In utero and childhood polybrominated diphenyl ether (PBDE) exposures and neurodevelopment in the CHAMACOS study.

BackgroundCalifornia children's exposures to polybrominated diphenyl ether flame retardants (PBDEs) are among the highest worldwide. PBDEs are known endocrine disruptors and neurotoxicants in animals.ObjectiveHere we investigate the relation of in utero and child PBDE exposure to neurobehavioral development among participants in CHAMACOS (Center for the Health Assessment of Mothers and Children of Salinas), a California birth cohort.MethodsWe measured PBDEs in maternal prenatal and child serum samples and examined the association of PBDE concentrations with children's attention, motor functioning, and cognition at 5 (n = 310) and 7 years of age (n = 323).ResultsMaternal prenatal PBDE concentrations were associated with impaired attention as measured by a continuous performance task at 5 years and maternal report at 5 and 7 years of age, with poorer fine motor coordination-particularly in the nondominant-at both age points, and with decrements in Verbal and Full-Scale IQ at 7 years. PBDE concentrations in children 7 years of age were significantly or marginally associated with concurrent teacher reports of attention problems and decrements in Processing Speed, Perceptual Reasoning, Verbal Comprehension, and Full-Scale IQ. These associations were not altered by adjustment for birth weight, gestational age, or maternal thyroid hormone levels.ConclusionsBoth prenatal and childhood PBDE exposures were associated with poorer attention, fine motor coordination, and cognition in the CHAMACOS cohort of school-age children. This study, the largest to date, contributes to growing evidence suggesting that PBDEs have adverse impacts on child neurobehavioral development

Spatial Distribution of Macrophages During Callus Formation and Maturation Reveals Close Crosstalk Between Macrophages and Newly Forming Vessels

Macrophages are essential players in the process of fracture healing, acting by remodeling of the extracellular matrix and enabling vascularization. Whilst activated macrophages of M1-like phenotype are present in the initial pro-inflammatory phase of hours to days of fracture healing, an anti-inflammatory M2-like macrophage phenotype is supposed to be crucial for the induction of downstream cascades of healing, especially the initiation of vascularization. In a mouse-osteotomy model, we provide a comprehensive characterization of vessel (CD31+, Emcn+) and macrophage phenotypes (F4/80, CD206, CD80, Mac-2) during the process of fracture healing. To this end, we phenotype the phases of vascular regeneration-the expansion phase (d1-d7 after injury) and the remodeling phase of the endothelial network, until tissue integrity is restored (d14-d21 after injury). Vessels which appear during the bone formation process resemble type H endothelium (CD31hiEmcnhi), and are closely connected to osteoprogenitors (Runx2+, Osx+) and F4/80+ macrophages. M1-like macrophages are present in the initial phase of vascularization until day 3 post osteotomy, but they are rare during later regeneration phases. M2-like macrophages localize mainly extramedullary, and CD206+ macrophages are found to express Mac-2+ during the expansion phase. VEGFA expression is initiated by CD80+ cells, including F4/80+ macrophages, until day 3, while subsequently osteoblasts and chondrocytes are main contributors to VEGFA production at the fracture site. Using Longitudinal Intravital Microendoscopy of the Bone (LIMB) we observe changes in the motility and organization of CX3CR1+ cells, which infiltrate the injury site after an osteotomy. A transient accumulation, resulting in spatial polarization of both, endothelial cells and macrophages, in regions distal to the fracture site, is evident. Immunofluorescence histology followed by histocytometric analysis reveals that F4/80+CX3CR1+ myeloid cells precede vascularization

On the meaning of averages in genome-wide association studies: What should come next?

Identifying the association between phenotypes and genotypes is the fundamental basis of genetic analyses. Although genomic technologies used to generate data have rapidly advanced within the last 20 years, the statistical models used in genome-wide associations studies (GWAS) to analyse the data are still predominantly based on the model developed by Fisher more than 100 years ago. The question is, does Fisher’s theory need to be replaced or improved, and if so, what should come next? The theory developed by Fisher was inspired by the field of probability. To make use of probability not only did Fisher have to assume valid a number of questionable hypotheses, but he also had to conceptually frame genotypephenotype associations in a specific way giving primordial importance to the notion of average. However, the ‘average’ in probability results from the notions of ‘imprecision’ or ‘ignorance’. After reviewing thehistorical emergence and societal impact of probability as a method, it is clear what is needed now is a new method acknowledging precision in measurements. That is, a method that does not rely on categorizing or binning data

Analysis of Genotype-Phenotype Association using Genomic Informational Field Theory (GIFT)

We show how field-and information theory can be used to quantify the relationship between genotype and phenotype in cases where phenotype is a continuous variable. Given a sample population of phenotype measurements, from various known genotypes, we show how the ordering of phenotype data can lead to quantification of the effect of genotype. This method does not assume that the data has a Gaussian distribution, it is particularly effective at extracting weak and unusual dependencies of genotype on phenotype. However, in cases where data has a special form, (eg Gaussian), we observe that the effective phenotype field has a special form. We use asymptotic analysis to solve both the forward and reverse formulations of the problem. We show how p-values can be calculated so that the significance of correlation between phenotype and genotype can be quantified. This provides a significant generalisation of the traditional methods used in genome-wide association studies GWAS. We derive a field-strength which can be used to deduce how the correlations between genotype and phenotype, and their impact on the distribution of phenotypes. Highlights: • new method for quantifying relationship between genotype and continuous phenotype • statistical significance can be calculated via explicit expressions for p-values • method makes no assumption on shape of distribution data • forward and inverse problems solved explicitly for the case of weak gene effec

Sex and poverty modify associations between maternal peripartum concentrations of DDT/E and pyrethroid metabolites and thyroid hormone levels in neonates participating in the VHEMBE study, South Africa

Indoor Residual Spraying (IRS), the application of insecticides on the inside walls of dwellings, is used by 84 countries for malaria control. Although effective in preventing malaria, this practice results in elevated insecticide exposure to>100 million people, most of whom are Africans. Pyrethroid insecticides and dichlorodiphenyl trichloroethane (DDT) are currently used for IRS. Animal and in vitro studies suggest that pyrethroids and DDT interfere with thyroid hormone homeostasis but human studies are inconsistent and no prior study has investigated this question in a population residing in an area where IRS is conducted. Our objective was thus to evaluate whether prenatal exposure to pyrethroids, DDT or DDT's breakdown product dichlorodiphenyl dichloroethylene (DDE) is associated with altered thyroid hormone levels among neonates from Limpopo, South Africa, where pyrethroids and DDT are used annually to control malaria. We measured serum DDT/E and urinary pyrethroid metabolite concentrations in maternal peripartum samples from 717 women participating in the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE), a birth cohort study conducted in Limpopo's Vhembe district. We measured total thyroxine (T4) and thyroidstimulating hormone (TSH) in dried blood spots collected via heel stick. We found that all pyrethroid metabolites were positively associated with TSH; trans-DCCA and 3-PBA showed the strongest associations with a 12.3% (95%CI=3.0, 22.3) and 14.0% (95%CI=0.5, 30.2) change for each 10-fold increase in biomarker concentration, respectively. These associations were substantially stronger among children from households below the South African food poverty line. DDT and DDE were associated with lower total T4 among boys only (β=−0.27 μg/dL per 10-fold increase; 95%CI=−0.47, −0.04). Results suggest that prenatal exposure to DDT, DDE and pyrethroid insecticides is associated with changes in neonatal thyroid hormones consistent with hypothyroidism/hypothyroxinemia and that sex and poverty modify associations. Further research is needed to confirm these findings and examine whether they have implications for child development.The U.S. National Institute of Environmental Health Sciences (1R01ES020360) and a Canada Research Chair in Environmental Health Sciences.http://www.elsevier.com/locate/envintam2020School of Health Systems and Public Health (SHSPH

Investigative power of Genomic Informational Field Theory (GIFT) relative to GWAS for genotype-phenotype mapping

Identifying associations between phenotype and genotype is the fundamental basis of genetic analyses. Inspired by frequentist probability and the work of R.A. Fisher, genome-wide association studies (GWAS) extract information using averages and variances from genotype-phenotype datasets. Averages and variances are legitimated upon creating distribution density functions obtained through the grouping of data into categories. However, as data from within a given category cannot be differentiated, the investigative power of such methodologies is limited. Genomic Informational Field Theory (GIFT) is a method specifically designed to circumvent this issue. The way GIFT proceeds is opposite to that of GWAS. Whilst GWAS determines the extent to which genes are involved in phenotype formation (bottom-up approach), GIFT determines the degree to which the phenotype can select microstates (genes) for its subsistence (top-down approach). Doing so requires dealing with new genetic concepts, a.k.a. genetic paths, upon which significance levels for genotype-phenotype associations can be determined. By using different datasets obtained in ovis aries related to bone growth (Dataset-1) and to a series of linked metabolic and epigenetic pathways (Dataset-2), we demonstrate that removing the informational barrier linked to categories enhances the investigative and discriminative powers of GIFT, namely that GIFT extracts more information than GWAS. We conclude by suggesting that GIFT is an adequate tool to study how phenotypic plasticity and genetic assimilation are linked.</p

Specifications for a digital training toolbox for industry 4.0.

The development in the past decade of Industry 4.0 technologies has brought many new opportunities to manufacturers. The increased digitization of manufacturing operations has led to new modes of production and product development. This digitization has also increased the quantity of sensorial data which is easily available and which can be used to support real-time decision making. That said, with the oppor– tunities come as well a number of challenges. Principally amongst these is a skills gap within the workforce. Without the required knowledge organisations will find it difficult and complex not only to employ these technologies, but also to develop the new manufacturing paradigms of tomorrow. Hence an innovative and effective training methodology is required to address this skills and knowledge gap. As part of the development of this methodology, this paper presents the finding of a study carried out to analyse the knowledge and skills gap, preferred learning methods and styles of trainers, current and past students in engineering Higher Education Institutions. This requirements analysis has led to the specifications for a Digital Training Toolbox, which can be utilised to support the implementation of Inudstry 4.0 technologies and organisational concepts.peer-reviewe

Reducing distance errors for standard candles and standard sirens with weak-lensing shear and flexion maps

Gravitational lensing induces significant errors in the measured distances to high-redshift standard candles and standard sirens such as type-Ia supernovae, gamma-ray bursts, and merging supermassive black hole binaries. There will therefore be a significant benefit from correcting for the lensing error by using independent and accurate estimates of the lensing magnification. We investigate how accurately the magnification can be inferred from convergence maps reconstructed from galaxy shear and flexion data. We employ ray-tracing through the Millennium Simulation to simulate lensing observations in large fields, and perform a weak-lensing reconstruction on these fields. We identify optimal ways to filter the reconstructed convergence maps and to convert them to magnification maps. We find that a shear survey with 100 galaxies/arcmin^2 can help to reduce the lensing-induced distance errors for standard candles/sirens at redshifts z=1.5 (z=5) on average by 20% (10%), whereas a futuristic survey with shear and flexion estimates from 500 galaxies/arcmin^2 yields much larger reductions of 50% (35%). For redshifts z>=3, a further improvement by 5% can be achieved, if the individual redshifts of the galaxies are used in the reconstruction. Moreover, the reconstruction allows one to identify regions for which the convergence is low, and in which an error reduction by up to 75% can be achieved.Comment: 16 pages, 18 figures, submitted to MNRAS, minor changes, references extended, comments welcom

Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants

Background Tetralogy of Fallot (TOF) is common in individuals with hemizygous deletions of chromosome 22q11.2 that remove the cardiac transcription factor TBX1.Objective To assess the contribution of common and rare TBX1 genetic variants to TOF.Design Rare TBX1 variants were sought by resequencing coding exons and splice-site boundaries. Common TBX1 variants were investigated by genotyping 20 haplotype-tagging SNPs capturing all the common variations present at the locus. Association analysis was performed using the program UNPHASED.Patients TBX1 exons were sequenced in 93 patients with non-syndromic TOF. Single nucleotide polymorphism analysis was performed in 356 patients with TOF, their parents and healthy controls.Results Three novel variants not present in 1000 chromosomes from healthy ethnically matched controls were identified. One of these variants, an in-frame 57 base-pair deletion in the third exon which removed 19 evolutionarily conserved residues, decreased transcriptional activity by 40% in a dual luciferase assay (p=0.008). Protein expression studies demonstrated that this mutation affected TBX1 protein stability. After correction for multiple comparisons, no significant associations between common genetic variants and TOF susceptibility were found.Conclusion This study demonstrates that rare TBX1 variants with functional consequences are present in a small proportion of non-syndromic TOF