contemporary faith in pharmaceuticals perpetuates a colonial governmentality of bodies, medicines, and healthcare.     

Qualitative stability and ambiguity in model ecosystems

Qualitative analysis of stability in model ecosystems has previously been limited to determining whether a community matrix is sign stable or not with little analytical means to assess the impact of complexity on system stability. Systems are seen as either unconditionally or conditionally stable with little distinction and therefore much ambiguity in the likelihood of stability. First, we reexamine Hurwitz's principal theorem for stability and propose two "Hurwitz criteria" that address different aspects of instability: positive feedback and insufficient lower-level feedback. Second, we derive two qualitative metrics based on these criteria: weighted feedback (wF(n)) and weighted determinants (wDelta(n)). Third, we test the utility of these qualitative metrics through quantitative simulations in a random and evenly distributed parameter space in models of various sizes and complexities. Taken together they provide a practical means to assess the relative degree to which ambiguity has entered into calculations of stability as a result of system structure and complexity. From these metrics we identify two classes of models that may have significant relevance to system research and management. This work helps to resolve some of the impasse between theoretical and empirical discussions on the complexity and stability of natural communities.     

Chitosan derivatives obtained by chemical modifications for biomedical and environmental applications

Chitosan is a natural based polymer, obtained by alkaline deacetylation of chitin, which presents excellent biological properties such as biodegradability and immunological, antibacterial and wound-healing activity. Recently, there has been a growing interest in the chemical modification of chitosan in order to improve its solubility and widen its applications. The main chemical modifications of chitosan that have been proposed in the literature are reviewed in this paper. Moreover, these chemical modifications lead to a wide range of derivatives with a broad range of applications. Recent and relevant examples of the distinct applications, with particular emphasis on tissue engineering, drug delivery and environmental applications, are presented.     

Chimpanzees and bonobos distinguish between risk and ambiguity

Although recent research has investigated animal decision-making under risk, little is known about how animals choose under conditions of ambiguity when they lack information about the available alternatives. Many models of choice behaviour assume that ambiguity does not impact decision-makers, but studies of humans suggest that people tend to be more averse to choosing ambiguous options than risky options with known probabilities. To illuminate the evolutionary roots of human economic behaviour, we examined whether our closest living relatives, chimpanzees (Pan troglodytes) and bonobos (Pan paniscus), share this bias against ambiguity. Apes chose between a certain option that reliably provided an intermediately preferred food type, and a variable option that could vary in the probability that it provided a highly preferred food type. To examine the impact of ambiguity on ape decision-making, we interspersed trials in which chimpanzees and bonobos had no knowledge about the probabilities. Both species avoided the ambiguous option compared with their choices for a risky option, indicating that ambiguity aversion is shared by humans, bonobos and chimpanzees.