Infants born to women with substance use: Exploring early neurobehavior with the Dubowitz neurological examination

BackgroundThere is a special concern regarding substance using pregnant women due to the possible adverse effects on the infant. While the immediate effects of prenatal substance exposure are well known, the long-term data on the infants' neurodevelopment is inconclusive.AimsThe purpose of this study was to assess early neurobehavior of infants of mothers with substance use using the Dubowitz examination and to follow their neuromotor development until one year of age.Study design and subjectsNinety-five pregnant women with a recent history of substance use were recruited and followed up at the maternity outpatient clinic. Follow-up data was collected from hospital records and maternal interviews. The Dubowitz neurological examination was performed to the 54 clinically healthy term infants. The results were converted into optimality scores and compared to normative values from clinically healthy term infants derived from a separate normative population. The infant's neuromotor development was followed up to one year of age.ResultsOnly 7% of the infants born to women with recent or current substance use reached optimal scores (n = 30) of these infants was found normal.ConclusionsA high percentage of infants of mothers who were referred prenatally to hospital due to substance use showed suboptimal neurological findings during their first days of life.</div

GPR37 is processed in the N‐terminal ectodomain by ADAM10 and furin

GPR37 is an orphan G protein-coupled receptor (GPCR) implicated in several neurological diseases and important physiological pathways in the brain. We previously reported that its long N-terminal ectodomain undergoes constitutive metalloprotease-mediated cleavage and shedding, which have been rarely described for class A GPCRs. Here, we demonstrate that the protease that cleaves GPR37 at Glu167↓Gln168 is a disintegrin and metalloprotease 10 (ADAM10). This was achieved by employing selective inhibition, RNAi-mediated downregulation, and genetic depletion of ADAM10 in cultured cells as well as in vitro cleavage of the purified receptor with recombinant ADAM10. In addition, the cleavage was restored in ADAM10 knockout cells by overexpression of the wild type but not the inactive mutant ADAM10. Finally, postnatal conditional depletion of ADAM10 in mouse neuronal cells was found to reduce cleavage of the endogenous receptor in the brain cortex and hippocampus, confirming the physiological relevance of ADAM10 as a GPR37 sheddase. Additionally, we discovered that the receptor is subject to another cleavage step in cultured cells. Using site-directed mutagenesis, the site (Arg54↓Asp55) was localized to a highly conserved region at the distal end of the ectodomain that contains a recognition site for the proprotein convertase furin. The cleavage by furin was confirmed by using furin-deficient human colon carcinoma LoVo cells and proprotein convertase inhibitors. GPR37 is thus the first multispanning membrane protein that has been validated as an ADAM10 substrate and the first GPCR that is processed by both furin and ADAM10. The unconventional N-terminal processing may represent an important regulatory element for GPR37

Late glacial and Holocene landscape change and rapid climate and coastal impacts in the Canal Beagle, southernmost Patagonia

Palaeoenvironmental data for the Late Glacial and Holocene periods are provided from Caleta Eugenia, in the eastern sector of Canal Beagle, southernmost Patagonia. The record commences at c. 16 200 cal a bp following glacier retreat in response to climatic warming. However, cooler conditions persisted during the Late Glacial period. The onset of more temperate conditions after c. 12 390 cal a bp is indicated by the arrival of southern beech forest and later establishment at c. 10 640 cal a bp, but the woodland growth was restricted by lower levels of effective moisture. The climate signal is then truncated by a rapid marine incursion at c. 8640 cal a bp which lasted until a more gradual emergence of the coast at c. 6600 cal a bp. During this period the pollen record appears to be dominated by the southern beech woodland. A punctuated hydroseral succession follows the isolation of the site from the sea leading to the re‐establishment of a peat bog. Between c. 5770 cal a bp and the present there were several periods of short rapid climatic change leading to drier conditions, probably as a result of late Holocene periods of climatic warming

Late glacial and Holocene landscape change and rapid climate and coastal impacts in the Canal Beagle, southernmost Patagonia

Palaeoenvironmental data for the Late Glacial and Holocene periods are provided from Caleta Eugenia, in the eastern sector of Canal Beagle, southernmost Patagonia. The record commences at c. 16 200 cal a bp following glacier retreat in response to climatic warming. However, cooler conditions persisted during the Late Glacial period. The onset of more temperate conditions after c. 12 390 cal a bp is indicated by the arrival of southern beech forest and later establishment at c. 10 640 cal a bp, but the woodland growth was restricted by lower levels of effective moisture. The climate signal is then truncated by a rapid marine incursion at c. 8640 cal a bp which lasted until a more gradual emergence of the coast at c. 6600 cal a bp. During this period the pollen record appears to be dominated by the southern beech woodland. A punctuated hydroseral succession follows the isolation of the site from the sea leading to the re‐establishment of a peat bog. Between c. 5770 cal a bp and the present there were several periods of short rapid climatic change leading to drier conditions, probably as a result of late Holocene periods of climatic warming

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P &lt; 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.</p

A Pregnancy and Childhood Epigenetics Consortium (PACE) meta-analysis highlights potential relationships between birth order and neonatal blood DNA methylation

Higher birth order is associated with altered risk of many disease states. Changes in placentation and exposures to in utero growth factors with successive pregnancies may impact later life disease risk via persistent DNA methylation alterations. We investigated birth order with Illumina DNA methylation array data in each of 16 birth cohorts (8164 newborns) with European, African, and Latino ancestries from the Pregnancy and Childhood Epigenetics Consortium. Meta-analyzed data demonstrated systematic DNA methylation variation in 341 CpGs (FDR adjusted P &lt; 0.05) and 1107 regions. Forty CpGs were located within known quantitative trait loci for gene expression traits in blood, and trait enrichment analysis suggested a strong association with immune-related, transcriptional control, and blood pressure regulation phenotypes. Decreasing fertility rates worldwide with the concomitant increased proportion of first-born children highlights a potential reflection of birth order-related epigenomic states on changing disease incidence trends.</p

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications.

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases

Epigenome-wide meta-analysis of prenatal maternal stressful life events and newborn DNA methylation.

This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this recordCode availability: The code used for this EWAS meta-analysis is available from the corresponding authors upon reasonable request.Prenatal maternal stressful life events are associated with adverse neurodevelopmental outcomes in offspring. Biological mechanisms underlying these associations are largely unknown, but DNA methylation likely plays a role. This meta-analysis included twelve non-overlapping cohorts from ten independent longitudinal studies (N = 5,496) within the international Pregnancy and Childhood Epigenetics consortium to examine maternal stressful life events during pregnancy and DNA methylation in cord blood. Children whose mothers reported higher levels of cumulative maternal stressful life events during pregnancy exhibited differential methylation of cg26579032 in ALKBH3. Stressor-specific domains of conflict with family/friends, abuse (physical, sexual, and emotional), and death of a close friend/relative were also associated with differential methylation of CpGs in APTX, MyD88, and both UHRF1 and SDCCAG8, respectively; these genes are implicated in neurodegeneration, immune and cellular functions, regulation of global methylation levels, metabolism, and schizophrenia risk. Thus, differences in DNA methylation at these loci may provide novel insights into potential mechanisms of neurodevelopment in offspring.Medical Research Council and Wellcome Trus