"Missing" G x E Variation Controls Flowering Time in Arabidopsis thaliana

Understanding how genetic variation interacts with the environment is essential for understanding adaptation. In particular, the life cycle of plants is tightly coordinated with local environmental signals through complex interactions with the genetic variation (G x E). The mechanistic basis for G x E is almost completely unknown. We collected flowering time data for 173 natural inbred lines of Arabidopsis thaliana from Sweden under two growth temperatures (10°C and 16°C), and observed massive G x E variation. To identify the genetic polymorphisms underlying this variation, we conducted genome-wide scans using both SNPs and local variance components. The SNP-based scan identified several variants that had common effects in both environments, but found no trace of G x E effects, whereas the scan using local variance components found both. Furthermore, the G x E effects appears to be concentrated in a small fraction of the genome (0.5%). Our conclusion is that G x E effects in this study are mostly due to large numbers of allele or haplotypes at a small number of loci, many of which correspond to previously identified flowering time genes.     

Genetic homogeneity/heterogeneity of Propionibacterium acnes isolated from patients during cardiothoracic reoperation

Following cardiothoracic surgery, deep sternal wound infection (SWI) remains one of the most severe complications. Recently, Propionibacterium acnes has been suspected as an etiological agent of deep SWI. However, this bacterium constitutes part of the resident micro-flora of the human skin. Consequently, findings of P. acnes in invasive samples are difficult to value. The aims of this study were to develop and optimize a pulsed-field gel electrophoresis (PFGE) protocol for P. acnes, in order to investigate the genetic homogeneity/heterogeneity of P. acnes isolates from multiple tissue samples (predominantly biopsies), collected at different locations, from 12 patients during cardiothoracic reoperation. There were 24 distinguishable PFGE fingerprints identified among the P. acnes isolates (n=54). Five (42%) of the patients carried only isolates that were interpreted as presumably clonally related. From the remaining seven patients, two or three different P. acnes clones were cultured, however, from six of them, the clones were identified in multiple samples. P. acnes may be a relatively frequent etiological agent of postoperative cardiothoracic infections. Existence of several clonally related P. acnes isolates derived from multiple samples from patients suffering from deep SWI after cardiothoracic surgery has not previously been shown.     

Proteomics in prostate cancer research

The incidence of early prostate cancer (PCa) among middle-aged men has increased rapidly. For many of these men, curatively intended treatment does more harm than good. Established prognostic factors are tumor stage and grade. As a result of earlier detection a majority of patients now have nonpalpable tumors (T1c) of intermediate grade (Gleason score 6). Prostate specific antigen in serum in such cases is generally at a low level and not a reliable predictor of prognosis. Altogether there is an urgent need for adjunctive prognostic indicators. In the search for relevant tumor markers for improved patient selection an exploration of the proteome (the human proteins) could be fruitful. This paper critically reviews the use of 2-dimensional gel electrophoresis (2-DE) for proteome research. Additional steps such as image analysis and mass spectrometry are described. Techniques based on non-2-DE platforms: surface-enhanced laser desorption/ionization (SELDI), isotope coded affinity tags (ICAT) and array-based technologies are also summarized. Although labor-intensive and time-consuming, 2-DE is presently the most powerful method for analysis of cellular protein phenotype and may potentially reveal gene regulations that cannot be detected on a genetic level.     

Up-regulation of alpha1-microglobulin by hemoglobin and reactive oxygen species in hepatoma and blood cell lines

alpha(1)-Microglobulin is a 26-kDa glycoprotein synthesized in the liver, secreted to the blood, and rapidly distributed to the extravascular compartment of all tissues. Recent results show that alpha(1)-microglobulin has heme-binding and heme-degrading properties and it has been suggested that the protein is involved in the defense against oxidation by heme and reactive oxygen species. In the present study the influence of hemoglobin and reactive oxygen species (ROS) on the cellular expression of alpha(1)-microglobulin was investigated. Oxy- and methemoglobin, free heme, and Fenton reaction-induced hydroxyl radicals induced a dose-dependent up-regulation of alpha(1)-microglobulin on both mRNA and protein levels in hepatoma cells and an increased secretion of alpha(1)-microglobulin. The up-regulation was reversed by the addition of catalase and ascorbate, and by reacting hemoglobin with cyanide which prevents redox reactions. Furthermore, the blood cell lines U937 and K562 expressed alpha(1)-microglobulin at low levels, and this expression increased up to 11-fold by the addition of hemoglobin. These results suggest that alpha(1)-microglobulin expression is induced by ROS, arising from redox reactions of hemoglobin or from other sources and are consistent with the hypothesis that alpha(1)-microglobulin participates in the defense against oxidation by hemoglobin, heme, and reactive oxygen species.     

Malleability of protein folding pathways: a simple reason for complex behaviour

Although the structures of native proteins are generally unique, the pathways by which they form are often free to vary. Some proteins fold by a multitude of different pathways, whereas others seem restricted to only one choice. An explanation for this variation in folding behaviour has recently emerged from studies of transition state changes: the number of accessible pathways is linked to the number of nucleation motifs contained within the native topology. We refer to these nucleation motifs as 'foldons', as they approach the size of an independent cooperative unit. Thus, with respect to pathway malleability and the composition of the folding funnel, proteins can be seen as modular assemblies of competing foldons. For the split beta-alpha-beta fold, these foldons are two-strand-helix motifs coupled by spatial overlap.     

Discovery and SAR studies of novel GlyT1 inhibitors

Inhibition of the glycine transporter GlyT1 is a potential strategy for the treatment of schizophrenia. A novel series of GlyT1 inhibitors and their structure-activity relationships (SAR) are described. Members of this series are highly potent and selective transport inhibitors which are shown to elevate glycine levels in cerebrospinal fluid.     

How training and testing histories affect generalization: a test of simple neural networks

We show that a simple network model of associative learning can reproduce three findings that arise from particular training and testing procedures in generalization experiments: the effect of (i) 'errorless learning', (ii) extinction testing on peak shift, and (iii) the central tendency effect. These findings provide a true test of the network model which was developed to account for other phenomena, and highlight the potential of neural networks to study the phenomena that depend on sequences of experiences with many stimuli. Our results suggest that at least some such phenomena, e.g. stimulus range effects, may derive from basic mechanisms of associative memory rather than from more complex memory processes.     

Binding of ring-substituted indole-3-acetic acids to human serum albumin

The plant hormone, indole-3-acetic acid (IAA), and its ring-substituted derivatives have recently attracted attention as promising pro-drugs in cancer therapy. Here we present relative binding constants to human serum albumin for IAA and 34 of its derivatives, as obtained using the immobilized protein bound to a support suitable for high-performance liquid chromatography. We also report their octanol-water partition coefficients (logK(ow)) computed from retention data on a C(18) coated silica gel column. A four-parameter QSPR (quantitative structure-property relationships) model, based on physico-chemical properties, is put forward, which accounts for more than 96% of the variations in the binding affinities of these compounds. The model confirms the importance of lipophilicity as a global parameter governing interaction with serum albumin, but also assigns significant roles to parameters specifically related to the molecular topology of ring-substituted IAAs. Bulky substituents at ring-position 6 increase affinity, those at position 2 obstruct binding, while no steric effects were noted at other ring-positions. Electron-withdrawing substituents at position 5 enhance binding, but have no obvious effect at other ring positions.