The quest for a humanori

Attempts at identifying DNA replication origins in human cells have been performed with a variety of molecular genetic and biochemical approaches, with often controversial results.The combination of bromodeoxyuridine labelling, immunopurification of newly synthesized labelled DNA, measurement of the relative abundance of markers in this DNA by quantitative competitive PCR, has allowed the identification within 450 bp of the start-site of DNA replication located at the human lamin B2 gene. The origin is located near the non-transcribed spacer between two highly transcribed genes and shows evidence of a number of specific protein-DNA interactions, the most prominent of which disappears when the cells are differentiated into a non-proliferating state.     

The common patterns of nature

We typically observe large‐scale outcomes that arise from the interactions of many hidden, small‐scale processes. Examples include age of disease onset, rates of amino acid substitutions and composition of ecological communities. The macroscopic patterns in each problem often vary around a characteristic shape that can be generated by neutral processes. A neutral generative model assumes that each microscopic process follows unbiased or random stochastic fluctuations: random connections of network nodes; amino acid substitutions with no effect on fitness; species that arise or disappear from communities randomly. These neutral generative models often match common patterns of nature. In this paper, I present the theoretical background by which we can understand why these neutral generative models are so successful. I show where the classic patterns come from, such as the Poisson pattern, the normal or Gaussian pattern and many others. Each classic pattern was often discovered by a simple neutral generative model. The neutral patterns share a special characteristic: they describe the patterns of nature that follow from simple constraints on information. For example, any aggregation of processes that preserves information only about the mean and variance attracts to the Gaussian pattern; any aggregation that preserves information only about the mean attracts to the exponential pattern; any aggregation that preserves information only about the geometric mean attracts to the power law pattern. I present a simple and consistent informational framework of the common patterns of nature based on the method of maximum entropy. This framework shows that each neutral generative model is a special case that helps to discover a particular set of informational constraints; those informational constraints define a much wider domain of non‐neutral generative processes that attract to the same neutral pattern.     

The quest for the Holy Grail: a disease-modifying osteoarthritis drug

The unfortunate story of the matrix metalloproteinase inhibitor PG116800, which had no effect on the osteoarthritic process but had unexpected side effects, highlights the following. First, reality does not always match the theory. Second, cell biology data must be interpreted within the context of a specific environment. Third, the specificity of an enzyme inhibitor is always relative. Finally, a critical evaluation of the benefit/risk ratio of a drug must be carefully conducted and checked before and after launch. Well designed post-marketing surveillance is mandatory.     

The quest for florigen: a review of recent progress

The photoperiodic induction of flowering is a systemic process requiring translocation of a floral stimulus from the leaves to the shoot apical meristem. In response to this stimulus, the apical meristem stops producing leaves to initiate floral development; this switch in morphogenesis involves a change in the identity of the primordia initiated and in phyllotaxis. The physiological study of the floral transition has led to the identification of several putative floral signals such as sucrose, cytokinins, gibberellins, and reduced N-compounds that are translocated in the phloem sap from leaves to the shoot apical meristem. On the other hand, the genetic approach developed more recently in Arabidopsis thaliana allowed the discovery of many genes that control flowering time. These genes function in 'cascades' within four promotive pathways, the 'photoperiodic', 'autonomous', 'vernalization', and 'gibberellin' pathways, which all converge on the 'integrator' genes SUPPRESSOR OF OVEREXPRESSION OF CO 1 (SOC1) and FLOWERING LOCUS T (FT). Recently, several studies have highlighted a role for a product of FT as a component of the floral stimulus or 'florigen'. These recent advances and the proposed mode of action of FT are discussed here.     

X chromosome monosomy: a common mechanism for autoimmune diseases

The majority of human autoimmune diseases are characterized by female predominance. Although sex hormone influences have been suggested to explain this phenomenon, the mechanism remains unclear. In contrast to the role of hormones, it has been suggested, based on pilot data in primary biliary cirrhosis, that there is an elevation of monosomy X in autoimmune disease. Using peripheral white blood cells from women with systemic sclerosis (SSc), autoimmune thyroid disease (AITD), or healthy age-matched control women, we studied the presence of monosomy X rates using fluorescence in situ hybridization. We also performed dual-color fluorescence in situ hybridization analysis with a chromosome Y alpha-satellite probe to determine the presence of the Y chromosome in the monosomic cells. In subsets of patients and controls, we determined X monosomy rates in white blood cell subpopulations. The rates of monosomy X increased with age in all three populations. However, the rate of monosomy X was significantly higher in patients with SSc and AITD when compared with healthy women (6.2 +/- 0.3% and 4.3 +/- 0.3%, respectively, vs 2.9 +/- 0.2% in healthy women, p < 0.0001 in both comparisons). Importantly, X monosomy rate was more frequent in peripheral T and B lymphocytes than in the other blood cell populations, and there was no evidence for the presence of male fetal microchimerism. These data highlight the thesis that chromosome instability is common to women with SSc and AITD and that haploinsufficiency for X-linked genes may be a critical factor for the female predominance of autoimmune diseases.     

The quest for the mechanisms of life

The genomic revolution, manifested by the sequencing of the complete genome of many organisms, along with technological advances, such as DNA microarrays and developments in high-throughput analysis of proteins, metabolites, and isotopic tracer distribution patterns, challenged the conventional ways in which questions are approached in the biological sciences: (a) rather than examining a small number of genes and/or reactions at any one time;, we can now analyze gene expression and protein activity in the context of systems of interacting genes and gene products; (b) comprehensive analysis of biological systems requires the integration of all cellular fingerprints: genome sequence, maps of gene expression, protein expression, metabolic output, and in vivo enzymatic activity; and (c) collecting, managing, and analyzing comparable data from various cellular profiles requires expertise from several fields that transcend traditional discipline boundaries. While researchers in systems biology have still to address difficult challenges in both experimental and computational arenas, they possess, for the first time, the opportunity to unravel the mechanisms of life. The enormous impact of these discoveries in diverse areas, such as metabolic engineering, strain selection, drug screening and development, bioprocess development, disease prognosis and diagnosis, gene and other medical therapies, is an obvious motivation for pursuing integrated analyses of cellular systems.     

The quest for a tumor suppressor gene phenotype

Our current definitions of the tumor suppressor gene (TSG) have been guided by the identification of the prototypical gene, RB1, a TSG that is implicated in the development of both the inherited and sporadic forms of retinoblastoma. The hallmark feature of this TSG is loss of function in tumoral cells, which can be restored by reintroduction of a normally functioning protein with concomitant reversion of tumorigenicity. Key to this discovery was that loss of function is often achieved by deletion of a normal copy of the TSG and retention of a mutated allele, which was either inherited or acquired. Suppression of tumorigenicity and the loss-of-function concept of TSGs was also demonstrated in early studies where normal cellular growth was achieved when tumorigenic cells were fused with normal cells. Thus loss of genetic content and restoration of gene function has guided studies aimed at the discovery of novel TSGs. Here we review the successes of TSG discovery using three approaches that are based on the genetic analysis of inherited predisposition to cancer, tumors that display chromosome loss, and tumorigenic cells that display a suppression of tumorigenicity as a result of transfer of normal chromosomes. Based on a review of the literature we conclude that the discovery of TSGs has been highly successful in the genetic analysis of inherited predisposition to cancer with a dominant mode of inheritance. In contrast, the latter two approaches have yielded a paucity of TSGs that exhibit features similar to the prototypical RB1 in that they are rarely inactivated by somatic mutations in tumors displaying LOH, although decreased gene expression is observed. Nevertheless, some of these genes have been shown to suppress tumorigenicity when normal function is restored in tumorigenic cells consistent with the loss-of-function concept. These observations continue to challenge our current definition of TSG.     

Flectofin: a hingeless flapping mechanism inspired by nature

This paper presents a novel biomimetic approach to the kinematics of deployable systems for architectural purposes. Elastic deformation of the entire structure replaces the need for local hinges. This change becomes possible by using fibre-reinforced polymers (FRP) such as glass fibre reinforced polymer (GFRP) that can combine high tensile strength with low bending stiffness, thus offering a large range of calibrated elastic deformations. The employment of elasticity within a structure facilitates not only the generation of complex geometries, but also takes the design space a step further by creating elastic kinetic structures, here referred to as pliable structures. In this paper, the authors give an insight into the abstraction strategies used to derive elastic kinetics from plants, which show a clear interrelation of form, actuation and kinematics. Thereby, the focus will be on form-finding and simulation methods which have been adopted to generate a biomimetic principle which is patented under the name Flectofin?. This bio inspired hingeless flapping device is inspired by the valvular pollination mechanism that was derived and abstracted from the kinematics found in the Bird-Of-Paradise flower (Strelitzia reginae, Strelitziaceae).     

The quest for a biomarker of circulating osteoclast precursors

Osteoclast precursors arise from the CD14+ CD16- population in controls but details about cell surface marker expression and functional characteristics of these cells is unknown, particularly in patients with inflammatory arthritis. In a recent issue of Arthritis, Research and Therapy, Lari and colleagues found that osteoclasts developed from a proliferative CD14+ CD16- subset in healthy controls. These cells took on the morphology of osteoclasts, expressed mRNA for osteoclast-related genes and excavated pits on bone wafers. These findings provide new insights into monocyte diversity and provide evidence that osteoclast precursors arise from a small proliferating monocyte population in controls. Additional studies are needed in patients with inflammatory arthritis     

The quest for the ancestor of the Ciliophora: a brief review of the continuing problem

Although the assumption has long been made that the Ciliophora arose from flagellates, limited progress has been made in determining exactly what extant group - flagellate or other - may best resemble the ancestral "preciliate" assemblage. The distinctiveness of the ciliates and of the many protist phyla containing flagellated stages in their life cycles makes the recognition of potentially homologous features difficult. The suggestion that there may be a phylogenetic relationship between dinoflagellates and ciliates, while seeming unlikely from consideration of a number of specialized characters, is attracting increased attention. This is because some basic similarities (possibly shared derived characters) are characteristic of many species from both groups: cortical alveoli, tubular mitochondrial cristae, kinetidal systems, acentric mitoses with persisting nuclear envelope, functional cytostome, extrusomes (mucocytsts and explosive trichocysts), locomotory organelles, and small subunit rRNAs (close structural similarity values). But many questions remain unanalyzed or unanswered, and caution is still advisable in drawing any firm conclusions about the evolutionary closeness of ciliates and dinoflagellates.     

Group selection: The quest for social preferences

This paper surveys the literature on group selection. I describe the early contributions and the group selection controversy. I also describe the main approaches to group selection in the recent literature; fixation, assortative group formation, and reproductive externalities.     

Autism: the quest for the genes

Autism, at its most extreme, is a severe neurodevelopmental disorder, and recent studies have indicated that autism spectrum disorders are considerably more common than previously supposed. However, although one of the most heritable neuropsychiatric syndromes, autism has so far eluded attempts to discover its genetic origins in the majority of cases. Several whole-genome scans for autism-susceptibility loci have identified specific chromosomal regions, but the results have been inconclusive and fine mapping and association studies have failed to identify the underlying genes. Recent advances in knowledge from the Human Genome and HapMap Projects, and progress in technology and bioinformatic resources, have aided study design and made data generation more efficient and cost-effective. Broadening horizons about the landscape of structural genetic variation and the field of epigenetics are indicating new possible mechanisms underlying autism aetiology, while endophenotypes are being used in an attempt to break down the complexity of the syndrome and refine genetic data. Although the genetic variants underlying idiopathic autism have proven elusive so far, the future for this field looks promising.     

The quest for quantitative microscopy

With the aid of informatics, microscopy is in the midst of a crucial evolution into a more quantitative and powerful technique.