More than 80 years after iron accumulation was initially described in the substantia nigra (SN) of Parkinson's disease (PD) patients, the mechanisms responsible for this phenomenon are still unknown. Similarly, how iron is delivered to its major recipients in the cell - mitochondria and the respiratory complexes - has yet to be elucidated. Here, we report a novel transferrin/transferrin receptor 2 (Tf/TfR2)-mediated iron transport pathway in mitochondria of SN dopamine neurons. We found that TfR2 has a previously uncharacterized mitochondrial targeting sequence that is sufficient to import the protein into these organelles. Importantly, the Tf/TfR2 pathway can deliver Tf bound iron to mitochondria and to the respiratory complex I as well. The pathway is redox-sensitive and oxidation of Tf thiols to disulfides induces release from Tf of highly reactive ferrous iron, which contributes to free radical production. In the rotenone model of PD, Tf accumulates in dopamine neurons, with much of it accumulating in the mitochondria. This is associated with iron deposition in SN, similar to what occurs in PD. In the human SN, TfR2 is also found in mitochondria of dopamine neurons, and in PD there is a dramatic increase of oxidized Tf in SN. Thus, we have discovered a novel mitochondrial iron transport system that goes awry in PD, and which may provide a new target for therapeutic intervention.

We have previously proposed that intravascular thrombosis and subsequent vasoocclusion contribute to the development of pseudopalisading necrosis, a pathologic hallmark that distinguishes glioblastoma (WHO grade 4) from lower grade astrocytomas. To better understand the potential prothrombotic mechanisms underlying the formation of these structures that drive tumor angiogenesis, we investigated tissue factor (TF), a potent procoagulant protein known to be overexpressed in astrocytomas. We hypothesized that PTEN loss and tumor hypoxia, which characterize glioblastoma but not lower grade astrocytomas, could up-regulate TF expression and cause intravascular thrombotic occlusion. We examined the effect of PTEN restoration and hypoxia on TF expression and plasma coagulation using a human glioma cell line containing an inducible wt-PTEN cDNA. Cell exposure to hypoxia (1% O(2)) markedly increased TF expression, whereas restoration of wt-PTEN caused decreased cellular TF. The latter effect was at least partially dependent on PTEN's protein phosphatase activity. Hypoxic cells accelerated plasma clotting in tilt tube assays and this effect was prevented by both inhibitory antibodies to TF and plasma lacking factor VII, implicating TF-dependent mechanisms. To further examine the genetic events leading to TF up-regulation during progression of astrocytomas, we investigated its expression in a series of human astrocytes sequentially infected with E6/E7/human telomerase, Ras, and Akt. Cells transformed with Akt showed the greatest incremental increase in hypoxia-induced TF expression and secretion. Together, our results show that PTEN loss and hypoxia up-regulate TF expression and promote plasma clotting by glioma cells, suggesting that these mechanisms may underlie intravascular thrombosis and pseudopalisading necrosis in glioblastoma.

The aim of the present study was to investigate whether cyclic fatigue resistance is increased for nickel-titanium instruments manufactured by using new processes. This was evaluated by comparing instruments produced by using the twisted method (TF; SybronEndo, Orange, CA) and those using the M-wire alloy (GTX; Dentsply Tulsa-Dental Specialties, Tulsa, OK) with instruments produced by a traditional NiTi grinding process (K3, SybronEndo). Tests were performed with a specific cyclic fatigue device that evaluated cycles to failure of rotary instruments inside curved artificial canals. Results indicated that size 06-25 TF instruments showed a significant increase (p < 0.05) in the mean number of cycles to failure when compared with size 06-25 K3 files. Size 06-20 K3 instruments showed no significant increase (p>> 0.05) in the mean number of cycles to failure when compared with size 06-20 GT series X instruments. The new manufacturing process produced nickel-titanium rotary files (TF) significantly more resistant to fatigue than instruments produced with the traditional NiTi grinding process. Instruments produced with M-wire (GTX) were not found to be more resistant to fatigue than instruments produced with the traditional NiTi grinding process.

Although production of reactive oxygen species (ROS) such as superoxide (O(2)(.-)) has been implicated in chronic hypoxia-induced pulmonary hypertension (PH) and pulmonary vascular remodeling, the transcription factors and gene targets through which ROS exert their effects have not been completely identified. We used mice overexpressing the extracellular antioxidant enzyme extracellular superoxide dismutase (EC-SOD TG) to test the hypothesis that O(2)(.-) generated in the extracellular compartment under hypoxic conditions contributes to PH through the induction of the transcription factor, early growth response-1 (Egr-1), and its downstream gene target, tissue factor (TF). We found that chronic hypoxia decreased lung EC-SOD activity and protein expression in wild-type mice, but that EC-SOD activity remained five to seven times higher in EC-SOD TG mice under hypoxic conditions. EC-SOD overexpression attenuated chronic hypoxic PH, and vascular remodeling, measured by right ventricular systolic pressures, proliferation of cells in the vessel wall, muscularization of small pulmonary vessels, and collagen deposition. EC-SOD overexpression also prevented the early hypoxia-dependent upregulation of the redox-sensitive transcription factor Egr-1 and the procoagulant protein TF. These data provide the first evidence that EC-SOD activity is disrupted in chronic hypoxia, and increased EC-SOD activity can attenuate chronic hypoxic PH by limiting the hypoxic upregulation of redox-sensitive genes.

Oct4, Sox2, Klf4, and cMyc (OSKM) reprogram somatic cells to pluripotency. To gain a mechanistic understanding of their function, we mapped OSKM-binding, stage-specific transcription factors (TFs), and chromatin states in discrete reprogramming stages and performed loss- and gain-of-function experiments. We found that OSK predominantly bind active somatic enhancers early in reprogramming and immediately initiate their inactivation genome-wide by inducing the redistribution of somatic TFs away from somatic enhancers to sites elsewhere engaged by OSK, recruiting Hdac1, and repressing the somatic TF Fra1. Pluripotency enhancer selection is a stepwise process that also begins early in reprogramming through collaborative binding of OSK at sites with high OSK-motif density. Most pluripotency enhancers are selected later in the process and require OS and other pluripotency TFs. Somatic and pluripotency TFs modulate reprogramming efficiency when overexpressed by altering OSK targeting, somatic-enhancer inactivation, and pluripotency enhancer selection. Together, our data indicate that collaborative interactions among OSK and with stage-specific TFs direct both somatic-enhancer inactivation and pluripotency-enhancer selection to drive reprogramming.

Abiotic stresses such as high temperature, salinity, and drought adversely affect the survival, growth, and reproduction of plants. Plants respond to such unfavorable changes through developmental, physiological, and biochemical ways, and these responses require expression of stress-responsive genes, which are regulated by a network of transcription factors (TFs), including heat stress transcription factors (HSFs). HSFs play a crucial role in plants response to several abiotic stresses by regulating the expression of stress-responsive genes, such as heat shock proteins (Hsps). In this review, we describe the conserved structure of plant HSFs, the identification of HSF gene families from various plant species, their expression profiling under abiotic stress conditions, regulation at different levels and function in abiotic stresses. Despite plant HSFs share highly conserved structure, their remarkable diversification across plants reflects their numerous functions as well as their integration into the complex stress signaling and response networks, which can be employed in crop improvement strategies via biotechnological intervention.

Tissue factor (TF) is the high-affinity receptor and cofactor for factor (F)VII/VIIa. The TF-FVIIa complex is the primary initiator of blood coagulation and plays an essential role in hemostasis. TF is expressed on perivascular cells and epithelial cells at organ and body surfaces where it forms a hemostatic barrier. TF also provides additional hemostatic protection to vital organs, such as the brain, lung, and heart. Under pathological conditions, TF can trigger both arterial and venous thrombosis. For instance, atherosclerotic plaques contain high levels of TF on macrophage foam cells and microvesicles that drives thrombus formation after plaque rupture. In sepsis, inducible TF expression on monocytes leads to disseminated intravascular coagulation. In cancer patients, tumors release TF-positive microvesicles into the circulation that may contribute to venous thrombosis. TF also has nonhemostatic roles. For instance, TF-dependent activation of the coagulation cascade generates coagulation proteases, such as FVIIa, FXa, and thrombin, which induce signaling in a variety of cells by cleavage of protease-activated receptors. This review will focus on the roles of TF in protective hemostasis and pathological thrombosis.

Multiple transcription factors (TFs) play essential roles in plants under abiotic stress, but how these multiple TFs cooperate in abiotic stress responses remains largely unknown. In this study, we provide evidence that the NAC (for NAM, ATAF1/2, and CUC2) TF ANAC096 cooperates with the bZIP-type TFs ABRE binding factor and ABRE binding protein (ABF/AREB) to help plants survive under dehydration and osmotic stress conditions. ANAC096 directly interacts with ABF2 and ABF4, but not with ABF3, both in vitro and in vivo. ANAC096 and ABF2 synergistically activate RD29A transcription. Our genome-wide gene expression analysis revealed that a major proportion of abscisic acid (ABA)-responsive genes are under the transcriptional regulation of ANAC096. We found that the Arabidopsis thaliana anac096 mutant is hyposensitive to exogenous ABA and shows impaired ABA-induced stomatal closure and increased water loss under dehydration stress conditions. Furthermore, we found the anac096 abf2 abf4 triple mutant is much more sensitive to dehydration and osmotic stresses than the anac096 single mutant or the abf2 abf4 double mutant. Based on these results, we propose that ANAC096 is involved in a synergistic relationship with a subset of ABFs for the transcriptional activation of ABA-inducible genes in response to dehydration and osmotic stresses.

Chicken ovalbumin upstream promoter transcription factors (COUP-TFs) are orphan members of the steroid/thyroid hormone receptor superfamily. They have been shown to negatively regulate the activation function of vitamin D, thyroid hormone, retinoic acid, the retinoid X and the peroxisome proliferator-activated receptors. COUP-TF genes have been cloned from many species and their sequences are exceptionally conserved through evolution. This suggests a critical role for the COUP-TFs in these organisms. Indeed, the Drosophila COUP-TF, seven-up and mouse COUP-TFII are essential for development and differentiation during embryogenesis. Our current understanding of COUP-TF function suggests that they serve vital physiological roles during development despite extensive overlaps of expression. This defines the COUP-TFs as important factors in regulation of development and differentiation in multiple organisms.

The major iron (Fe) sources available to Neisseria gonorrhoeae in the human host are probably transferrin (TF) and lactoferrin (LF). Although a number of studies have examined Fe uptake by Neisseria meningitidis, no comparable studies have been done on Fe uptake by the gonococcus from TF and LF. We found that, like meningococci, gonococci removed Fe from TF and LF in an energy-dependent manner; uptake was repressed by Fe and did not proceed by a siderophore-mediated uptake system. Unlike published studies examining meningococcal Fe uptake from TF, our study showed that gonococcal Fe uptake from both TF and LF was highly efficient; uptake saturated at 1 microM protein, and growth with 5% saturated TF and LF occurred at maximal rates when the protein was present in appreciable concentrations. We conclude that the availability of protein-bound Fe probably does not limit growth of N. gonorrhoeae in the human body.

Our understanding of gene regulation in plants is constrained by our limited knowledge of plant cis-regulatory DNA and its dynamics. We mapped DNase I hypersensitive sites (DHSs) in A. thaliana seedlings and used genomic footprinting to delineate ∼ 700,000 sites of in vivo transcription factor (TF) occupancy at nucleotide resolution. We show that variation associated with 72 diverse quantitative phenotypes localizes within DHSs. TF footprints encode an extensive cis-regulatory lexicon subject to recent evolutionary pressures, and widespread TF binding within exons may have shaped codon usage patterns. The architecture of A. thaliana TF regulatory networks is strikingly similar to that of animals in spite of diverged regulatory repertoires. We analyzed regulatory landscape dynamics during heat shock and photomorphogenesis, disclosing thousands of environmentally sensitive elements and enabling mapping of key TF regulatory circuits underlying these fundamental responses. Our results provide an extensive resource for the study of A. thaliana gene regulation and functional biology.

BACKGROUND

Determining the functional impact of non-coding disease-associated single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) is challenging. Many of these SNPs are likely to be regulatory SNPs (rSNPs): variations which affect the ability of a transcription factor (TF) to bind to DNA. However, experimental procedures for identifying rSNPs are expensive and labour intensive. Therefore, in silico methods are required for rSNP prediction. By scoring two alleles with a TF position weight matrix (PWM), it can be determined which SNPs are likely rSNPs. However, predictions in this manner are noisy and no method exists that determines the statistical significance of a nucleotide variation on a PWM score.

RESULTS

We have designed an algorithm for in silico rSNP detection called is-rSNP. We employ novel convolution methods to determine the complete distributions of PWM scores and ratios between allele scores, facilitating assignment of statistical significance to rSNP effects. We have tested our method on 41 experimentally verified rSNPs, correctly predicting the disrupted TF in 28 cases. We also analysed 146 disease-associated SNPs with no known functional impact in an attempt to identify candidate rSNPs. Of the 11 significantly predicted disrupted TFs, 9 had previous evidence of being associated with the disease in the literature. These results demonstrate that is-rSNP is suitable for high-throughput screening of SNPs for potential regulatory function. This is a useful and important tool in the interpretation of GWAS.

BACKGROUND

is-rSNP software is available for use at: www.genomics.csse.unimelb.edu.au/is-rSNP.

Glucocorticoids stimulate hepatic phosphoenolpyruvate carboxykinase (PEPCK; EC 4.1.1.32) gene expression, thereby increasing the rate of gluconeogenesis. The effect of glucocorticoids on PEPCK gene expression is mediated by a set of promoter elements collectively referred to as the glucocorticoid response unit. The response unit spans a 100-bp segment and includes two glucocorticoid receptor binding sites (GR1 and GR2) and two accessory factor binding sites (AF1 and AF2), all of which are required for a maximal glucocorticoid response. The AF1 element also serves as a retinoic acid response element and may be involved in developmental and tissue-specific expression of the gene. In this study we report that COUP-TF and HNF-4, two orphan members of the nuclear receptor superfamily, bind to the AF1 element and function as accessory factors for the glucocorticoid response of the PEPCK gene.

Identifying transcription factor (TF) binding sites is essential for understanding regulatory networks. The specificity of most TFs is currently modeled using position weight matrices (PWMs) that assume the positions within a binding site contribute independently to binding affinity for any site. Extensive, high-throughput quantitative binding assays let us examine, for the first time, the independence assumption for many TFs. We find that the specificity of most TFs is well fit with the simple PWM model, but in some cases more complex models are required. We introduce a binding energy model (BEM) that can include energy parameters for nonindependent contributions to binding affinity. We show that in most cases where a PWM is not sufficient, a BEM that includes energy parameters for adjacent dinucleotide contributions models the specificity very well. Having more accurate models of specificity greatly improves the interpretation of in vivo TF localization data, such as from chromatin immunoprecipitation followed by sequencing (ChIP-seq) experiments.

Although factor VII/factor VIIa (FVII/FVIIa) is known to interact with many non-vascular cells, activated monocytes, and endothelial cells via its binding to tissue factor (TF), the interaction of FVII/FVIIa with unperturbed endothelium and the role of this interaction in clearing FVII/FVIIa from the circulation are unknown. To investigate this, in the present study we examined the binding of radiolabeled FVIIa to endothelial cells and its subsequent internalization. (125)I-FVIIa bound to non-stimulated human umbilical vein endothelial cells (HUVEC) in time- and dose-dependent manner. The binding is specific and independent of TF and negatively charged phospholipids. Protein C and monoclonal antibodies to endothelial cell protein C receptor (EPCR) blocked effectively (125)I-FVIIa binding to HUVEC. FVIIa binding to EPCR is confirmed by demonstrating a marked increase in (125)I-FVIIa binding to CHO cells that had been stably transfected with EPCR compared with the wild-type. Binding analysis revealed that FVII, FVIIa, protein C, and activated protein C (APC) bound to EPCR with similar affinity. FVIIa binding to EPCR failed to accelerate FVIIa activation of factor X or protease-activated receptors. FVIIa binding to EPCR was shown to facilitate FVIIa endocytosis. Pharmacological concentrations of FVIIa were found to impair partly the EPCR-dependent protein C activation and APC-mediated cell signaling. Overall, the present data provide convincing evidence that EPCR serves as a cellular binding site for FVII/FVIIa. Further studies are needed to evaluate the pathophysiological consequences and relevance of FVIIa binding to EPCR.

Cancer patients exhibit a high rate of thromboembolism (VTE). In this study, we analyzed levels of microparticle (MP) tissue factor (TF) activity in cancer patients with or without VTE. Blood was collected from cancer patients within 24 h of objectively diagnosed VTE (n=53) and from cancer patients without VTE (n=13). MPs were isolated from platelet poor plasma by centrifugation at 20,000g for 15 min. MP TF activity was measured using a two-stage chromogenic assay. Cancer patients with VTE had a significantly higher mean MP TF activity compared with cancer patients without VTE (1.7+/-3.8 pg/mL vs 0.6+/-0.4 pg/mL, p<0.05). Further prospective studies are required to determine if levels of MP TF activity may be a useful biomarker to identify patients at increased risk for VTE.

Nutritional intake is often compromised in elderly, multimorbid patients. Enteral nutrition (EN) by means of oral nutritional supplements (ONS) and tube feeding (TF) offers the possibility to increase or to insure nutrient intake in case of insufficient oral food intake. The present guideline is intended to give evidence-based recommendations for the use of ONS and TF in geriatric patients. It was developed by an interdisciplinary expert group in accordance with officially accepted standards and is based on all relevant publications since 1985. The guideline was discussed and accepted in a consensus conference. EN by means of ONS is recommended for geriatric patients at nutritional risk, in case of multimorbidity and frailty, and following orthopaedic-surgical procedures. In elderly people at risk of undernutrition ONS improve nutritional status and reduce mortality. After orthopaedic-surgery ONS reduce unfavourable outcome. TF is clearly indicated in patients with neurologic dysphagia. In contrast, TF is not indicated in final disease states, including final dementia, and in order to facilitate patient care. Altogether, it is strongly recommended not to wait until severe undernutrition has developed, but to start EN therapy early, as soon as a nutritional risk becomes apparent.

Transcription factors (TFs) are very attractive but difficult drug targets. The difficulties come from several directions including the binding promiscuity of TFs and the intrinsically disordered nature of their binding sites, which often resemble 'protein clouds'. For a long time the targeting of proteins without defined structures was considered infeasible. Data have now emerged showing that selective blocking of specific interactions of intrinsically disordered TFs with their protein binding partners is possible. Initial hits have been optimized to increase their specificity and affinity. Several strategies have been elaborated for elucidating the mechanisms of blocking of intrinsic disorder-based protein-protein interactions. However, challenges remain in the field of drug development for 'protein clouds'; such development is still in its earliest stage.

The release of iron from transferrin (Tf) in the acidic milieu of endosomes and its translocation into the cytosol are integral steps in the process of iron acquisition via receptor-mediated endocytosis (RME). The translocated metal is thought to enter a low molecular weight cytoplasmic pool, presumed to contain the form of iron which is apparently sensed by iron responsive proteins and is the direct target of iron chelators. The process of iron delivery into the cytoplasmic chelatable pool of K562 cells was studied in situ by continuous monitoring of the fluorescence of cells loaded with the metal-sensitive probe calcein. Upon exposure to Tf at 37 degrees C, intracellular fluorescence decayed, corresponding to an initial iron uptake of 40 nM/min. The Tf-mediated iron uptake was profoundly inhibited by weak bases, the protonophore monensin, energy depletion, or low temperatures (< 25 degrees C), all properties characteristic of RME. Cell iron levels were affected by the slowly permeating chelator desferrioxamine only after prolonged incubations. Conversely, rapidly penetrating, lipophilic iron-(II) chelators such as 2,2'-bipyridyl, evoked swift increases in cell calcein fluorescence, equivalent to sequestration of 0.2-0.5 microM cytosolic iron, depending on the degree of pre-exposure to Tf. Addition of iron(III) chelators to permeabilized 2,2'-bipyridyl-treated cells, failed to reveal significant levels of chelatable iron(III). The finding that the bulk of the in situ cell chelatable pool is comprised of iron(II) was corroborated by pulsing K562 cells with Tf-55Fe, followed by addition of iron(II) and/or iron(III) chelators and extraction of chelator-55Fe complexes into organic solvent. Virtually all of the accumulated 55Fe in the chelatable pool could be complexed by iron(II) chelators. The cytoplasmic concentration of iron(II) fluctuated between 0.3 and 0.5 microM, and its mean transit time through the chelatable pool was 1-2 h. We conclude that after iron is translocated from the endosomes, it is maintained in the cytosol as a transit pool of chelatable iron(II). The ostensible absence of chelatable iron(III) implicates the intracellular operation of vigorous reductive mechanisms.

OBJECTIVE

The principle underlying this project is that, despite nervous reorganization following upper limb amputation, original pathways and CNS relays partially maintain their function and can be exploited for interfacing prostheses. Aim of this study is to evaluate a novel peripheral intraneural multielectrode for multi-movement prosthesis control and for sensory feed-back, while assessing cortical reorganization following the re-acquired stream of data.

METHODS

Four intrafascicular longitudinal flexible multielectrodes (tf-LIFE4) were implanted in the median and ulnar nerves of an amputee; they reliably recorded output signals for 4 weeks. Artificial intelligence classifiers were used off-line to analyse LIFE signals recorded during three distinct hand movements under voluntary order.

RESULTS

Real-time control of motor output was achieved for the three actions. When applied off-line artificial intelligence reached >85% real-time correct classification of trials. Moreover, different types of current stimulation were determined to allow reproducible and localized hand/fingers sensations. Cortical organization was observed via TMS in parallel with partial resolution of symptoms due to the phantom-limb syndrome (PLS).

CONCLUSIONS

tf-LIFE4s recorded output signals in human nerves for 4 weeks, though the efficacy of sensory stimulation decayed after 10 days. Recording from a number of fibres permitted a high percentage of distinct actions to be classified correctly. Reversal of plastic changes and alleviation of PLS represent corollary findings of potential therapeutic benefit.

CONCLUSIONS

This study represents a breakthrough in robotic hand use in amputees.

Adhesion of circulating tumor cells to the blood vessel endothelium is a critical step in cancer metastasis. We show in this study that galectin-3, the concentration of which is greatly increased in the circulation of cancer patients, increases cancer cell adhesion to macrovascular and microvascular endothelial cells under static and flow conditions, increases transendothelial invasion, and decreases the latency of experimental metastasis in athymic mice. These effects of galectin-3 are shown to be a consequence of its interaction with cancer-associated MUC1, which breaks the "protective shield" of the cell-surface MUC1 by causing MUC1 polarization, leading to exposure of smaller cell-surface adhesion molecules/ligands including CD44 and ligand(s) for E-selectin. Thus, the interaction in the bloodstream of cancer patients between circulating galectin-3 and cancer cells expressing MUC1 bearing the galectin-3 ligand TF (Galbeta1,3GalNAc-) promotes metastasis. This provides insight into the molecular regulation of metastasis and has important implications for the development of novel therapeutic strategies for prevention of metastasis.

The histone modification state of genomic regions is hypothesized to reflect the regulatory activity of the underlying genomic DNA. Based on this hypothesis, the ENCODE Project Consortium measured the status of multiple histone modifications across the genome in several cell types and used these data to segment the genome into regions with different predicted regulatory activities. We measured the cis-regulatory activity of more than 2000 of these predictions in the K562 leukemia cell line. We tested genomic segments predicted to be Enhancers, Weak Enhancers, or Repressed elements in K562 cells, along with other sequences predicted to be Enhancers specific to the H1 human embryonic stem cell line (H1-hESC). Both Enhancer and Weak Enhancer sequences in K562 cells were more active than negative controls, although surprisingly, Weak Enhancer segmentations drove expression higher than did Enhancer segmentations. Lower levels of the covalent histone modifications H3K36me3 and H3K27ac, thought to mark active enhancers and transcribed gene bodies, associate with higher expression and partly explain the higher activity of Weak Enhancers over Enhancer predictions. While DNase I hypersensitivity (HS) is a good predictor of active sequences in our assay, transcription factor (TF) binding models need to be included in order to accurately identify highly expressed sequences. Overall, our results show that a significant fraction (-26%) of the ENCODE enhancer predictions have regulatory activity, suggesting that histone modification states can reflect the cis-regulatory activity of sequences in the genome, but that specific sequence preferences, such as TF-binding sites, are the causal determinants of cis-regulatory activity.

Transcription factors (TFs) form large paralogous gene families and have complex evolutionary histories. Here, we ask whether putative orthologs of TFs, from bidirectional best BLAST hits (BBHs), are evolutionary orthologs with conserved functions. We show that BBHs of TFs from distantly related bacteria are usually not evolutionary orthologs. Furthermore, the false orthologs usually respond to different signals and regulate distinct pathways, while the few BBHs that are evolutionary orthologs do have conserved functions. To test the conservation of regulatory interactions, we analyze expression patterns. We find that regulatory relationships between TFs and their regulated genes are usually not conserved for BBHs in Escherichia coli K12 and Bacillus subtilis. Even in the much more closely related bacteria Vibrio cholerae and Shewanella oneidensis MR-1, predicting regulation from E. coli BBHs has high error rates. Using gene-regulon correlations, we identify genes whose expression pattern differs between E. coli and S. oneidensis. Using literature searches and sequence analysis, we show that these changes in expression patterns reflect changes in gene regulation, even for evolutionary orthologs. We conclude that the evolution of bacterial regulation should be analyzed with phylogenetic trees, rather than BBHs, and that bacterial regulatory networks evolve more rapidly than previously thought.

The evidence implicating oligodendroglia in major mental disorders has grown significantly in the past few years. Microarray analysis revealed altered expression of oligodendroglia-related genes in multiple brain regions from several, clinically diverse groups of subjects with schizophrenia (SZ) as well as subjects with bipolar disorder (BD) and major depressive disorders (MDD), alcoholics and cocaine users. In line with gene expression findings, evidence for ultrastructural changes in white matter and altered oligodendroglia in these disorders were reported in neuroimaging and neuropathological studies. Changes in oligodendroglia-related genes reported in SZ, BD and MDD appear to display considerable similarities (particularly decreased expression of MAG, ERBB, TF, PLP1, MOG, MOBP, MOG), while changes in cocaine abuse and alcoholism are more diverse. Common oligodendroglial abnormalities might indicate aetiological or pathophysiological overlaps between different disorders. The possible mechanisms of oligodendroglial abnormalities may involve functional variations in oligodendroglia-related genes, epigenetic regulation of chromatin, DA system hyperactivity and other mechanisms.