Neuregulin 1 Type III/ErbB Signaling Is Crucial for Schwann Cell Colonization of Sympathetic Axons

Analysis of Schwann cell (SC) development has been hampered by the lack of growing axons in many commonly used in vitro assays. As a consequence, the molecular signals and cellular dynamics of SC development along peripheral axons are still only poorly understood. Here we use a superior cervical ganglion (SCG) explant assay, in which axons elongate after treatment with nerve growth factor (NGF). Migration as well as proliferation and apoptosis of endogenous SCG-derived SCs along sympathetic axons were studied in these cultures using pharmacological interference and time-lapse imaging. Inhibition of ErbB receptor tyrosine kinases leads to reduced SC proliferation, increased apoptosis and thereby severely interfered with SC migration to distal axonal sections and colonization of axons. Furthermore we demonstrate that SC colonization of axons is also strongly impaired in a specific null mutant of an ErbB receptor ligand, Neuregulin 1 (NRG1) type III. Taken together, using a novel SC development assay, we demonstrate that NRG1 type III serves as a critical axonal signal for glial ErbB receptors that drives SC development along sympathetic axons

Effects of mental health self-efficacy on outcomes of a mobile phone and web intervention for mild-to-moderate depression, anxiety and stress: secondary analysis of a randomised controlled trial.

Background: Online psychotherapy is clinically effective yet why, how, and for whom the effects are greatest remain largely unknown. In the present study, we examined whether mental health self-efficacy (MHSE), a construct derived from Bandura’s Social Learning Theory (SLT), influenced symptom and functional outcomes of a new mobile phone and web-based psychotherapy intervention for people with mild-to-moderate depression, anxiety and stress. Methods: STUDY I: Data from 49 people with symptoms of depression, anxiety and/or stress in the mild-to-moderate range were used to examine the reliability and construct validity of a new measure of MHSE, the Mental Health Self-efficacy Scale (MHSES). STUDY II: We conducted a secondary analysis of data from a recently completed randomised controlled trial (N = 720) to evaluate whether MHSE effected post-intervention outcomes, as measured by the Depression, Anxiety and Stress Scales (DASS) and Work and Social Adjustment Scale (WSAS), for people with symptoms in the mild-to-moderate range. Results: STUDY I: The data established that the MHSES comprised a unitary factor, with acceptable internal reliability (Cronbach’s alpha = .89) and construct validity. STUDY II: The intervention group showed significantly greater improvement in MHSE at post-intervention relative to the control conditions (p’s < = .000). MHSE mediated the effects of the intervention on anxiety and stress symptoms. Furthermore, people with low pre-treatment MHSE reported the greatest post-intervention gains in depression, anxiety and overall distress. No effects were found for MHSE on work and social functioning. Conclusion: Mental health self-efficacy influences symptom outcomes of a self-guided mobile phone and web-based psychotherapeutic intervention and may itself be a worthwhile target to increase the effectiveness and efficiency of online treatment programs

A Draft of the Human Septin Interactome

Background: Septins belong to the GTPase superclass of proteins and have been functionally implicated in cytokinesis and the maintenance of cellular morphology. They are found in all eukaryotes, except in plants. In mammals, 14 septins have been described that can be divided into four groups. It has been shown that mammalian septins can engage in homo- and heterooligomeric assemblies, in the form of filaments, which have as a basic unit a hetero-trimeric core. In addition, it has been speculated that the septin filaments may serve as scaffolds for the recruitment of additional proteins. Methodology/Principal Findings: Here, we performed yeast two-hybrid screens with human septins 1-10, which include representatives of all four septin groups. Among the interactors detected, we found predominantly other septins, confirming the tendency of septins to engage in the formation of homo- and heteropolymeric filaments. Conclusions/Significance: If we take as reference the reported arrangement of the septins 2, 6 and 7 within the heterofilament, (7-6-2-2-6-7), we note that the majority of the observed interactions respect the ""group rule"", i.e. members of the same group (e. g. 6, 8, 10 and 11) can replace each other in the specific position along the heterofilament. Septins of the SEPT6 group preferentially interacted with septins of the SEPT2 group (p<0.001), SEPT3 group (p<0.001) and SEPT7 group (p<0.001). SEPT2 type septins preferentially interacted with septins of the SEPT6 group (p<0.001) aside from being the only septin group which interacted with members of its own group. Finally, septins of the SEPT3 group interacted preferentially with septins of the SEPT7 group (p<0.001). Furthermore, we found non-septin interactors which can be functionally attributed to a variety of different cellular activities, including: ubiquitin/sumoylation cycles, microtubular transport and motor activities, cell division and the cell cycle, cell motility, protein phosphorylation/signaling, endocytosis, and apoptosis.Fundao de Amparo a Pesquisa do Estado Sao Paulo (Fapesp)CAPES: Coordenao de Aperfeioamento de Pessoal de Navel SuperiorConselho Nacional de Pesquisa e Desenvolvimento (CNPq)Laboratorio Nacional de Biociencias-Centro Nacional de Pesquisa em Energia e Materais (LNBio-CNPEM

Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion? A critical analysis

The ADA and the EASD recently published a consensus statement for the medical management of hyperglycaemia in patients with type 2 diabetes. The authors advocate initial treatment with metformin monotherapy and lifestyle modification, followed by addition of basal insulin or a sulfonylurea if glycaemic goals are not met (tier 1 recommendations). All other glucose-lowering therapies are relegated to a secondary (tier 2) status and only recommended for selected clinical settings. In our view, this algorithm does not offer physicians and patients the appropriate selection of options to individualise and optimise care with a view to sustained control of blood glucose and reduction both of diabetes complications and cardiovascular risk. This paper critically assesses the basis of the ADA/EASD algorithm and the resulting tiers of treatment options

Molybdenum accumulation at Ferrite : Austenite interfaces during isothermal transformation of an Fe-0.24 Pct C-0.93 Pct Mo alloy

A scanning transmission electron microscope (STEM) technique was used to measure Mo concentrations at ferrite: austenite (alpha:gamma) interfaces in an Fe-0.24 pct C-0.93 pet Mo alloy partially transformed at 650 degreesC, 630 degreesC, and 610 degreesC. These concentrations were quite small at 650 degreesC, which is just below the bay temperature of the time-temperature-transformation (TTT) curve for the initiation of ferrite formation. There were larger concentrations at 630 degreesC, a temperature at which transformation stasis (incomplete transformation) occurred. Concentrations at 610 degreesC were intermediate between the values observed at 650 degreesC and 630 degreesC. The average accumulation at the latter temperatures increased appreciably as a function of transformation time. After each heat treatment, there was considerable variation in Mo accumulation from one alpha:gamma interface to another and, to a lesser extent, from one region to another along the same interface. These higher Mo concentrations were deduced to have developed largely through volume diffusion of Mo, mainly through ferrite, to interfaces whose ledgewise growth had been interrupted by growth stasis. (Mo2C precipitation at alpha:gamma boundaries occurred only at the end of growth stasis.) It appears that only a very small amount of Mo segregation is needed, probably at specific interfacial sites, in order to produce growth cessation. Growth kinetics anomalies of this kind continue to provide the best evidence available for the operation of a coupled-solute drag effect

DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human Methylation EPIC array, we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women’s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR≤0.05) and 236 (Bonferroni corrected p ≤ 6.45×10−8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer ≤0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195 g (95%CI: −241, −149 g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin-releasing hormone-binding protein (CRHBP). Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p = 1.37×10−255), maternal smoking (7.71%, p = 1.50 x 10−57) and maternal plasma folate levels during pregnancy (0.33%, p = 0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs

Dataset to support the article &quot;DNA methylation signatures in cord blood associated with birthweight are enriched for dmCpGs previously associated with maternal hypertension or pre-eclampsia, smoking and folic acid intake&quot;

Many epidemiological studies have linked low birthweight to an increased risk of non-communicable diseases (NCDs) in later life, with epigenetic proceseses suggested as an underlying mechanism. Here, we sought to identify neonatal methylation changes associated with birthweight, at both the individual CpG and genomic regional level, and whether the birthweight-associated methylation signatures were associated with specific maternal factors. Using the Illumina Human MethylationEPIC array we assessed DNA methylation in the cord blood of 557 and 483 infants from the UK Pregnancies Better Eating and Activity Trial and Southampton Women&rsquo;s Survey, respectively. Adjusting for gestational age and other covariates, an epigenome-wide association study identified 2911 (FDR&le;0.05) and 236 (Bonferroni corrected p&le;6.45x10&minus;8) differentially methylated CpGs (dmCpGs), and 1230 differentially methylated regions (DMRs) (Stouffer &le;0.05) associated with birthweight. The top birthweight-associated dmCpG was located within the Homeobox Telomere-Binding Protein 1 (HMBOX1) gene with a 195g (95%CI: -241, -149g) decrease in birthweight per 10% increase in methylation, while the top DMR was located within the promoter of corticotropin releasing hormone binding protein (CRHBP).. Furthermore, the birthweight-related dmCpGs were enriched for dmCpGs previously associated with gestational hypertension/pre-eclampsia (14.51%, p=1.37x10&minus;255), maternal smoking (7.71%, p=1.50x10&minus;57) and maternal plasma folate levels during pregnancy (0.33%, p=0.029). The identification of birthweight-associated methylation markers, particularly those connected to specific pregnancy complications and exposures, may provide insights into the developmental pathways that affect birthweight and/or suggest surrogate markers to identify adverse prenatal exposures for stratifying for individuals at risk of later NCDs.</span