Correction: Genetic risk for schizophrenia and psychosis in Alzheimer disease.

A number of collaborators were not acknowledged for their contribution to this published article. The acknowledgements that were missing in this published article can now be found in the associated correction.

Ultra-dry air plasma treatment for enhancing the dielectric properties of Al2O3-GPTMS-PMMA hybrid dielectric gate layers in a-IGZO TFT applications.

We assessed the effects of ultra dry-air plasma surface treatments on the properties of Al2O3-GPTMS-PMMA hybrid dielectric layers for applications to high-performance amorphous Indium Gallium Zinc Oxide (a-IGZO) thin film transistors (TFTs). The hybrid layers were deposited by an easy dip coating sol-gel process at low temperature and then treated with dry-air plasma at 1, 2 and 3 consecutive cycles. Their properties were analyzed as a function of the number of plasma cycles and contrasted with those of the untreated ones. The dielectric characteristics of the hybrid layers were determined from I-V and C-f measurements performed on metal-insulator-metal and metal-insulator-semiconductor devices. The results show that the plasma treatments increase the surface energy and wettability of the hybrid films. There is also a reduction of the OH groups and oxygen vacancies in the hybrid network improving the dielectric properties. The incorporation of nitrogen into the hybrid films surface is also observed. The plasma-treated hybrid dielectric layers were applied as dielectric gate in the fabrication of a-IGZO TFTs. The best electrical performance of the fabricated TFTs was achieved with the 3 cycles plasma-treated hybrid dielectric gate, showing high mobility, 29.3 cm2 V-1 s-1, low threshold voltage, 2.9 V, high I ON/OFF current ratio, 106, and low subthreshold swing of 0.42 V dec-1.

Genetic risk for schizophrenia and psychosis in Alzheimer disease.

Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer disease (AD), affecting ~40 to 60% of individuals with AD (AD with psychosis (AD+P)). In comparison with AD subjects without psychosis, AD+P subjects have more rapid cognitive decline and poor outcomes. Prior studies have estimated the heritability of psychosis in AD at 61%, but the underlying genetic sources of this risk are not known. We evaluated a Discovery Cohort of 2876 AD subjects with (N=1761) or without psychosis (N=1115). All subjects were genotyped using a custom genotyping array designed to evaluate single-nucleotide polymorphisms (SNPs) with evidence of genetic association with AD+P and include SNPs affecting or putatively affecting risk for schizophrenia and AD. Results were replicated in an independent cohort of 2194 AD subjects with (N=734) or without psychosis (N=1460). We found that AD+P is associated with polygenic risk for a set of novel loci and inversely associated with polygenic risk for schizophrenia. Among the biologic pathways identified by the associations of schizophrenia SNPs with AD+P are endosomal trafficking, autophagy and calcium channel signaling. To the best of our knowledge, these findings provide the first clear demonstration that AD+P is associated with common genetic variation. In addition, they provide an unbiased link between polygenic risk for schizophrenia and a lower risk of psychosis in AD. This provides an opportunity to leverage progress made in identifying the biologic effects of schizophrenia alleles to identify novel mechanisms protecting against more rapid cognitive decline and psychosis risk in AD.

Fatty acids, epigenetic mechanisms and chronic diseases: a systematic review.

BACKGROUND: Chronic illnesses like obesity, type 2 diabetes (T2D) and cardiovascular diseases, are worldwide major causes of morbidity and mortality. These pathological conditions involve interactions between environmental, genetic, and epigenetic factors. Recent advances in nutriepigenomics are contributing to clarify the role of some nutritional factors, including dietary fatty acids in gene expression regulation. This systematic review assesses currently available information concerning the role of the different fatty acids on epigenetic mechanisms that affect the development of chronic diseases or induce protective effects on metabolic alterations. METHODS: A targeted search was conducted in the PubMed/Medline databases using the keywords "fatty acids and epigenetic". The data were analyzed according to the PRISMA-P guidelines. RESULTS: Consumption fatty acids like n-3 PUFA: EPA and DHA, and MUFA: oleic and palmitoleic acid was associated with an improvement of metabolic alterations. On the other hand, fatty acids that have been associated with the presence or development of obesity, T2D, pro-inflammatory profile, atherosclerosis and IR were n-6 PUFA, saturated fatty acids (stearic and palmitic), and trans fatty acids (elaidic), have been also linked with epigenetic changes. CONCLUSIONS: Fatty acids can regulate gene expression by modifying epigenetic mechanisms and consequently result in positive or negative impacts on metabolic outcomes.

Differential lipid metabolism outcomes associated with ADRB2 gene polymorphisms in response to two dietary interventions in overweight/obese subjects.

BACKGROUND AND AIMS: A precise nutrigenetic management of hypercholesterolemia involves the understanding of the interactions between the individual's genotype and dietary intake. The aim of this study was to analyze the response to two dietary energy-restricted interventions on cholesterol changes in carriers of two ADRB2 polymorphisms. METHODS AND RESULTS: A 4-month nutritional intervention was conducted involving two different hypo-energetic diets based on low-fat (LF) and moderately high-protein (MHP) dietary patterns. A total of 107 unrelated overweight/obese individuals were genotyped for two ADRB2 non-synonymous polymorphisms: Arg16Gly (rs1042713) and Gln27Glu (rs1042714). Genotyping was performed by next-generation sequencing and haplotypes were phenotypically screened. Anthropometric measurements and the biochemical profile were assessed by conventional methods. Both diets induced cholesterol decreases at the end of both nutritional interventions. Interestingly, phenotypical differences were observed according to the Arg16Gly polymorphism. Within the MHP group, Gly16Gly homozygotes had lower reductions in total cholesterol (-6.5 mg/dL vs. -24.2 mg/dL, p = 0.009), LDL-c levels (-1.4 mg/dL vs. -16.5 mg/dL, p = 0.005), and non-HDL-c (-4.5 mg/dL vs. -21.5 mg/dL, p = 0.008) than Arg16 allele carriers. Conversely, within the LF group, Gly16Gly homozygotes underwent similar falls in total cholesterol (-18.5 mg/dL vs. -18.7 mg/dL, ns), LDL-c levels (-9.7 mg/dL vs. -13.1 mg/dL, ns), and non-HDL-c (-15.3 mg/dL vs. -15.7 mg/dL, ns) than Arg16 allele carriers. The Gln27Glu polymorphism and the Gly16/Glu27 haplotype showed similar, but not greater effects. CONCLUSIONS: An energy-restricted LF diet could be more beneficial than a MHP diet to reduce serum cholesterol, LDL-c, and non-HDL-c among Gly16Gly genotype carriers. CLINICALTRIALS.GOV: Identifier: NCT02737267.

First industrial-grade coherent fiber link for optical frequency standard dissemination.

We report on a fully bidirectional 680 km fiber link connecting two cities for which the equipment, the setup, and the characterization are managed for the first time by an industrial consortium. The link uses an active telecommunication fiber network with parallel data traffic and is equipped with three repeater laser stations and four remote double bidirectional erbium-doped fiber amplifiers. We report a short-term stability at 1 s integration time of 5.4×10-16 in 0.5 Hz bandwidth and a long-term stability of 1.7×10-20 at 65,000 s of integration time. The accuracy of the frequency transfer is evaluated as 3×10-20. No shift is observed within the statistical uncertainty. We show a continuous operation over five days with an uptime of 99.93%. This performance is comparable with the state-of-the-art coherent links established by National Metrology Institutes in Europe. It is a first step in the construction of an optical fiber network for metrology in France, which will give access to an ultrahigh performance frequency standard to a wide community of scientific users.

DNA methylation patterns at sweet taste transducing genes are associated with BMI and carbohydrate intake in an adult population.

Individual differences in taste perception may influence appetite, dietary intakes, and subsequently, disease risk. Correlations of DNA methylation patterns at taste transducing genes with BMI and dietary intakes were studied. A nutriepigenomic analysis within the Methyl Epigenome Network Association (MENA) project was conducted in 474 adults. DNA methylation in peripheral white blood cells was analyzed by a microarray approach. KEGG pathway analyses were performed concerning the characterization and discrimination of genes involved in the taste transduction pathway. Adjusted FDR values (p < 0.0001) were used to select those CpGs that showed best correlation with BMI. A total of 29 CpGs at taste transducing genes met the FDR criteria. However, only 12 CpGs remained statistically significant after linear regression analyses adjusted for age and sex. These included cg15743657 (TAS1R2), cg02743674 (TRPM5), cg01790523 (SCN9A), cg15947487 (CALHM1), cg11658986 (ADCY6), cg04149773 (ADCY6), cg02841941 (P2RY1), cg02315111 (P2RX2), cg08273233 (HTR1E), cg14523238 (GABBR2), cg12315353 (GABBR1) and cg05579652 (CACNA1C). Interestingly, most of them were implicated in the sweet taste signaling pathway, except CACNA1C (sour taste). In addition, TAS1R2 methylation at cg15743657 was strongly correlated with total energy (p < 0.0001) and carbohydrate intakes (p < 0.0001). This study suggests that methylation in genes related to sweet taste could be an epigenetic mechanism associated with obesity.

Colorimetric Analysis of Hibiscus Beverages and their Potential Antioxidant Properties.

In food industry, roselle beverages and their subproducts could be functional ingredients since they are an excellent source of bioactive compounds with improved performance due to their important anthocyanins content. The aim of this study was to analyze anthocyanin content and antioxidant properties of aqueous infusions elaborated with color contrasting Hibiscus materials and design a mathematical model in order to predict color-composition relationship. Color measurements of beverages from roselle (Negra, Sudan and Rosa) were made by transmission spectrophotometry, anthocyanins quantification was determined by HPLC, and antioxidant potential was evaluated by in vitro methods (ABTS and FRAP assays). Beverages prepared with particle size minor of 250 µm presented until 4- and 2- times more anthocyanins content and antioxidant capacity respectively, in comparison to beverages prepared with powders with particle size major of 750 µm. Positive correlations among pigments composition and color parameters were found (p < 0.05), showing that anthocyanins content, antioxidant capacity, C*ab and hab values increased in relation with the smallest particle size of flours. Also, mathematical models were stablished to predict anthocyanin content (r ≥ 0.97) and antioxidant capacity (r ≥ 0.89) from color data; we propose equations for quick estimation of the antioxidant capacity in the Hibiscus beverages with high anthocyanin content. The obtained models could be an important tool to be used in food industry for pigment characterization or functional compounds with potential health benefits.

Test of Special Relativity Using a Fiber Network of Optical Clocks.

Phase compensated optical fiber links enable high accuracy atomic clocks separated by thousands of kilometers to be compared with unprecedented statistical resolution. By searching for a daily variation of the frequency difference between four strontium optical lattice clocks in different locations throughout Europe connected by such links, we improve upon previous tests of time dilation predicted by special relativity. We obtain a constraint on the Robertson-Mansouri-Sexl parameter |α|≲1.1×10^{-8}, quantifying a violation of time dilation, thus improving by a factor of around 2 the best known constraint obtained with Ives-Stilwell type experiments, and by 2 orders of magnitude the best constraint obtained by comparing atomic clocks. This work is the first of a new generation of tests of fundamental physics using optical clocks and fiber links. As clocks improve, and as fiber links are routinely operated, we expect that the tests initiated in this Letter will improve by orders of magnitude in the near future.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Genetic diversity and patterns of population structure in Creole goats from the Americas.

Biodiversity studies are more efficient when large numbers of breeds belonging to several countries are involved, as they allow for an in-depth analysis of the within- and between-breed components of genetic diversity. A set of 21 microsatellites was used to investigate the genetic composition of 24 Creole goat breeds (910 animals) from 10 countries to estimate levels of genetic variability, infer population structure and understand genetic relationships among populations across the American continent. Three commercial transboundary breeds were included in the analyses to investigate admixture with Creole goats. Overall, the genetic diversity of Creole populations (mean number of alleles = 5.82 ± 1.14, observed heterozygosity = 0.585 ± 0.074) was moderate and slightly lower than what was detected in other studies with breeds from other regions. The Bayesian clustering analysis without prior information on source populations identified 22 breed clusters. Three groups comprised more than one population, namely from Brazil (Azul and Graúna; Moxotó and Repartida) and Argentina (Long and shorthair Chilluda, Pampeana Colorada and Angora-type goat). Substructure was found in Criolla Paraguaya. When prior information on sample origin was considered, 92% of the individuals were assigned to the source population (threshold q ≥ 0.700). Creole breeds are well-differentiated entities (mean coefficient of genetic differentiation = 0.111 ± 0.048, with the exception of isolated island populations). Dilution from admixture with commercial transboundary breeds appears to be negligible. Significant levels of inbreeding were detected (inbreeding coefficient > 0 in most Creole goat populations, P < 0.05). Our results provide a broad perspective on the extant genetic diversity of Creole goats, however further studies are needed to understand whether the observed geographical patterns of population structure may reflect the mode of goat colonization in the Americas.

Plasma biosignature and brain pathology related to persistent cognitive impairment in late-life depression.

Cognitive impairment is highly prevalent among individuals with late-life depression (LLD) and tends to persist even after successful treatment. The biological mechanisms underlying cognitive impairment in LLD are complex and likely involve abnormalities in multiple pathways, or 'cascades,' reflected in specific biomarkers. Our aim was to evaluate peripheral (blood-based) evidence for biological pathways associated with cognitive impairment in older adults with LLD. To this end, we used a data-driven comprehensive proteomic analysis (multiplex immunoassay including 242 proteins), along with measures of structural brain abnormalities (gray matter atrophy and white matter hyperintensity volume via magnetic resonance imaging), and brain amyloid-ß (Aß) deposition (PiB-positron emission tomography). We analyzed data from 80 older adults with remitted major depression (36 with mild cognitive impairment (LLD+MCI) and 44 with normal cognitive (LLD+NC)) function. LLD+MCI was associated with differential expression of 24 proteins (P<0.05 and q-value <0.30) related mainly to the regulation of immune-inflammatory activity, intracellular signaling, cell survival and protein and lipid homeostasis. Individuals with LLD+MCI also showed greater white matter hyperintensity burden compared with LLD+NC (P=0.015). We observed no differences in gray matter volume or brain Aß deposition between groups. Machine learning analysis showed that a group of three proteins (Apo AI, IL-12 and stem cell factor) yielded accuracy of 81.3%, sensitivity of 75% and specificity of 86.4% in discriminating participants with MCI from those with NC function (with an averaged cross-validation accuracy of 76.3%, sensitivity of 69.4% and specificity of 81.8% with nested cross-validation considering the model selection bias). Cognitive impairment in LLD seems to be related to greater cerebrovascular disease along with abnormalities in immune-inflammatory control, cell survival, intracellular signaling, protein and lipid homeostasis, and clotting processes. These results suggest that individuals with LLD and cognitive impairment may be more vulnerable to accelerated brain aging and shed light on possible mediators of their elevated risk for progression to dementia.

Concentrations of Metals, Metalloids, and Chlorinated Pollutants in Blood and Plasma of White Stork (Ciconia ciconia) Nestlings From Spain.

The aim of this study was to determine the levels of different inorganic elements (lead [Pb], mercury [Hg], and arsenic [As]) and persistent chlorinated pollutants (including polychlorinated biphenyls [PCBs] and organochlorine pesticides [OCPs]) in blood and plasma of White stork (Ciconia ciconia) nestlings from northwest (NW) Spain. The concentrations of PCBs were lower than the limit of detection in all samples. The OCPs γ-HCH, 4,4'-DDE, HCB, and endosulfan were detected most frequently in plasma from White stork nestlings. These OCPs were detected in 98, 54, 39, and 37 % of all samples, respectively. However, the concentrations of organic pollutants were lower than the risk thresholds for birds. The mean levels of the inorganic elements Pb, Hg, and As were found to be 36.92 ± 33.48, 16.48 ± 12.87, and 9.813 ± 13.84 µg/L, respectively. These levels were also lower than the risk thresholds for birds. This study not only provides a snapshot of the levels of both inorganic and organic contaminants in wild White storks in NW Spain, it also provides a useful baseline for biomonitoring levels of the measured contaminants in this area.

Genetic relationships among American donkey populations: insights into the process of colonization.

This study presents the first insights into the genetic diversity and structure of the American donkey metapopulation. The primary objectives were to detect the main structural features underlying variability among American donkey populations, identify boundaries between differentiated gene pools, and draw the main colonization pathways since the introduction of donkeys into America in the 15th century. A panel of 14 microsatellite markers was applied for genotyping 350 American donkeys from 13 countries. The genetic structure of this metapopulation was analysed using descriptive statistics and Bayesian model-based methods. These populations were then compared to a database containing information on 476 individuals from 11 European breeds to identify the most likely ancestral donor populations. Results showed the presence of two distinct genetic pools, with confluence of the two in Colombia. The southern pool showed a unique genetic signature subsequent to an older founder event, but lacked any significant influence of modern gene flow from Europe. The northern pool, conversely, may have retained more ancestral polymorphisms and/or have experienced modern gene flow from Spanish breeds. The Andalusian and, to a lesser extent, the Catalan breeds have left a more pronounced footprint in some of the American donkey populations analysed.

A genome-wide association meta-analysis of plasma Aß peptides concentrations in the elderly.

Amyloid beta (Aß) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aß peptides' functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aß peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aß-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aß1-40 and Aß1-42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10(-)(5)). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aß1-42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aß1-42 secretion. In conclusion, our study results suggest that plasma Aß peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk.

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10(-6) were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10(-7) in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10(-9)). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation.

Chromosome 16 abnormalities in embryos and in sperm from a male with a fragile site at 16q22.1.

Two fragile sites, FRA16B and FRA16C, are located in the chromosome band 16q22.1. Neither of them is associated with any specific clinical condition. We report the development and outcome of a clinically applied PGD cycle in a couple who had difficulty in achieving pregnancy. The woman was a carrier of a balanced reciprocal translocation, t(11;22)(q23;q11.2), and the man presented high expression of the fragile site 16q22.1 (FRA16B/C) in peripheral blood lymphocytes. Gains and losses of chromosome 16 fragments were detected in sperm and embryos. To our knowledge, this is the first documented case suggesting a link between FRA16B/C and chromosome 16 abnormalities in embryos and sperm from a carrier.

Measuring patient tolerance for future adverse events in low-risk emergency department chest pain patients.

STUDY OBJECTIVE: We assess emergency department (ED) patients' risk thresholds for preferring admission versus discharge when presenting with chest pain and determine how the method of information presentation affects patients' choices. METHODS: In this cross-sectional survey, we enrolled a convenience sample of lower-risk acute chest pain patients from an urban ED. We presented patients with a hypothetical value for the risk of adverse outcome that could be decreased by hospitalization and asked them to identify the risk threshold at which they preferred admission versus discharge. We randomized patients to a method of numeric presentation (natural frequency or percentage) and the initial risk presented (low or high) and followed each numeric assessment with an assessment based on visually depicted risks. RESULTS: We enrolled 246 patients and analyzed data on 234 with complete information. The geometric mean risk threshold with numeric presentation was 1 in 736 (1 in 233 with a percentage presentation; 1 in 2,425 with a natural frequency presentation) and 1 in 490 with a visual presentation. Fifty-nine percent of patients (137/234) chose the lowest or highest risk values offered. One hundred fourteen patients chose different thresholds for numeric and visual risk presentations. We observed strong anchoring effects; patients starting with the lowest risk chose a lower threshold than those starting with the highest risk possible and vice versa. CONCLUSION: Using an expected utility model to measure patients' risk thresholds does not seem to work, either to find a stable risk preference within individuals or in groups. Further work in measurement of patients' risk tolerance or methods of shared decisionmaking not dependent on assessment of risk tolerance is needed.