Developmental regulation of eukaryotic gene loci: which cis-regulatory information is required?

It is becoming increasingly accepted that gene loci comprise an extensive cis-regulatory system that encodes different layers of regulatory information, all of which are necessary to achieve and maintain tissue-specific gene expression in ontogeny. To gain a detailed understanding of developmental processes, it is clearly necessary to unravel the molecular basis behind the different regulatory processes that control gene expression. This information is also of utmost importance for any practical application that uses gene transfer technology.     

Somatic recombination in adult tissues: What is there to learn?

Somatic recombination is essential to protect genomes of somatic cells from DNA damage but it also has important clinical implications, as it is a driving force of tumorigenesis leading to inactivation of tumor suppressor genes. Despite this importance, our knowledge about somatic recombination in adult tissues remains very limited. Our recent work, using the Drosophila adult midgut has demonstrated that spontaneous events of mitotic recombination accumulate in aging adult intestinal stem cells and result in frequent loss of heterozygosity (LOH). In this Extra View article, we provide further data supporting long-track chromosome LOH and discuss potential mechanisms involved in the process. In addition, we further discuss relevant questions surrounding somatic recombination and how the mechanisms and factors influencing somatic recombination in adult tissues can be explored using the Drosophila midgut model.     

Neuronal migration in the adult brain: are we there yet?

The generation and targeting of appropriate numbers and types of neurons to where they are needed in the brain is essential for the establishment, maintenance and modification of neural circuitry. This review aims to summarize the patterns, mechanisms and functional significance of neuronal migration in the postnatal brain, with an emphasis on the migratory events that persist in the mature brain.     

Sexual dimorphism in birds: why are there so many different forms of dimorphism?

Variation in the extent of sexual dimorphism among bird species is traditionally attributed to differences in social mating system. However, there are many different forms of dimorphism among birds, and not all of them show an obvious correlation with social mating system. For example, recent work has shown that many highly polygamous species are, in fact, monomorphic, whereas many putatively monogamous species are dimorphic. In this paper we break up sexual dimorphism into subcomponents and then use comparative analyses to examine the pattern of covariation between these subcomponents and various aspects of sexual, social, and parental behaviour. Our first finding is that size dimorphism and plumage-colour dimorphism do not show the same pattern of covariation. Differences in size dimorphism are associated with variation in social mating system and sex differences in parental care, whereas differences in plumage-colour dimorphism are associated with variation in the frequency of extra-bond paternity. These results suggest that size dimorphism is associated with the sort of intrasexual competition described by traditional classifications of social mating system, whereas plumage-colour dimorphism is associated with cryptic female choice. However, when we break up plumage-colour dimorphism according to whether it is due to melanins, carotenoids or structural colours, we find that each category of plumage-colour dimorphism shows a different pattern of covariation. The correlation between overall plumage-colour dimorphism and the rate of extra-bond paternity is due to structural colours, whereas melanin-based dimorphism is associated with sex differences in parental care. The former result is particularly interesting given that new work suggests structural colours are associated with active sexual displays and the reflection of ultraviolet light.     

Ghrelin and obestatin: different role in fetal lung development?

Ghrelin and obestatin are two proteins that originate from post-translational processing of the preproghrelin peptide. Various authors claim an opposed role of ghrelin and obestatin in several systems. Preproghrelin mRNA is significantly expressed in airway epithelium throughout lung development, predominantly during the earliest stages. The aim of this study was to evaluate the role of ghrelin and obestatin in fetal lung development in vitro. Immunohistochemistry studies were performed at different gestational ages in order to clarify the expression pattern of ghrelin, GHS-R1a, obestatin and GPR39 during fetal lung development. Fetal rat lung explants were harvested at 13.5 days post-conception (dpc) and cultured during 4 days with increasing doses of total ghrelin, acylated ghrelin, desacyl-ghrelin, ghrelin antagonist (D-Lys(3)-GHRP-6) or obestatin. Immunohistochemistry studies demonstrated that ghrelin, GHS-R1a, obestatin and GPR39 proteins were expressed in primitive rat lung epithelium throughout all studied gestational ages. Total and acylated ghrelin supplementation significantly increased the total number of peripheral airway buds, whereas desacyl-ghrelin induced no effect. Moreover, GHS-R1a antagonist significantly decreased lung branching. Finally, obestatin supplementation induced no significant effect in the measured parameters. The present study showed that ghrelin has a positive effect in fetal lung development through its GHS-R1a receptor, whereas obestatin has no effect on lung branching.     

Avian β-endorphin: Alterations in immunoreactive forms in plasma and pituitary of embryonic and adult chickens

1. A heterologous radioimmunoassay for β-endorphin (β-endo) was established. Plasma and/or extracts of pituitaries from embryonic (days 14.5 and 17.5 of incubation), newly hatched, and adult chickens were chromatographed on a Sephadex G-75 column with 0.1 M acetic acid.2. Embryonic plasma had only a single immunoreactive peak that eluted similar to a β-lipotropin (β-LPH) standard. In contrast, adult plasma had 2 peaks, co-eluting with β-LPH (34%) and β-endo (66%).3. Chromatography of pituitary extracts demonstrated two immunoreactive peaks in both embryonic and adult birds. Although 70% of immunoreactivity eluted with β-endo for embryonic birds, 80% eluted with β-LPH from adults.4. The smaller proportion of β-endo in adult pituitaries may reflect a higher rate of secretion of this hormone into the blood.     

Avian thyroid development in chemically contaminated environments: is there evidence of alterations in thyroid function and development?

Poor reproductive success, developmental abnormalities, and behavioral alterations in fish-eating birds in some Great Lakes areas have led to more than 35 years of toxicological studies and residue monitoring of herring gull (Larus argentatus) populations. Polyhalogenated aromatic hydrocarbons (PHAHs), especially polychlorinated biphenyls (PCBs), are widespread contaminants in the Great Lakes ecosystem. The introduction of regulations and elimination of point sources since the 1970s have resulted in decreased PHAHs in fish-eating bird eggs and tissues. PCB exposure is associated with thyroid disruption (hypothyroidism) in mammals, but much less is known of PCB effects on avian thyroid function. Our 1998-2000 studies of herring gulls from the Great Lakes show that both pipping embryos and prefledglings from highly contaminated sites have marked depletion of thyroid gland hormone stores compared with similarly aged gulls at the reference sites. However, organismal hypothyroidism was not apparent in many embryo and chick collections where severe depletion of thyroid gland hormone was observed. Adults, sampled at two high PCB sites and a low PCB site in the Great Lakes and the maritime reference colony in 2001, showed no differences in organismal thyroid status across sites, but gulls from the high sites had enlarged thyroid glands and depressed thyroid gland hormone stores. Here we discuss the evidence that ecological exposure to PHAHs are responsible for thyroid deficiencies in gulls and that during development these deficiencies lead to developmental abnormalities in young gulls from highly contaminated Great Lakes sites.     

Subjective and psychopathological response in patients under different antipsychotic treatments: are there differences in real clinical practice?

The aim of this study is to investigate whether subjective well-being in patients under treatment with typical (ATPs) and atypical antipsychotic (ATPsA) compounds can be compared with the improvement of psychopathological state and to verify if both variables correlate to adherence to treatment. We assessed 106 consecutive patients receiving ATPs or ATPsA in the University Psychiatric Ward of L?Aquila, according to DSM-IV diagnosis of Schizophrenia and Bipolar Disorder. Psychopathological state was assessed by Brief Psychiatric Rating Scale-4.0 version (BPRS), adherence to treatment and subjective well-being was assessed by Drug Attitude Inventory (DAI-10) and Subjective Well-being under Neuroleptics (SWN), respectively. BPRS and DAI-10 were administered on admission (T0) and at the end of recovery (T1). The subjects enrolled in this study were divided into 2 groups according to ATP prescribed. We observed an improvement of BPRS and SWN total scores in each group, and increasing scores in DAI-10, from admission to discharge, both in total samples and in each group. There were statistical differences between the patients receiving ATPs and those receving ATPsA regardindg the SWN total score and its different dimensions. This study emphasizes that patients receiving ATPsA show better subjective response compared with patients undergoing ATP treatment, although the adherence to pharmacotherapy and clinical improvement do not differ between the groups.     

Integrin avidity regulation: are changes in affinity and conformation underemphasized?

Integrins play critical roles in development, wound healing, immunity and cancer. Central to their function is their unique ability to modulate dynamically their adhesiveness through both affinity- and valency-based mechanisms. Recent advances have shed light on the structural basis for affinity regulation and on the signaling mechanisms responsible for both affinity and valency modes of regulation.     

Methylation of adenovirus genes in transformed cells and in vitro: influence on the regulation of gene expression?

An inverse correlation has been described between the levels of DNA methylation in specific segments of adenovirus DNA integrated into the genomes of transformed and tumor cells and the extent to which these segments are expressed as messenger RNA. In the adenovirus type 2 (Ad2)-transformed hamster cell lines HE2 and HE3, the virus-specific DNA binding protein (DBP) is not expressed, and the DNA in the DBP gene is completely methylated in all 5'-CCGG-3' sites. At least part of the late promoter/leader sequence of the DBP gene is present in cell lines HE2 and HE3. In line HE1, on the other hand, the DBP is expressed, and the DNA in the DBP gene is unmethylated at the 5'-CCGG-3' (HpaII) sites. The late promotor/leader sequence of the DBP gene is expressed in cytoplasmic RNA isolated from line HE1. The effect of DNA methylation has also been tested in vitro in a microinjection system using Xenopus laevis oocytes. Unmethylated DNA fragments of Ad2 (E2a region) have been found to serve as active templates. When the same fragments are methylated at the 5'-CCGG-3' sites by the HpaII DNA-methyltransferase, viral RNA synthesis is inhibited upon microinjection into oocyte nuclei. These results provide direct evidence for the notion that DNA methylated at highly specific sites is somehow involved in the regulation of gene expression.     

Muscle contraction and movement of cellular organelles: are there two different types of mechanisms for their generation?

It has been shown that myosin molecules attached to Covaspheres can "walk along" polar actin filament in vitro. The driving force for this movement seems to explain only about 1% of the isometric tension developed by a muscle fibre. Therefore, the driving force for the bead movement seems to be incompatible with that found in muscle, and the bead movement cannot be considered as a model for muscle contraction. The origin of the bead movement may be related to a "molecular jet" process, resulting from the rapid ejection of the MgATP splitting products. This "molecular jet" might also explain the movements of many cellular organelles.     

Interleukin-10 and the regulation of mitogen-activated protein kinases: are these signalling modules targets for the anti-inflammatory action of this cytokine?

The many specific, yet overlapping and redundant activities of individual cytokines have been the basis for current concepts of therapeutical intervention. Cytokines are powerful two-edged weapons that can trigger a cascade of reactions and may show activities that often go beyond the single highly specific property that it is hoped they possess. Nevertheless, it can be stated that our new, though burgeoning, understanding of the biological mechanisms governing cytokine actions is an important contribution to medical knowledge. The crucial role of the anti-inflammatory cytokine, interleukin (IL)-10, in regulating potential molecular pathway mediating injury and cell death has attracted paramount attention in recent years. In this respect, the mitogen-activated protein kinase (MAPK) components have emerged as potential signalling cascades that regulate a plethora of cell functions, including inflammation and cell death. The biochemistry and molecular biology of cytokine actions, particularly IL-10, explain some well known and sometimes also some of the more obscure clinical aspects of the evolution of diseases.     

Inducible lymphoid tissues in the adult gut: recapitulation of a fetal developmental pathway?

The intestinal immune system faces an extraordinary challenge from the large numbers of commensal bacteria and potential pathogens that are restrained by only a single layer of epithelial cells. Here, I discuss evidence that the intestinal immune system develops an extensive network of inducible, reversible lymphoid tissues that contributes to the vital equilibrium between the gut and the bacterial flora. I propose that this network is induced by cryptopatches, which are small clusters of dendritic cells and lymphoid cells that are identical to fetal inducers of lymph-node and Peyer's-patch development.     

Phylogenetic distribution of catalase-peroxidases: are there patches of order in chaos?

Hydrogen peroxide features in many biological oxidative processes and must be continuously degraded enzymatically either via a catalatic or a peroxidatic mechanism. For this purpose ancestral bacteria evolved a battery of different heme and non-heme enzymes, among which heme-containing catalase-peroxidases (CP) are one of the most widespread representatives. They are unique since they can follow both H(2)O(2)-degrading mechanisms, the catalase activity being clearly dominant. With the fast increasing amount of genomic data available, we were able to perform an extensive search for CP and found almost 300 sequences covering a large range of microorganisms. Most of them were encoded by bacterial genomes, but we could also find some in eukaryotic organisms other than fungi, which has never been shown until now. Our screen also reveals that approximately 60% of the bacteria do not possess CP genes. Chaotic distribution among species and incongruous phylogenetic reconstruction indicated existence of numerous lateral gene transfers in addition to duplication events and regular speciation. The results obtained show an impressively complex gene transmission pattern, and give some new insights about the role of CP and the origin of life on earth. Finally, we propose for the first time bacterial candidates that may have participated in the transfer of CP from bacteria to eukaryotes.     

Robust computational reconstitution – a new method for the comparative analysis of gene expression in tissues and isolated cell fractions

Background  

Biological tissues consist of various cell types that differentially contribute to physiological and pathophysiological processes. Determining and analyzing cell type-specific gene expression under diverse conditions is therefore a central aim of biomedical research. The present study compares gene expression profiles in whole tissues and isolated cell fractions purified from these tissues in patients with rheumatoid arthritis and osteoarthritis.     

Detail in network models of epidemiology: are we there yet?

Network models of infectious disease epidemiology can potentially provide insight into how to tailor control strategies for specific regions, but only if the network adequately reflects the structure of the region's contact network. Typically, the network is produced by models that incorporate details about human interactions. Each detail added renders the models more complicated and more difficult to calibrate, but also more faithful to the actual contact network structure. We propose a statistical test to determine when sufficient detail has been added to the models and demonstrate its application to the models used to create a synthetic population and contact network for the USA.