Notch signaling in mouse blastocyst development and hatching

Research Areas: Developmental BiologyBackground: Mammalian early embryo development requires a well-orchestrated interplay of cell signaling pathways. Notch is a major regulatory pathway involved in cell-fate determination in embryonic and adult scenarios. However, the role of Notch in embryonic pre-implantation development is controversial. In particular, Notch role on blastocyst development and hatching remains elusive, and a complete picture of the transcription and expression patterns of Notch components during this time-period is not available. Results: This study provided a comprehensive view on the dynamics of individual embryo gene transcription and protein expression patterns of Notch components (receptors Notch1–4; ligands Dll1 and Dll4, Jagged1–2; and effectors Hes1–2), and their relationship with transcription of gene markers of pluripotency and differentiation (Sox2, Oct4, Klf4, Cdx2) during mouse blastocyst development and hatching. Transcription of Notch1–2, Jagged1–2 and Hes1 was highly prevalent and dynamic along stages of development, whereas transcription of Notch3–4, Dll4 and Hes2 had a low prevalence among embryos. Transcription levels of Notch1, Notch2, Jagged2 and Hes1 correlated with each other and with those of pluripotency and differentiation genes. Gene transcription was associated to protein expression, except for Jagged2, where high transcription levels in all embryos were not translated into protein. Presence of Notch signaling activity was confirmed through nuclear NICD and Hes1 detection, and downregulation of Hes1 transcription following canonical signaling blockade with DAPT. In vitro embryo culture supplementation with Jagged1 had no effect on embryo developmental kinetics. In contrast, supplementation with Jagged2 abolished Jagged1 transcription, downregulated Cdx2 transcription and inhibited blastocyst hatching. Notch signaling blockade by DAPT downregulated transcription of Sox2, and retarded embryo hatching. Conclusion: Transcription of Notch genes showed a dynamic pattern along blastocyst development and hatching. Data confirmed Notch signaling activity, and lead to the suggestion that Notch canonical signaling may be operating through Notch1, Notch3, Jagged1 and Hes1. Embryo culture supplementation with Jagged1 and Jagged2 unveiled a possible regulatory effect between Jagged1, Cdx2 and blastocyst hatching. Overall, results indicate that a deregulation in Notch signaling, either by its over or under-activation, affects blastocyst development and hatching.info:eu-repo/semantics/publishedVersio

Computing, Design, Art: Reflections on an Innovative Moment in History

The paper is concerned with the role of art and design in the history and philosophy of computing. It offers insights arising from research into a period in the 1960s and 70s, particularly in the UK, when computing became more available to artists and designers, focusing on John Lansdown (1929-1999) and Bruce Archer (1922-2005) in London. Models of computing interacted with conceptualisations of art, design and related creative activities in important ways

Prevalence of high frequency hearing loss consistent with noise exposure among people working with sound systems and general population in Brazil: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Music is ever present in our daily lives, establishing a link between humans and the arts through the senses and pleasure. Sound technicians are the link between musicians and audiences or consumers. Recently, general concern has arisen regarding occurrences of hearing loss induced by noise from excessively amplified sound-producing activities within leisure and professional environments. Sound technicians' activities expose them to the risk of hearing loss, and consequently put at risk their quality of life, the quality of the musical product and consumers' hearing. The aim of this study was to measure the prevalence of high frequency hearing loss consistent with noise exposure among sound technicians in Brazil and compare this with a control group without occupational noise exposure.</p> <p>Methods</p> <p>This was a cross-sectional study comparing 177 participants in two groups: 82 sound technicians and 95 controls (non-sound technicians). A questionnaire on music listening habits and associated complaints was applied, and data were gathered regarding the professionals' numbers of working hours per day and both groups' hearing complaint and presence of tinnitus. The participants' ear canals were visually inspected using an otoscope. Hearing assessments were performed (tonal and speech audiometry) using a portable digital AD 229 E audiometer funded by FAPESP.</p> <p>Results</p> <p>There was no statistically significant difference between the sound technicians and controls regarding age and gender. Thus, the study sample was homogenous and would be unlikely to lead to bias in the results. A statistically significant difference in hearing loss was observed between the groups: 50% among the sound technicians and 10.5% among the controls. The difference could be addressed to high sound levels.</p> <p>Conclusion</p> <p>The sound technicians presented a higher prevalence of high frequency hearing loss consistent with noise exposure than did the general population, although the possibility of residual confounding due to unmeasured factors such as socioeconomic status cannot be ruled out.</p

Autism-Associated Gene Expression in Peripheral Leucocytes Commonly Observed between Subjects with Autism and Healthy Women Having Autistic Children

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder

Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci

We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants

Evidence of Disseminated Intravascular Coagulation in a Hemorrhagic Fever with Renal Syndrome—Scoring Models and Severe Illness

Background: Viral hemorrhagic fevers (VHF) are considered to be a serious threat to public health worldwide with up to 100 million cases annually. The general hypothesis is that disseminated intravascular coagulation (DIC) is an important part of the pathogenesis. The study objectives were to study the variability of DIC in consecutive patients with acute hemorrhagic fever with renal syndrome (HFRS), and to evaluate if different established DIC-scores can be used as a prognostic marker for a more severe illness. Method and Findings: In a prospective study 2006–2008, data from 106 patients with confirmed HFRS were analyzed and scored for the presence of DIC according to six different templates based on criteria from the International Society on Thrombosis and Haemostasis (ISTH). The DIC-scoring templates with a fibrinogen/CRP-ratio were most predictive, with predictions for moderate/severe illness (p,0.01) and bleeding of moderate/major importance (p,0.05). With these templates, 18.9–28.3 % of the patients were diagnosed with DIC. Conclusions: DIC was found in about one fourth of the patients and correlated with a more severe disease. This supports that DIC is an important part of the pathogenesis in HFRS. ISTH-scores including fibrinogen/CRP-ratio outperform models without. The high negative predictive value could be a valuable tool for the clinician. We also believe that our findings coul

Hydration of dicalcium silicate and diffusion through neo-formed calcium-silicate-hydrates at weathered surfaces control the long-term leaching behaviour of basic oxygen furnace (BOF) steelmaking slag

Alkalinity generation and toxic trace metal (such as vanadium) leaching from basic oxygen furnace (BOF) steel slag particles must be properly understood and managed by pre-conditioning if beneficial reuse of slag is to be maximised. Water leaching under aerated conditions was investigated using fresh BOF slag at three different particle sizes (0.5–1.0, 2–5 and 10 × 10 × 20 mm blocks) and a 6-month pre-weathered block. There were several distinct leaching stages observed over time associated with different phases controlling the solution chemistry: (1) free-lime (CaO) dissolution (days 0–2); (2) dicalcium silicate (Ca₂SiO₄) dissolution (days 2–14) and (3) Ca–Si–H and CaCO₃ formation and subsequent dissolution (days 14–73). Experiments with the smallest size fraction resulted in the highest Ca, Si and V concentrations, highlighting the role of surface area in controlling initial leaching. After ~2 weeks, the solution Ca/Si ratio (0.7–0.9) evolved to equal those found within a Ca–Si–H phase that replaced dicalcium silicate and free-lime phases in a 30- to 150-μm altered surface region. V release was a two-stage process; initially, V was released by dicalcium silicate dissolution, but V also isomorphically substituted for Si into the neo-formed Ca–Si–H in the alteration zone. Therefore, on longer timescales, the release of V to solution was primarily controlled by considerably slower Ca–Si–H dissolution rates, which decreased the rate of V release by an order of magnitude. Overall, the results indicate that the BOF slag leaching mechanism evolves from a situation initially dominated by rapid hydration and dissolution of primary dicalcium silicate/free-lime phases, to a slow diffusion limited process controlled by the solubility of secondary Ca–Si–H and CaCO₃ phases that replace and cover more reactive primary slag phases at particle surfaces