An evolutionary analysis of cAMP-specific Phosphodiesterase 4 alternative splicing

<p>Abstract</p> <p>Background</p> <p>Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the intracellular second messengers: cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP). The cAMP-specific PDE family 4 (PDE4) is widely expressed in vertebrates. Each of the four PDE4 gene isoforms (PDE4 A-D) undergo extensive alternative splicing via alternative transcription initiation sites, producing unique amino termini and yielding multiple splice variant forms from each gene isoform termed long, short, super-short and truncated super-short. Many species across the vertebrate lineage contain multiple splice variants of each gene type, which are characterized by length and amino termini.</p> <p>Results</p> <p>A phylogenetic approach was used to visualize splice variant form genesis and identify conserved splice variants (genome conservation with EST support) across the vertebrate taxa. Bayesian and maximum likelihood phylogenetic inference indicated PDE4 gene duplication occurred at the base of the vertebrate lineage and reveals additional gene duplications specific to the teleost lineage. Phylogenetic inference and PDE4 splice variant presence, or absence as determined by EST screens, were further supported by the genomic analysis of select vertebrate taxa. Two conserved PDE4 long form splice variants were found in each of the PDE4A, PDE4B, and PDE4C genes, and eight conserved long forms from the PDE4 D gene. Conserved short and super-short splice variants were found from each of the PDE4A, PDE4B, and PDE4 D genes, while truncated super-short variants were found from the PDE4C and PDE4 D genes. PDE4 long form splice variants were found in all taxa sampled (invertebrate through mammals); short, super-short, and truncated super-short are detected primarily in tetrapods and mammals, indicating an increasing complexity in both alternative splicing and cAMP metabolism through vertebrate evolution.</p> <p>Conclusions</p> <p>There was a progressive independent incorporation of multiple PDE4 splice variant forms and amino termini, increasing PDE4 proteome complexity from primitive vertebrates to humans. While PDE4 gene isoform duplicates with limited alternative splicing were found in teleosts, an expansion of both PDE4 splice variant forms, and alternatively spliced amino termini predominantly occurs in mammals. Since amino termini have been linked to intracellular targeting of the PDE4 enzymes, the conservation of amino termini in PDE4 splice variants in evolution highlights the importance of compartmentalization of PDE4-mediated cAMP hydrolysis.</p

Technology Transfer and Competitive Advantage: The Managers’ Perspective

Achieving and sustaining competitive advantages is becoming extraordinarily difficult as strategic intangible resources are hidden from public consumption and information asymmetry rules a turbulence business environment. The how of competitive advantage debate revolves around different constructs but technology transfer (technology infrastructure, innovation, and adoption) constitutes the focus of this work. The paper argued from technology transfer proxies to explain firms’ competitive advantage through the knowledge lenses of managers. Cross- sectional survey research design was adopted, the unit of analysis was randomly selected and data were collected from 90 managers of telecommunication companies in Lagos State, Nigeria through a validated questionnaire whose reliability was established. The study provided empirical evidences that a relationship exist between technology transfer dimensions (technology adoption, technology infrastructure, and technology innovation) and competitive advantage (r =0.582, p&lt;0.05; 0.862, p&lt;0.05; 0.684, p&lt;0.05) and that these further affected significantly firms’ competitive advantage (Fstat.19.16, p-value 0.000) among the surveyed companies. The recommendation focused on technology transfer in the form of adoption, infrastructure and innovation within a business ecosystem to promote competitive advantage. Keywords: Technology transfer, competitive advantage, and Nigerian telecommunication industry. DOI: 10.7176/EJBM/11-28-08 Publication date:October 31st 201

Examining intersectoral integration for malaria control programmes in an urban and a rural district in Ghana: a multinomial multilevel analysis

Background: Intersectoral integration is acknowledged to be essential for improving provision of health care and outcomes, yet it remains one of the main primary health care strategic challenges. Although this is well articulated in the literature, the factors that explain differentials in levels of intersectoral integration have not been systematically studied, particularly in low and middle-income countries. In this study, we examine the levels and determinants of intersectoral integration amongst institutions engaged in malaria control programmes in an urban (Kumasi Metropolitan) district and a rural (Ahafo Ano South) district in Ghana. Methods: Interviews were conducted with representatives of 32 institutions engaged in promoting malaria prevention and control. The averaging technique proposed by Brown et al. and a two-level multinomial multilevel ordinal logistic regression were used to examine the levels of integration and the factors that explain the differentials. Results: The results show high disparity in levels of integration amongst institutions in the two districts. Integration was higher in the rural district compared to the urban district. The multivariate analysis revealed that the district effect explained 25% of the variations in integration. The type of institution, level of focus on malaria and source of funding are important predictors of intersectoral integration. Conclusion: Although not causal, integrated malaria control programmes could be important for improving malaria-related health outcomes in less developed regions as evident from the rapid decline in malaria fatality rates observed in the Ahafo Ano South district. Harmonisation of programmes should be encouraged amongst institutions and the public and private sectors should be motivated to work in partnership

Examining intersectoral integration for malaria control programmes in an urban and a rural district in Ghana: a multinomial multilevel analysis

Background: Intersectoral integration is acknowledged to be essential for improving provision of health care and outcomes, yet it remains one of the main primary health care strategic challenges. Although this is well articulated in the literature, the factors that explain differentials in levels of intersectoral integration have not been systematically studied, particularly in low and middle-income countries. In this study, we examine the levels and determinants of intersectoral integration amongst institutions engaged in malaria control programmes in an urban (Kumasi Metropolitan) district and a rural (Ahafo Ano South) district in Ghana. Methods: Interviews were conducted with representatives of 32 institutions engaged in promoting malaria prevention and control. The averaging technique proposed by Brown et al. and a two-level multinomial multilevel ordinal logistic regression were used to examine the levels of integration and the factors that explain the differentials. Results: The results show high disparity in levels of integration amongst institutions in the two districts. Integration was higher in the rural district compared to the urban district. The multivariate analysis revealed that the district effect explained 25% of the variations in integration. The type of institution, level of focus on malaria and source of funding are important predictors of intersectoral integration. Conclusion: Although not causal, integrated malaria control programmes could be important for improving malaria-related health outcomes in less developed regions as evident from the rapid decline in malaria fatality rates observed in the Ahafo Ano South district. Harmonisation of programmes should be encouraged amongst institutions and the public and private sectors should be motivated to work in partnershi

Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers

Background The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. Objective We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. Methods We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell–derived IL-1β levels were measured by means of ELISA. Results Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1β, an innate inflammatory mediator. Conclusions The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory

Organic electrode coatings for next-generation neural interfaces

Traditional neuronal interfaces utilize metallic electrodes which in recent years have reached a plateau in terms of the ability to provide safe stimulation at high resolution or rather with high densities of microelectrodes with improved spatial selectivity. To achieve higher resolution it has become clear that reducing the size of electrodes is required to enable higher electrode counts from the implant device. The limitations of interfacing electrodes including low charge injection limits, mechanical mismatch and foreign body response can be addressed through the use of organic electrode coatings which typically provide a softer, more roughened surface to enable both improved charge transfer and lower mechanical mismatch with neural tissue. Coating electrodes with conductive polymers or carbon nanotubes offers a substantial increase in charge transfer area compared to conventional platinum electrodes. These organic conductors provide safe electrical stimulation of tissue while avoiding undesirable chemical reactions and cell damage. However, the mechanical properties of conductive polymers are not ideal, as they are quite brittle. Hydrogel polymers present a versatile coating option for electrodes as they can be chemically modified to provide a soft and conductive scaffold. However, the in vivo chronic inflammatory response of these conductive hydrogels remains unknown. A more recent approach proposes tissue engineering the electrode interface through the use of encapsulated neurons within hydrogel coatings. This approach may provide a method for activating tissue at the cellular scale, however, several technological challenges must be addressed to demonstrate feasibility of this innovative idea. The review focuses on the various organic coatings which have been investigated to improve neural interface electrodes

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Exonic DNA Sequencing of ERBB4 in Bipolar Disorder

The Neuregulin-ErbB4 pathway plays a crucial role in brain development and constitutes one of the most biologically plausible signaling pathways implicated in schizophrenia and, to a lesser extent, in bipolar disorder (BP). However, recent genome-wide association analyses have not provided evidence for common variation in NRG1 or ERBB4 influencing schizophrenia or bipolar disorder susceptibility. In this study, we investigate the role of rare coding variants in ERBB4 in BP cases with mood-incongruent psychotic features, a form of BP with arguably the greatest phenotypic overlap with schizophrenia. We performed Sanger sequencing of all 28 exons in ERBB4, as well as part of the promoter and part of the 3′UTR sequence, hypothesizing that rare deleterious variants would be found in 188 cases with mood-incongruent psychosis from the GAIN BP study. We found 42 variants, of which 16 were novel, although none were non-synonymous or clearly deleterious. One of the novel variants, present in 11.2% of cases, is located next to an alternative stop codon, which is associated with a shortened transcript of ERBB4 that is not translated. We genotyped this variant in the GAIN BP case-control samples and found a marginally significant association with mood-incongruent psychotic BP compared with controls (additive model: OR = 1.64, P-value = 0.055; dominant model: OR = 1.73. P-value = 0.039). In conclusion, we found no rare variants of clear deleterious effect, but did uncover a modestly associated novel variant that could affect alternative splicing of ERBB4. However, the modest sample size in this study cannot definitively rule out a role for rare variants in bipolar disorder and studies with larger sample sizes are needed to confirm the observed association

The effect of perinatal brain injury on dopaminergic function and hippocampal volume in adult life

Perinatal brain injuries, including hippocampal lesions, cause lasting changes in dopamine function in rodents, but it is not known if this occurs in humans. We compared adults who were born very preterm with perinatal brain injury to those born very preterm without perinatal brain injury, and age-matched controls born at full term using [18F]-DOPA PET and structural MRI. Dopamine synthesis capacity was reduced in the perinatal brain injury group relative to those without brain injury (Cohen's d = 1.36, p=0.02) and the control group (Cohen's d = 1.07, p=0.01). Hippocampal volume was reduced in the perinatal brain injury group relative to controls (Cohen's d = 1.17, p=0.01) and was positively correlated with striatal dopamine synthesis capacity (r = 0.344, p=0.03). This is the first evidence in humans linking neonatal hippocampal injury to adult dopamine dysfunction, and provides a potential mechanism linking early life risk factors to adult mental illness

Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies

The presence and severity of cognitive symptoms, including working memory, executive dysfunction and attentional impairment, contributes materially to functional impairment in schizophrenia. Cognitive symptoms have proven resistant to both first- and second-generation antipsychotic drugs. Efforts to develop a consensus set of cognitive domains that are both disrupted in schizophrenia and are amenable to cross-species validation (e.g. the NIMH CNTRICS and RDoC initiatives) are an important step towards standardisation of outcome measures that can used in preclinical testing of new drugs. While causative genetic mutations have not been identified, new technologies have identified novel genes as well as hitherto candidate genes previously implicated in the pathophysiology of schizophrenia and/or mechanisms of antipsychotic efficacy. This review comprises a selective summary of these developments, particularly phenotypic data arising from preclinical genetic models for cognitive dysfunction in schizophrenia, with the aim of indicating potential new directions for pro-cognitive therapeutics