Review: Placental mitochondrial function and structure in gestational disorders

The aetiology of many gestational disorders is still unknown. However, insufficient trans-placental nutrient and oxygen transfer due to abnormal placentation is characteristic of several pathologies, and may alter the function of placental mitochondria. Mitochondria are multifunctional organelles that respond to a wide range of stimuli - such as physiological changes in cellular energy demands or various pathologies - by reshaping via fusion or fission, increasing/decreasing in number, altering oxidative phosphorylation, and signalling cellular functions such as apoptosis. Mitochondrial function is integral to tissue functions including energy production, metabolism, and regulation of various cellular responses including response to oxidative stress. This review details the functions of placental mitochondria and investigates mitochondrial function and structure in gestational disorders including preeclampsia, intrauterine growth restriction, diabetes mellitus, and obesity. Placental mitochondrial dysfunction may be critical in a range of gestational disorders which have important implications for maternal and fetal/offspring health

Imaging Spectroscopy for Extrasolar Planet Detection

Coronagraphic imaging in combination with moderate to high spectral resolution may prove more effective in both detecting extrasolar planets and characterizing them than a standard coronagraphic imaging approach. We envisage an integral-field spectrograph coupled to a coronagraph to produce a 3D datacube. For the idealised case where the spectrum of the star is well-known and unchanging across the field, we discuss the utility of cross-correlation to seek the extrasolar planet signal, and describe a mathematical approach to completely eliminate stray light from the host star (although not its Poisson noise). For the case where the PSF is dominated by diffraction and scattering effects, and comprises a multitude of speckles within an Airy pattern typical of a space-based observation, we turn the wavelength dependence of the PSF to advantage and present a general way to eliminate the contribution from the star while preserving both the flux and spectrum of the extrasolar planet. We call this method `spectral deconvolution'. We illustrate the dramatic gains by showing an idealized simulation that results in a 20-sigma detection of a Jovian planet at 2 pc with a 2-m coronagraphic space telescope, even though the planet's peak flux is only 1% that of the PSF wings of the host star. This scales to detection of a terrestrial extrasolar planet at 2 pc with an 8-m coronagraphic Terrestrial Planet Finder (TPF) in ~7 hr (or less with appropriate spatial filtering). Data on the spectral characteristics of the extrasolar planet and hence on its atmospheric constituents and possible biomarkers are obtained naturally as part of this process.Comment: 62 pages 27 figures accepted for publication in Ap

Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet.

BACKGROUND: Linoleic acid (LA) is an essential polyunsaturated fatty acid (PUFA) that is required for foetal growth and development. Excess intake of LA can be detrimental for metabolic health due to its pro-inflammatory properties; however, the effect of a diet high in LA on offspring metabolites is unknown. In this study, we aimed to determine the role of maternal or postnatal high linoleic acid (HLA) diet on plasma metabolites in adult offspring. METHODS: Female Wistar Kyoto (WKY) rats were fed with either low LA (LLA) or HLA diet for 10 weeks prior to conception and during gestation/lactation. Offspring were weaned at postnatal day 25 (PN25), treated with either LLA or HLA diets and sacrificed at PN180. Metabolite analysis was performed in plasma samples using Nuclear Magnetic Resonance. RESULTS: Maternal and postnatal HLA diet did not alter plasma metabolites in male and female adult offspring. There was no specific clustering among different treatment groups as demonstrated by principal component analysis. Interestingly, there was clustering among male and female offspring independent of maternal and postnatal dietary intervention. Lysine was higher in female offspring, while 3-hydroxybutyric acid and acetic acid were significantly higher in male offspring. CONCLUSION: In summary, maternal or postnatal HLA diet did not alter the plasma metabolites in the adult rat offspring; however, differences in metabolites between male and female offspring occurred independently of dietary intervention

The Nearby Evolved Stars Survey I. JCMT/SCUBA-2 Submillimeter Detection of the Detached Shell of U Antliae

We present the highest resolution single-dish submillimetre observations of the detached shell source U Antliae to date. The observations were obtained at 450 and 850m with SCUBA-2 instrument on the James Clerk Maxwell Telescope as part of the Nearby Evolved Stars Survey. The emission at 850m peaks at 40 arcsec with hints of a second peak seen at 20 arcsec. The emission can be traced out to a radius of 56 arcsec at a 3 level. The outer peak observed at 850m aligns well with the peak observed at Herschel/PACS wavelengths. With the help of spectral energy distribution fitting and radiative transfer calculations of multiple-shell models for the circumstellar envelope, we explore the various shell structures and the variation of grain sizes along the in the circumstellar envelope. We determine a total shell dust mass of (2.0 0.3) 105 M and established that the thermal pulse that gave rise to the detached shell occurred 3500 500 yr ago

SPACA3gene variants in a New Zealand cohort of infertile and fertile couples

SPRASA (also referred to as SLLP1) is a protein identified in the acrosome of human sperm and encoded by the gene SPACA3. SPRASA is associated with sperm-oocyte recognition and binding, and may play a role in fertility. In order to determine whether variants in the SPACA3 gene are associated with human infertility, we undertook a genetic analysis of 102 infertile and 104 fertile couples. Three gene variants were identified using PCR-based DNA sequencing; 1) an insertion of TGC within a quadruple tri-nucleotide (TGC) repeat region in the 5’ untranslated region (UTR) (g.–22TGC(4_5), 2) a guanine to adenosine transition at position 239 (c.239G> A) resulting in a non-synonymous amino acid substitution from cysteine to tyrosine (p.C80Y) at position 80 in the putative transmembrane region, and 3) a novel nucleotide variant (c.691G> C) located in the 3’UTR. A functional effect of the g.–22TGC (4_5) was confirmed by a luciferase expression assay, while the effects of the variants c.239G> A and c.691G> C were predicted using in silico analysis. Although the frequencies of these variants were not significantly different between the infertile and fertile populations, we present evidence that the variants could affect the expression levels or function of SPRASA, thereby affecting a couple's fertility. Larger populations, especially individuals/couples with unexplained infertility, need to be screened for these variants to validate a relationship with fertility

Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome : a cross-sectional study

Altres ajuts: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health.Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid β peptides 1-42 and 1-40 and their ratio (Aβ), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18 F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aβ and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18 F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5-54·1), and Alzheimer's disease dementia at 53·7 years (49·5-57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90-100% in the seventh decade of life. Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health

Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-β 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein ɛ4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein ɛ4, female ɛ4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein ɛ4 and biomarkers showed that female ɛ4 carriers tended to exhibit lower CSF amyloid-β 42/amyloid-β 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein ɛ4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine

Association of biological sex with clinical outcomes and biomarkers of Alzheimer’s disease in adults with Down syndrome

The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-beta 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein.4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein.4, female.4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, P = 0.01). This difference was not seen in males (52.2 versus 52.5 years, P = 0.76). Our exploratory analyses considering sex, apolipoprotein.4 and biomarkers showed that female.4 carriers tended to exhibit lower CSF amyloid-beta 42/amyloid-beta 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein.4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine

Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study.

INTRODUCTION: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium. METHODS: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects. RESULTS: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar. CONCLUSIONS: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are