Proportionality between variances in gene expression induced by noise and mutation: consequence of evolutionary robustness

<p>Abstract</p> <p>Background</p> <p>Characterization of robustness and plasticity of phenotypes is a basic issue in evolutionary and developmental biology. The robustness and plasticity are concerned with changeability of a biological system against external perturbations. The perturbations are either genetic, i.e., due to mutations in genes in the population, or epigenetic, i.e., due to noise during development or environmental variations. Thus, the variances of phenotypes due to genetic and epigenetic perturbations provide quantitative measures for such changeability during evolution and development, respectively.</p> <p>Results</p> <p>Using numerical models simulating the evolutionary changes in the gene regulation network required to achieve a particular expression pattern, we first confirmed that gene expression dynamics robust to mutation evolved in the presence of a sufficient level of transcriptional noise. Under such conditions, the two types of variances in the gene expression levels, i.e. those due to mutations to the gene regulation network and those due to noise in gene expression dynamics were found to be proportional over a number of genes. The fraction of such genes with a common proportionality coefficient increased with an increase in the robustness of the evolved network. This proportionality was generally confirmed, also under the presence of environmental fluctuations and sexual recombination in diploids, and was explained from an evolutionary robustness hypothesis, in which an evolved robust system suppresses the so-called error catastrophe - the destabilization of the single-peaked distribution in gene expression levels. Experimental evidences for the proportionality of the variances over genes are also discussed.</p> <p>Conclusions</p> <p>The proportionality between the genetic and epigenetic variances of phenotypes implies the correlation between the robustness (or plasticity) against genetic changes and against noise in development, and also suggests that phenotypic traits that are more variable epigenetically have a higher evolutionary potential.</p

A fresh look at the evolution and diversification of photochemical reaction centers

In this review, I reexamine the origin and diversification of photochemical reaction centers based on the known phylogenetic relations of the core subunits, and with the aid of sequence and structural alignments. I show, for example, that the protein folds at the C-terminus of the D1 and D2 subunits of Photosystem II, which are essential for the coordination of the water-oxidizing complex, were already in place in the most ancestral Type II reaction center subunit. I then evaluate the evolution of reaction centers in the context of the rise and expansion of the different groups of bacteria based on recent large-scale phylogenetic analyses. I find that the Heliobacteriaceae family of Firmicutes appears to be the earliest branching of the known groups of phototrophic bacteria; however, the origin of photochemical reaction centers and chlorophyll synthesis cannot be placed in this group. Moreover, it becomes evident that the Acidobacteria and the Proteobacteria shared a more recent common phototrophic ancestor, and this is also likely for the Chloroflexi and the Cyanobacteria. Finally, I argue that the discrepancies among the phylogenies of the reaction center proteins, chlorophyll synthesis enzymes, and the species tree of bacteria are best explained if both types of photochemical reaction centers evolved before the diversification of the known phyla of phototrophic bacteria. The primordial phototrophic ancestor must have had both Type I and Type II reaction centers

Can i have a second child? dilemmas of mothers of children with pervasive developmental disorder: a qualitative study

<p>Abstract</p> <p>Background</p> <p>Pervasive developmental disorder (PDD) has an uncertain etiology, no method of treatment, and results in communication deficiencies and other behavioral problems. As the reported recurrence risk is 5%-10% and there are no methods of either prevention or prenatal testing, mothers of PDD children may face unique challenges when contemplating second pregnancies. The purpose of this study was to explore the mothers' lived experiences of second child-related decision-making after the birth of a child with PDD.</p> <p>Methods</p> <p>The participants for this study were restricted to mothers living within the greater Tokyo metropolitan area who had given birth to a first child with PDD within the past 18 years. The ten participants were encouraged to describe their experiences of second-child related decision-making after the birth of a child with PDD on the basis of semi-structured interviews. Data analysis was performed by using Interpretive Phenomenological Analysis (IPA), which is concerned with understanding what the participant thinks or believes about the topic under discussion.</p> <p>Results</p> <p>We identified two superordinate themes. The first was balancing hopes and fears, in which hope was the potential joy to be gained by the birth of a new child without PDD and fears were characterized as uncertainty of PDD and perception of recurrence risk, burden on later-born children, and negative effects on a child with PDD.</p> <p>The second superordinate theme was assessing the manageability of the situation, which was affected by factors as diverse as severity of PDD, relationship between mother and father, and social support and acceptance for PDD. Our 10 participants suffered from extreme psychological conflict, and lack of social support and acceptance for PDD created numerous practical difficulties in having second children.</p> <p>Conclusions</p> <p>Our participants faced various difficulties when considering second pregnancies after the birth of children with PDD in the Japanese society. As lack of social support and acceptance for PDD also played a large role in second child-related decision-making, creating a social environment that more fully accepts those disabled and providing flexible support systems for families of children with PDD are crucial.</p

Mechanical properties of femoral trabecular bone in dogs

BACKGROUND: Studying mechanical properties of canine trabecular bone is important for a better understanding of fracture mechanics or bone disorders and is also needed for numerical simulation of canine femora. No detailed data about elastic moduli and degrees of anisotropy of canine femoral trabecular bone has been published so far, hence the purpose of this study was to measure the elastic modulus of trabecular bone in canine femoral heads by ultrasound testing and to assess whether assuming isotropy of the cancellous bone in femoral heads in dogs is a valid simplification. METHODS: From 8 euthanized dogs, both femora were obtained and cubic specimens were cut from the centre of the femoral head which were oriented along the main pressure and tension trajectories. The specimens were tested using a 100 MHz ultrasound transducer in all three orthogonal directions. The directional elastic moduli of trabecular bone tissue and degrees of anisotropy were calculated. RESULTS: The elastic modulus along principal bone trajectories was found to be 11.2 GPa ± 0.4, 10.5 ± 2.1 GPa and 10.5 ± 1.8 GPa, respectively. The mean density of the specimens was 1.40 ± 0.09 g/cm(3). The degrees of anisotropy revealed a significant inverse relationship with specimen densities. No significant differences were found between the elastic moduli in x, y and z directions, suggesting an effective isotropy of trabecular bone tissue in canine femoral heads. DISCUSSION: This study presents detailed data about elastic moduli of trabecular bone tissue obtained from canine femoral heads. Limitations of the study are the relatively small number of animals investigated and the measurement of whole specimen densities instead of trabecular bone densities which might lead to an underestimation of Young's moduli. Publications on elastic moduli of trabecular bone tissue present results that are similar to our data. CONCLUSION: This study provides data about directional elastic moduli and degrees of anisotropy of canine femoral head trabecular bone and might be useful for biomechanical modeling of proximal canine femora

Drosophila Immunity: Analysis of PGRP-SB1 Expression, Enzymatic Activity and Function

Peptidoglycan is an essential and specific component of the bacterial cell wall and therefore is an ideal recognition signature for the immune system. Peptidoglycan recognition proteins (PGRPs) are conserved from insects to mammals and able to bind PGN (non-catalytic PGRPs) and, in some cases, to efficiently degrade it (catalytic PGRPs). In Drosophila, several non-catalytic PGRPs function as selective peptidoglycan receptors upstream of the Toll and Imd pathways, the two major signalling cascades regulating the systemic production of antimicrobial peptides. Recognition PGRPs specifically activate the Toll pathway in response to Lys-type peptidoglycan found in most Gram-positive bacteria and the Imd pathway in response to DAP-type peptidoglycan encountered in Gram-positive bacilli-type bacteria and in Gram-negative bacteria. Catalytic PGRPs on the other hand can potentially reduce the level of immune activation by scavenging peptidoglycan. In accordance with this, PGRP-LB and PGRP-SC1A/B/2 have been shown to act as negative regulators of the Imd pathway. In this study, we report a biochemical and genetic analysis of PGRP-SB1, a catalytic PGRP. Our data show that PGRP-SB1 is abundantly secreted into the hemolymph following Imd pathway activation in the fat body, and exhibits an enzymatic activity towards DAP-type polymeric peptidoglycan. We have generated a PGRP-SB1/2 null mutant by homologous recombination, but its thorough phenotypic analysis did not reveal any immune function, suggesting a subtle role or redundancy of PGRP-SB1/2 with other molecules. Possible immune functions of PGRP-SB1 are discussed

Defining an olfactory receptor function in airway smooth muscle cells

Pathways that control, or can be exploited to alter, the increase in airway smooth muscle (ASM) mass and cellular remodeling that occur in asthma are not well defined. Here we report the expression of odorant receptors (ORs) belonging to the superfamily of G-protein coupled receptors (GPCRs), as well as the canonical olfaction machinery (G olf and AC3) in the smooth muscle of human bronchi. In primary cultures of isolated human ASM, we identified mRNA expression for multiple ORs. Strikingly, OR51E2 was the most highly enriched OR transcript mapped to the human olfactome in lung-resident cells. In a heterologous expression system, OR51E2 trafficked readily to the cell surface and showed ligand selectivity and sensitivity to the short chain fatty acids (SCFAs) acetate and propionate. These endogenous metabolic byproducts of the gut microbiota slowed the rate of cytoskeletal remodeling, as well as the proliferation of human ASM cells. These cellular responses in vitro were found in ASM from non-asthmatics and asthmatics, and were absent in OR51E2-deleted primary human ASM. These results demonstrate a novel chemo-mechanical signaling network in the ASM and serve as a proof-of-concept that a specific receptor of the gut-lung axis can be targeted to treat airflow obstruction in asthma.open0

Stage 4 neuroblastoma: sequential hemi-body irradiation or high-dose chemotherapy plus autologous haemopoietic stem cell transplantation to consolidate primary treatment

The aim of the present study was to evaluate the effectiveness of two consecutive nonrandomised treatment programs applied between 1989 and 1999 at the Istituto Nazionale Tumori of Milan in an unselected cohort of 59 children over the age of one with stage 4 neuroblastoma. Both treatment programs consisted of two phases, the induction of the remission phase and the consolidation phase. The induction of the remission phase consisted of intensive chemotherapy, and remained the same throughout the study period. The consolidation phase consisted of sequential hemi-body irradiation (HBI) (10 Gy per session, 6 weeks apart) in the first period (1988–June 1994) and sequential high-dose cyclophosphamide, etoposide, mitoxantrone+L-PAM and autologous haemopoietic stem cell transplantation in the second (July 1994–1999). Intention-to-treat analysis revealed a significantly better outcome for patients treated with the second program, the 5-year event-free survival probability being 0.12 for program 1 and 0.31 for program 2 (P=0.03). This finding led us to conclude that sequential HBI is useless as consolidation treatment. The high-dose chemotherapy adopted in the second program enabled a proportion of patients to obtain long-term survival but, since the clinical results remain unsatisfactory, new treatment strategies are warranted

Diversity of 23S rRNA Genes within Individual Prokaryotic Genomes

The concept of ribosomal constraints on rRNA genes is deduced primarily based on the comparison of consensus rRNA sequences between closely related species, but recent advances in whole-genome sequencing allow evaluation of this concept within organisms with multiple rRNA operons. was the only species in which intragenomic diversity >3% was observed among 4 paralogous 23S rRNA genes.These findings indicate tight ribosomal constraints on individual 23S rRNA genes within a genome. Although classification using primary 23S rRNA sequences could be erroneous, significant diversity among paralogous 23S rRNA genes was observed only once in the 184 species analyzed, indicating little overall impact on the mainstream of 23S rRNA gene-based prokaryotic taxonomy

Rapid and simultaneous detection of human hepatitis B virus and hepatitis C virus antibodies based on a protein chip assay using nano-gold immunological amplification and silver staining method

BACKGROUND: Viral hepatitis due to hepatitis B virus and hepatitis C virus are major public health problems all over the world. Traditional detection methods including polymerase chain reaction (PCR)-based assays and enzyme-linked immunosorbent assays (ELISA) are expensive and time-consuming. In our assay, a protein chip assay using Nano-gold Immunological Amplification and Silver Staining (NIASS) method was applied to detect HBV and HCV antibodies rapidly and simultaneously. METHODS: Chemically modified glass slides were used as solid supports (named chip), on which several antigens, including HBsAg, HBeAg, HBcAg and HCVAg (a mixture of NS3, NS5 and core antigens) were immobilized respectively. Colloidal nano-gold labelled staphylococcal protein A (SPA) was used as an indicator and immunogold silver staining enhancement technique was applied to amplify the detection signals, producing black image on array spots, which were visible with naked eyes. To determine the detection limit of the protein chip assay, a set of model arrays in which human IgG was spotted were structured and the model arrays were incubated with different concentrations of anti-IgG. A total of 305 serum samples previously characterized with commercial ELISA were divided into 4 groups and tested in this assay. RESULTS: We prepared mono-dispersed, spherical nano-gold particles with an average diameter of 15 ± 2 nm. Colloidal nano-gold-SPA particles observed by TEM were well-distributed, maintaining uniform and stable. The optimum silver enhancement time ranged from 8 to 12 minutes. In our assay, the protein chips could detect serum antibodies against HBsAg, HBeAg, HBcAg and HCVAg with the absence of the cross reaction. In the model arrays, the anti-IgG as low as 3 ng/ml could be detected. The data for comparing the protein chip assay with ELISA indicated that no distinct difference (P > 0.05) existed between the results determined by our assay and ELISA respectively. CONCLUSION: Results showed that our assay can be applied with serology for the detection of HBV and HCV antibodies rapidly and simultaneously in clinical detection

Anti-Aβ Drug Screening Platform Using Human iPS Cell-Derived Neurons for the Treatment of Alzheimer's Disease

Background:Alzheimer's disease (AD) is a neurodegenerative disorder that causes progressive memory and cognitive decline during middle to late adult life. The AD brain is characterized by deposition of amyloid β peptide (Aβ), which is produced from amyloid precursor protein by β- and γ-secretase (presenilin complex)-mediated sequential cleavage. Induced pluripotent stem (iPS) cells potentially provide an opportunity to generate a human cell-based model of AD that would be crucial for drug discovery as well as for investigating mechanisms of the disease. Methodology/Principal Findings:We differentiated human iPS (hiPS) cells into neuronal cells expressing the forebrain marker, Foxg1, and the neocortical markers, Cux1, Satb2, Ctip2, and Tbr1. The iPS cell-derived neuronal cells also expressed amyloid precursor protein, β-secretase, and γ-secretase components, and were capable of secreting Aβ into the conditioned media. Aβ production was inhibited by β-secretase inhibitor, γ-secretase inhibitor (GSI), and an NSAID; however, there were different susceptibilities to all three drugs between early and late differentiation stages. At the early differentiation stage, GSI treatment caused a fast increase at lower dose (Aβ surge) and drastic decline of Aβ production. Conclusions/Significance:These results indicate that the hiPS cell-derived neuronal cells express functional β- and γ-secretases involved in Aβ production; however, anti-Aβ drug screening using these hiPS cell-derived neuronal cells requires sufficient neuronal differentiation