The evolution of controlled multitasked gene networks: The role of introns and other noncoding RNAs in the development of complex organisms

Eukaryotic phenotypic diversity arises from multitasking of a core proteome of limited size. Multitasking is routine in computers, as well as in other sophisticated information systems, and requires multiple inputs and outputs to control and integrate network activity. Higher eukaryotes have a mosaic gene structure with a dual output, mRNA (protein-coding) sequences and introns, which are released from the pre-mRNA by posttranscriptional processing. Introns have been enormously successful as a class of sequences and comprise up to 95% of the primary transcripts of protein-coding genes in mammals. In addition, many other transcripts (perhaps more than half) do not encode proteins at all, but appear both to be developmentally regulated and to have genetic function. We suggest that these RNAs (eRNAs) have evolved to function as endogenous network control molecules which enable direct gene-gene communication and multitasking of eukaryotic genomes. Analysis of a range of complex genetic phenomena in which RNA is involved or implicated, including co-suppression, transgene silencing, RNA interference, imprinting, methylation, and transvection, suggests that a higher-order regulatory system based on RNA signals operates in the higher eukaryotes and involves chromatin remodeling as well as other RNA-DNA, RNA-RNA, and RNA-protein interactions. The evolution of densely connected gene networks would be expected to result in a relatively stable core proteome due to the multiple reuse of components, implying,that cellular differentiation and phenotypic variation in the higher eukaryotes results primarily from variation in the control architecture. Thus, network integration and multitasking using trans-acting RNA molecules produced in parallel with protein-coding sequences may underpin both the evolution of developmentally sophisticated multicellular organisms and the rapid expansion of phenotypic complexity into uncontested environments such as those initiated in the Cambrian radiation and those seen after major extinction events.

Early diagnosis of lymphedema using multiple frequency bioimpedance

Multiple frequency bioelectrical impedance analysis (MFBIA) has previously been shown to provide accurate relative measures of lymphedema in the upper limb of patients (1). This paper reports the results of a three year prospective study to evaluate the efficacy of MFBIA to predict the early onset of lymphedema in patients following treatment for breast cancer. Bioelectrical impedance measurements and circumferential measurements of each upper limb were recorded in healthy control subjects (n=60) to determine the normal range of the ratio (dominant/non-dominant) of extracellular and total limb volumes respectively. Patients undergoing surgery for the treatment of breast cancer were recruited as the study group; MFBIA and circumferential measurements were recorded pre-surgery, one month post-surgery and then at two month intervals for 24 months. One hundred and two patients were recruited into the study. Twenty patients developed lymphedema in the 24 months follow up period of this study. In each of these 20 cases MFBIA predicted the onset of the condition up to 10 months before the condition could be clinically diagnosed. Estimates of the sensitivity and specificity were both approximately 100%. At the time of detection by MFBIA, only one of the patients returned a positive test result from the total limb volumes determined from the circumferential measures. These results confirmed the suitability of the MFBIA technique as a reliable diagnostic procedure for the early detection of lymphedema.

Reduced expression of intercellular adhesion molecule-1 in ovarian adenocarcinomas

Ovarian adenocarcinomas develop as the result of multiple genetic, and epigenetic changes in the precursor ovarian surface epithelial (OSE) cells which result in a malignant phenotype. We investigated changes in gene expression in ovarian adenocarcinoma using a cDNA array containing 588 known human genes. We found that intercellular adhesion molecule-1 (ICAM-1) was expressed at lower levels in the ovarian tumour cell lines OAW42, PEO1 and JAM than in the immortalised human ovarian surface epithelial cell line HOSE 17.1. Further investigation revealed ICAM-1 was expressed in the surface epithelium of normal ovaries and both mRNA and protein expression levels were reduced in the majority of ovarian adenocarcinoma cell lines and primary tumours. ICAM-1 expression was increased in 8/8 cell lines treated with the de novo methyltransferase inhibitor 5-aza-2'-deoxycytidiine, indicating that methylation of CpG islands may play a role in the down-regulation of its expression in primary tumours. 'There was a significant association between patients whose tumours expressed ICAM-1 and survival (P = 0.03), suggesting that expression levels of ICAM-1 may have clinical relevance. (C) 2001 Cancer Research Campaign.

Application of DNA microarrays to study human alcoholism

An emerging idea is that long-term alcohol abuse results in changes in gene expression in the brain and that these changes are responsible at least partly for alcohol tolerance, dependence and neurotoxicity, The overall goal of our research is to identify genes which are differentia[ly expressed in the brains of well-characterized human alcoholics as compared with non-alcoholics. This should identify as-yet-unknown alcohol-responsive genes, and may well confirm changes in the expression of genes which have been delineated in animal models of alcohol abuse. Cases were carefully selected and samples pooled on the basis of relevant criteria; differential expression was monitored by microarray hybridization. The inherent diversity of human alcoholics can be exploited to identify genes associated with specific pathological processes, as well as to assess the effects of concomitant disease, severity of brain damage, drinking behavior, and factors such as gender and smoking history. initial results show selective changes in gene expression in alcoholics; of particular importance is a coordinated reduction in genes coding for myelin components, Copyright (C) 2001 National Science Council, ROC and S. Karger AG, Basel.

Multiple impacts of the HIV/AIDS epidemic on the aged in rural Uganda

This paper reports research conducted among theaged residents of a rural, Southwestern Ugandanvillage. It documents their knowledge ofHIV/AIDS, their perceptions of their own riskof infection, and the multiple impacts of thecurrent HIV/AIDS epidemic on their lives. Mostolder individuals have a sound understanding ofthe sexual transmission of HIV, and someconsider themselves to be at risk of infectionthrough having multiple sexual partners. Theyattempt to limit their children's exposure toHIV, but many of these children have left thevillage to live in urban areas of relativelyhigh HIV prevalence. The loss of adult childrendeprives the aged of any support these childrenmight have provided as their parents'capabilities declined with advancing age.Female-headed households were more affected inthis way than were male-headed households. TheAIDS epidemic has increased the number ofburials taking place in the village, and theiraccumulated costs, both in time and money, andcreated new hardships for the aged, who alsohave to cope with grief that accompaniescontinuing deaths among their children andtheir contemporaries' children.

Using Theory to Understand the Multiple Determinants of Low Participation in Worksite Health Promotion Programs

Low participation at the employee or worksite level limits the potential public health impact of worksite-based interventions. Ecological models suggest that multiple levels of influence operate to determine participation patterns in worksite health promotion programs. Most investigations into the determinants of low participation study the intrapersonal, interpersonal, and institutional influences on employee participation. Community- and policy-level influences have not received attention, nor has consideration been given to worksite-level participation issues. The purpose of this article is to discuss one macrosocial theoretical perspective—political economy of health—that may guide practitioners and researchers interested in addressing the community- and policy-level determinants of participation in worksite health promotion programs. The authors argue that using theory to investigate the full spectrum of determinants offers a more complete range of intervention and research options for maximizing employee and worksite levels of participation.

Multiple bifurcations in atom optics

We report the observation of multiple bifurcations in a nonlinear Hamiltionian system: laser-cooled atoms in a standing wave with single-frequency intensity modulation. We provide clear evidence of the occurrence of bifurcations by analyzing the atomic momentum distributions.

Applying statistical approaches in the dissection of genes versus environment for asthma and allergic disease

Now that some of the genes involved in asthma and allergy have been identified, interest is turning to how genetic predisposition interacts with exposure to environmental risk factors. These questions are best answered by studies in which both genotypes and other risk factors are measured, but even simpler studies, in which family history is used as a proxy for genotype, have made suggestive findings. For example, early breast feeding may increase the risk of allergic disease in genetically susceptible children, and decrease the risk of 'sporadic' allergy. This review also addresses the overall importance of genetic causes of allergic disease in the general population.

Fluorescence spectrum of a two-level atom driven by a multiple modulated field

We investigate the fluorescence spectrum of a two-level atom driven by a multiple amplitude-modulated field. The driving held is modeled as a polychromatic field composed of a strong central (resonant) component and a large number of symmetrically detuned sideband fields displaced from the central component by integer multiples of a constant detuning. Spectra obtained here differ qualitatively from those observed for a single pair of modulating fields [B. Blind, P.R. Fontana, and P. Thomann, J. Phys. B 13, 2717 (1980)]. In the case of a small number of the modulating fields, a multipeaked spectrum is obtained with the spectral features located at fixed frequencies that are independent of the number of modulating fields and their Rabi frequencies. As the number of the modulating fields increases, the spectrum ultimately evolves to the well-known Mellow triplet with the sidebands shifted from the central component by an effective Rabi frequency whose magnitude depends on the initial relative phases of the components of the driving held. For equal relative phases, the effective Rabi frequency of the driving field can be reduced to zero resulting in the disappearance of fluorescence spectrum, i.e., the atom can stop interacting with the field. When the central component and the modulating fields are 180 degrees out of phase, the spectrum retains its triplet structure with the sidebands located at frequencies equal to the sum of the Rabi frequencies of the component of the driving field. Moreover, we shaw that the frequency of spontaneous emission can be controlled and switched from one frequency to another when the Rabi frequency or initial phase of the modulating fields are varied.

Human pigmentation genes: identification, structure and consequences of polymorphic variation

The synthesis of the visible pigment melanin by the melanocyte cell is the basis of the human pigmentary system, those genes directing the formation, transport and distribution of the specialised melanosome organelle in which melanin accumulates can legitimately be called pigmentation genes. The genes involved in this process have been identified through comparative genomic studies of mouse coat colour mutations and by the molecular characterisation of human hypopigmentary genetic diseases such as OCA1 and OCA2. The melanocyte responds to the peptide hormones a-MSH or ACTH through the MC1R G-protein coupled receptor to stimulate melanin production through induced maturation or switching of melanin type. The pheomelanosome, containing the key enzyme of the pathway tyrosinase, produces light red/yellowish melanin, whereas the eumelanosome produces darker melanins via induction of additional TYRP1, TYRP2, SILV enzymes, and the P-protein. Intramelanosomal pH governed by the P-protein may act as a critical determinant of tyrosinase enzyme activity to control the initial step in melanin synthesis or TYRP complex formation to facilitate melanogenesis and melanosomal maturation. The search for genetic variation in these candidate human pigmentation genes in various human populations has revealed high levels of polymorphism in the MC1R locus, with over 30 variant alleles so far identified. Functional correlation of MC1R alleles with skin and hair colour provides evidence that this receptor molecule is a principle component underlying normal human pigment variation. (C) 2001 Elsevier Science B.V. All rights reserved.

Population screening for HFE-associated haemochromatosis: should we have to pay for our genes?

Haemochromatosis associated with mutations in the HFE gene is the most common inherited disorder in Caucasian populations. Early diagnosis and treatment allows for normal life expectancy whereas there is considerable morbidity and early mortality in those patients diagnosed late or untreated. Unfortunately, the development of symptoms and signs in haemochromatosis is usually associated with significant iron overload. For this reason, many clinicians and geneticists have advocated population screening. The recent identification of the HFE gene and the availability of a simple DNA-based diagnostic test have led to international debate as to the most cost-effective means of population screening for HFE-associated haemochromatosis. The present paper summarizes the evidence in favour of population screening and analyses the relative advantages of genotypic (DNA test) versus phenotypic (transferrin saturation) testing.