Biological and psychological rhythms: An integrative approach to rhythm disturbances in autistic disorder

Biological rhythms are crucial phenomena that are perfect examples of the adaptation of organisms to their environment. A considerable amount of work has described different types of biological rhythms (from circadian to ultradian), individual differences in their patterns and the complexity of their regulation. In particular, the regulation and maturation of the sleep–wake cycle have been thoroughly studied. Its desynchronization, both endogenous and exogenous, is now well understood, as are its consequences for cognitive impairments and health problems. From a completely different perspective, psychoanalysts have shown a growing interest in the rhythms of psychic life. This interest extends beyond the original focus of psychoanalysis on dreams and the sleep–wake cycle, incorporating central theoretical and practical psychoanalytic issues related to the core functioning of the psychic life: the rhythmic structures of drive dynamics, intersubjective developmental processes and psychic containment functions. Psychopathological and biological approaches to the study of infantile autism reveal the importance of specific biological and psychological rhythmic disturbances in this disorder. Considering data and hypotheses from both perspectives, this paper proposes an integrative approach to the study of these rhythmic disturbances and offers an etiopathogenic hypothesis based on this integrative approach.     

Challenges and solutions in proteomics

The accelerated growth of proteomics data presents both opportunities and challenges. Large-scale proteomic profiling of biological samples such as cells, organelles or biological fluids has led to discovery of numerous key and novel proteins involved in many biological/disease processes including cancers, as well as to the identification of novel disease biomarkers and potential therapeutic targets. While proteomic data analysis has been greatly assisted by the many bioinformatics tools developed in recent years, a careful analysis of the major steps and flow of data in a typical highthroughput analysis reveals a few gaps that still need to be filled to fully realize the value of the data. To facilitate functional and pathway discovery for large-scale proteomic data, we have developed an integrated proteomic expression analysis system, iProXpress, which facilitates protein identification using a comprehensive sequence library and functional interpretation using integrated data. With its modular design, iProXpress complements and can be integrated with other software in a proteomic data analysis pipeline. This novel approach to complex biological questions involves the interrogation of multiple data sources, thereby facilitating hypothesis generation and knowledge discovery from the genomic-scale studies and fostering disease diagnosis and drug development.     

The Lomb-Scargle Periodogram in Biological Rhythm Research: Analysis of Incomplete and Unequally Spaced Time-Series

This paper investigates the utility of the Lomb–Scargle periodogram for the analysis of biological rhythms. This method is particularly suited to detect periodic components in unequally sampled time-series and data sets with missing values, but restricts all calculations to actually measured values. The Lomb-Scargle method was tested on both real and simulated time-series with even and uneven sampling, and compared to a standard method in biomedical rhythm research, the Chi-square periodogram. Results indicate that the Lomb–Scargle algorithm shows a clearly better detection efficiency and accuracy in the presence of noise, and avoids possible bias or erroneous results that may arise from replacement of missing data by interpolation techniques. Hence, the Lomb–Scargle periodogram may serve as a useful method for the study of biological rhythms, especially when applied to telemetrical or observational time-series obtained from free-living animals, i.e., data sets that notoriously lack points.     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

The Lomb-Scargle Periodogram in Biological Rhythm Research: Analysis of Incomplete and Unequally Spaced Time-Series

This paper investigates the utility of the Lomb-Scargle periodogram for the analysis of biological rhythms. This method is particularly suited to detect periodic components in unequally sampled time-series and data sets with missing values, but restricts all calculations to actually measured values. The Lomb-Scargle method was tested on both real and simulated time-series with even and uneven sampling, and compared to a standard method in biomedical rhythm research, the Chi-square periodogram. Results indicate that the Lomb-Scargle algorithm shows a clearly better detection efficiency and accuracy in the presence of noise, and avoids possible bias or erroneous results that may arise from replacement of missing data by interpolation techniques. Hence, the Lomb-Scargle periodogram may serve as a useful method for the study of biological rhythms, especially when applied to telemetrical or observational time-series obtained from free-living animals, i.e., data sets that notoriously lack points.     

Rhythms and Community Dynamics of a Hydrothermal Tubeworm Assemblage at Main Endeavour Field – A Multidisciplinary Deep-Sea Observatory Approach

The NEPTUNE cabled observatory network hosts an ecological module called TEMPO-mini that focuses on hydrothermal vent ecology and time series, granting us real-time access to data originating from the deep sea. In 2011–2012, during TEMPO-mini’s first deployment on the NEPTUNE network, the module recorded high-resolution imagery, temperature, iron (Fe) and oxygen on a hydrothermal assemblage at 2186 m depth at Main Endeavour Field (North East Pacific). 23 days of continuous imagery were analysed with an hourly frequency. Community dynamics were analysed in detail for Ridgeia piscesae tubeworms, Polynoidae, Pycnogonida and Buccinidae, documenting faunal variations, natural change and biotic interactions in the filmed tubeworm assemblage as well as links with the local environment. Semi-diurnal and diurnal periods were identified both in fauna and environment, revealing the influence of tidal cycles. Species interactions were described and distribution patterns were indicative of possible microhabitat preference. The importance of high-resolution frequencies (<1 h) to fully comprehend rhythms in fauna and environment was emphasised, as well as the need for the development of automated or semi-automated imagery analysis tools.     

Early and late renin and ANP modifications induced by bedrest

A number of studies have been devoted to better understand the cardiovascular adaptation to space flights. These studies included hemodynamic and hormonal studies, but few investigations of the rhythms exist in the literature. However, the importance of the modifications of rhythms in true or simulated weightlessness was underlined in some published works. Several factors are probably associated to modify the circadian rhythms. First, there is a reduction or an absence of gravity, an important environmental factor: second, space missions or bed rest simulations are conducted under confinement conditions which may influence many psychological functions. The resulting instability of the circadian state will affect other physiological systems, because circadian variations are a fundamental feature of many biological systems (sleep, endocrine and cardiovascular functions). The present study was undertaken to study the effect of as well as a continuous 28-day bed rest on the rhythms of circulating PRA and ANP, the modification of rhythmicity of systolic and diastolic blood pressure and heart rate during bed rest.     

An intelligent biological information management system

MOTIVATION: As biomedical researchers are amassing a plethora of information in a variety of forms resulting from the advancements in biomedical research, there is a critical need for innovative information management and knowledge discovery tools to sift through these vast volumes of heterogeneous data and analysis tools. In this paper we present a general model for an information management system that is adaptable and scalable, followed by a detailed design and implementation of one component of the model. The prototype, called BioSifter, was applied to problems in the bioinformatics area. RESULTS: BioSifter was tested using 500 documents obtained from PubMed database on two biological problems related to genetic polymorphism and extracorporal shockwave lithotripsy. The results indicate that BioSifter is a powerful tool for biological researchers to automatically retrieve relevant text documents from biological literature based on their interest profile. The results also indicate that the first stage of information management process, i.e. data to information transformation, significantly reduces the size of the information space. The filtered data obtained through BioSifter is relevant as well as much smaller in dimension compared to all the retrieved data. This would in turn significantly reduce the complexity associated with the next level transformation, i.e. information to knowledge.     

Pathway analysis for genome-wide genetic variation data: Analytic principles,latest developments,and new opportunities

Pathway analysis, also known as gene-set enrichment analysis, is a multilocus analytic strategy that integrates a priori, biological knowledge into the statistical analysis of high-throughput genetics data. Originally developed for the studies of gene expression data, it has become a powerful analytic procedure for indepth mining of genome-wide genetic variation data. Astonishing discoveries were made in the past years,uncovering genes and biological mechanisms underlying common and complex disorders. However, as massive amounts of diverse functional genomics data accrue, there is a pressing need for newer generations of pathway analysis methods that can utilize multiple layers of high-throughput genomics data. In this review, we provide an intellectual foundation of this powerful analytic strategy, as well as an update of the state-of-the-art in recent method developments. The goal of this review is threefold:(1) introduce the motivation and basic steps of pathway analysis for genome-wide genetic variation data;(2) review the merits and the shortcomings of classic and newly emerging integrative pathway analysis tools; and(3)discuss remaining challenges and future directions for further method developments.     

A clockwork mollusc: Ultradian rhythms in bivalve activity revealed by digital photography

Time-lapse digital images can be acquired and archived using web-cameras, allowing non-invasive analysis of behavior patterns of bivalve molluscs at ultradian (sub-daily) time-scales over long intervals. These records can be analyzed directly by a human operator or through properly calibrated image analysis software. Preliminary results using species of marine and freshwater bivalves identify several ultradian biological rhythms of similar duration. Wavelet analysis indicates strong periodicity in mantle and siphon activity in the 3 to 7 min range, with longer duration shell contraction periods at 60-90 min. The recurrence of these rhythms among marine and freshwater bivalve species maintained under constant (but differing) conditions suggests the influence of common intrinsic drivers (chemico-physical mechanisms or biological clocks). Sub-daily growth increments preserved in the shells of rapidly growing bivalve species are potentially related to these biological rhythms, with implications for shell growth, biomineralization, and the temporal resolution of paleoclimate proxy data.     

The European Bioinformatics Institute's data resources

As the amount of biological data grows, so does the need for biologists to store and access this information in central repositories in a free and unambiguous manner. The European Bioinformatics Institute (EBI) hosts six core databases, which store information on DNA sequences (EMBL-Bank), protein sequences (SWISS-PROT and TrEMBL), protein structure (MSD), whole genomes (Ensembl) and gene expression (ArrayExpress). But just as a cell would be useless if it couldn't transcribe DNA or translate RNA, our resources would be compromised if each existed in isolation. We have therefore developed a range of tools that not only facilitate the deposition and retrieval of biological information, but also allow users to carry out searches that reflect the interconnectedness of biological information. The EBI's databases and tools are all available on our website at www.ebi.ac.uk.     

Routine libraries for pattern recognition in quasispecies

The results obtained through biological research usually need to be analyzed using computational tools, since manual analysis becomes unfeasible due to the complexity and size of these results. For instance, the study of quasispecies frequently demands the analysis of several, very lengthy sequences of nucleotides and amino acids. Therefore, bioinformatics tools for the study of quasispecies are constantly being developed due to different problems found by biologists. In the present study, we address the development of a software tool for the evaluation of population diversity in quasispecies. Special attention is paid to the localization of genome regions prone to changes, as well as of possible hot spots.     

Automated system for gene annotation and metabolic pathway reconstruction using general sequence databases

Despite the growing number of genomes published or currently being sequenced, there is a relative paucity of software for functional classification of newly discovered genes and their assignment to metabolic pathways. Available software for such analyses has a very steep learning curve and requires the installation, configuration, and maintenance of large amounts of complex infrastructure, including complementary software and databases. Many such tools are restricted to one or a few data sources and classification schemes. In this work, we report an automated system for gene annotation and metabolic pathway reconstruction (ASGARD), which was designed to be powerful and generalizable, yet simple for the biologist to install and run on centralized, commonly available computers. It avoids the requirement for complex resources such as relational databases and web servers, as well as the need for administrator access to the operating system. Our methodology contributes to a more rapid investigation of the potential biochemical capabilities of genes and genomes by the biological researcher, and is useful in biochemical as well as comparative and evolutionary studies of pathways and networks.     

Cephalo-adrenal interactions in the broader context of pragmatic and theoretical rhythm models

Some of the literature on modeling of biological rhythms with mathematical, physical, chemical, biochemical, in vivo and in vitro oscillations is succintly annotated. The need for biologic models that account for the interaction of 3 or more periodic entities is indicated, documented and illustrated, with emphasis on the cephalo-adrenal network of rodents. Patterns of interaction, in this context, involve attenuation, no-effect and/or amplification by a third entity, the modulator, of the effect of an actor upon the reactor. Such feedsidewards lead to chronomodulation, a phenomenon accounting for qualitatively as well as quantitatively different modulatory effects of the same drug or other stimulus. Controversies of long standing can thus be resolved and novel effects uncovered.     

PHOENIX, a web interface for (re)analysis of microarray data

Microarrays are tools to study the expression profile of an entire genome. Technology, statistical tools and biological knowledge in general have evolved over the past ten years and it is now possible to improve analysis of previous datasets. We have developed a web interface called PHOENIX that automates the analysis of microarray data from preprocessing to the evaluation of significance through manual or automated parameterization. At each analytical step, several methods are possible for (re)analysis of data. PHOENIX evaluates a consensus score from several methods and thus determines the performance level of the best methods (even if the best performing method is not known). With an estimate of the true gene list, PHOENIX can evaluate the performance of methods or compare the results with other experiments. Each method used for differential expression analysis and performance evaluation has been implemented in the PEGASE back-end package, along with additional tools to further improve PHOENIX. Future developments will involve the addition of steps (CDF selection, geneset analysis, meta-analysis), methods (PLIER, ANOVA, Limma), benchmarks (spike-in and simulated datasets), and illustration of the results (automatically generated report).     

WinCD: Windows Software for Complex Demodulation

We describe WinCD, a program for extracting quantitative information about periodicity in time-series data using the method of complex demodulation (CD). The method is particularly well suited for the analysis of the effects of variables that may produce changes in biological rhythms, such as sleep deprivation, adaptation to changes in work schedules, time zone displacements, and various sorts of pathology. WinCD enables exploratory analysis of time series data by providing graphical displays of raw and processed time series, as well as numerous options for viewing and saving quantitative data. We describe WinCD operations and examples of the use of the program.