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Genetics
A genome-wide association meta-analysis on lipoprotein(a) concentrations adjusted for apolipoprotein(a) isoforms
May 17, 2017   Journal Of Lipid Research
Mack S, Coassin S, Rueedi R, Yousri NA, Seppälä I,   . . . . . .   , Lehtimäki T, Hunt SC, Vollenweider P, Lamina C, Kronenberg F
A genome-wide association meta-analysis on lipoprotein(a) concentrations adjusted for apolipoprotein(a) isoforms
May 17, 2017
Journal Of Lipid Research
High lipoprotein(a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) KIV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n=13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease [CAD] risk. A rare SNP (rs186696265; MAF≈1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (OR=1.73, p=3.35x10-30). Median Lp(a) values increased from 2.1 mg/dL to 91.1 mg/dL with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (p=3.47x10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dL corresponding to ≈15% of the populations mean values. Performing a gene-based test of association including suspected Lp(a) receptors and regulators resulted in one significant association of the TLR2 gene with Lp(a) (p = 3.4x10-4). In summary, we identified a large number of independent SNPs in the LPA gene region as well as the APOE2 allele to be significantly associated with Lp(a) concentrations. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.
Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Sniekers S, Stringer S, Watanabe K, Jansen PR, Coleman JRI,   . . . . . .   , Plomin R, Rietveld CA, Tiemeier H, van Duijn CM, Posthuma D
Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence
May 22, 2017
Nature Genetics
Intelligence is associated with important economic and health-related life outcomes. Despite intelligence having substantial heritability (0.54) and a confirmed polygenic nature, initial genetic studies were mostly underpowered. Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 associated SNPs (METAL P < 5 × 10-8) in 18 genomic loci, of which 15 are new. Around half of the SNPs are located inside a gene, implicating 22 genes, of which 11 are new findings. Gene-based analyses identified an additional 30 genes (MAGMA P < 2.73 × 10-6), of which all but one had not been implicated previously. We show that the identified genes are predominantly expressed in brain tissue, and pathway analysis indicates the involvement of genes regulating cell development (MAGMA competitive P = 3.5 × 10-6). Despite the well-known difference in twin-based heratiblity for intelligence in childhood (0.45) and adulthood (0.80), we show substantial genetic correlation (rg = 0.89, LD score regression P = 5.4 × 10-29). These findings provide new insight into the genetic architecture of intelligence.
Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium
May 23, 2017   Scientific Reports
Skaaby T, Taylor AE, Jacobsen RK, Paternoster L, Thuesen BH,   . . . . . .   , Romundstad PR, Skorpen F, Kaprio J, R Munafò M, Linneberg A
Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium
May 23, 2017
Scientific Reports
Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P 
Sex-specific metabolic profiles of androgens and its main binding protein SHBG in a middle aged population without diabetes
May 23, 2017   Scientific Reports
Piontek U, Wallaschofski H, Kastenmüller G, Suhre K, Völzke H, Do KT, Artati A, Nauck M, Adamski J, Friedrich N, Pietzner M
Sex-specific metabolic profiles of androgens and its main binding protein SHBG in a middle aged population without diabetes
May 23, 2017
Scientific Reports
The role of androgens in metabolism with respect to sex-specific disease associations is poorly understood. Therefore, we aimed to provide molecular signatures in plasma and urine of androgen action in a sex-specific manner using state-of-the-art metabolomics techniques. Our study population consisted of 430 men and 343 women, aged 20-80 years, who were recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP-TREND), Germany. We used linear regression models to identify associations between testosterone, androstenedione and dehydroepiandrosterone-sulfate (DHEAS) as well as sex hormone-binding globulin and plasma or urine metabolites measured by mass spectrometry. The analyses revealed major sex-specific differences in androgen-associated metabolites, particularly for levels of urate, lipids and metabolic surrogates of lifestyle factors, like cotinine or piperine. In women, in particular in the postmenopausal state, androgens showed a greater impact on the metabolome than in men (especially DHEAS and lipids were highly related in women). We observed a novel association of androstenedione on the metabolism of biogenic amines and only a small sex-overlap of associations within steroid metabolism. The present study yields new insights in the interaction between androgens and metabolism, especially about their implication in female metabolism.
A novel N-methyltransferase in Arabidopsis appears to feed a conserved pathway for nicotinate detoxification among land plants and is associated with lignin biosynthesis
May 23, 2017   Plant Physiology
Li W, Zhang F, Wu R, Jia L, Li G, Guo Y, Liu C, Wang G
A novel N-methyltransferase in Arabidopsis appears to feed a conserved pathway for nicotinate detoxification among land plants and is associated with lignin biosynthesis
May 23, 2017
Plant Physiology
The Preiss-Handler pathway, which salvages nicotinate (NA) for NAD synthesis, is an indispensable biochemical pathway in land plants. Various NA conjugations (mainly methylation and glycosylation) have been detected, and have long been proposed for NA detoxification in plants. Previously, we demonstrated that NA O-glucosylation functions as a mobilizable storage form for NAD biosynthesis in the Brassicaceae. However, little is known about the functions of other NA conjugations in plants. In this study, we firstly found that N-methylnicotinate is a ubiquitous NA conjugation in land plants. Further, we functionally identified a novel methyltransferase (At3g53140, NANMT), which is mainly responsible for N-methylnicotinate formation, from Arabidopsis. We also established that trigonelline (Tg) is a detoxification form of endogenous NA in plants. Combined phylogenetic analysis and enzymatic assays revealed that NA N-methylation activity was likely derived from duplication and subfunctionalization of an ancestral caffeic acid O-methyltransferase (COMT) gene in the course of land plant evolution. COMT enzymes, which function in S-lignin biosynthesis, also have weak NANMT activity. Our data suggest that NA detoxification conferred by NANMT and COMT might have facilitated the retention of the Preiss-Handler pathway in land plants. {copyright, serif} 2017 American Society of Plant Biologists. All rights reserved.
Protein kinase C theta is dispensable for suppression mediated by CD25+CD4+ regulatory T cells
May 22, 2017   PloS One
Siegmund K, Thuille N, Wachowicz K, Hermann-Kleiter N, Baier G
Protein kinase C theta is dispensable for suppression mediated by CD25+CD4+ regulatory T cells
May 22, 2017
PloS One
The activation of conventional T cells upon T cell receptor stimulation critically depends on protein kinase C theta (PKCθ). However, its role in regulatory T (Treg) cell function has yet to be fully elucidated. Using siRNA or the potent and PKC family-selective pharmacological inhibitor AEB071, we could show that murine Treg-mediated suppression in vitro is independent of PKCθ function. Likewise, Treg cells of PKCθ-deficient mice were fully functional, showing a similar suppressive activity as wild-type CD25+CD4+ T cells in an in vitro suppression assay. Furthermore, in vitro-differentiated wild-type and PKCθ-deficient iTreg cells showed comparable Foxp3 expression as well as suppressive activity. However, we observed a reduced percentage of Foxp3+CD25+ CD4+ T cells in the lymphatic organs of PKCθ-deficient mice. Taken together, our results suggest that while PKCθ is involved in Treg cell differentiation in vivo, it is dispensable for Treg-mediated suppression.
Co-inheritance of glucose-6-phosphate dehydrogenase deficiency mutations and hemoglobin E in a Kachin population in a malaria-endemic region of Southeast Asia
May 22, 2017   PloS One
Deng Z, Yang F, Bai Y, He L, Li Q, Wu Y, Luo L, Li H, Ma L, Yang Z, He Y, Cui L
Co-inheritance of glucose-6-phosphate dehydrogenase deficiency mutations and hemoglobin E in a Kachin population in a malaria-endemic region of Southeast Asia
May 22, 2017
PloS One
Glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobin E (HbE, β26 Glu-Lys) are two common red cell disorders in Southeast Asia. G6PD deficiency produces hemolytic anemia, which can be triggered by certain drugs or infections. HbE is asymptomatic or is manifested as microcytic, minimally hemolytic anemia. The association between G6PD deficiency and HbE is little understood. This study aimed to investigate G6PD deficiency and HbE in a Kachin ethnic group in the China-Myanmar border area. G6PD enzyme activity was measured using a quantitative G6PD assay, G6PD variants genotyped by the SNaPshot assay, and an HbE gene mutation identified by an amplification refractory mutation system and subsequently confirmed by using a reverse dot blot hybridization assay from 100 unrelated individuals in the study area. G6PD enzyme activity ranged from 0.4 to 24.7 U/g Hb, and six males had severe G6PD deficiency (1.2-4.5 U/g Hb). Among the 24 G6PD-deficient subjects, 22 (92%) had the Mahidol 487G>A mutation (12 male hemizygotes, one female homozygote, and nine female heterozygotes), while the G6PD genotypes in two female subjects were unknown. HbE was identified in 39 subjects (20 males and 19 females), including 15 HbEE (seven males and eight females) and 24 HbAE (13 males and 11 females). Twenty-three subjects co-inherited both G6PD deficiency and HbE (22 with HbAE and one with HbEE). Whereas mean Hb levels were not significantly different between the HbA and HbE groups, G6PD-deficient males had significantly lower Hb levels than G6PD-normal males (P < 0.05, t-test). However, it is noteworthy that two G6PD-deficient hemizygous males with HbAE were severely anemic with Hb levels below 50 g/L. This study revealed high prevalence of co-inheritance of G6PD deficiency with HbAE in the Kachin ethnicity, and a potential interaction of the G6PD Mahidol 487G>A and HbAE in males leading to severe anemia. The presence of 6% males with severe G6PD deficiency raised a major concern in the use of primaquine for radical cure of vivax malaria.
Thermal stability and kinetic constants for 129 variants of a family 1 glycoside hydrolase reveal that enzyme activity and stability can be separately designed
May 22, 2017   PloS One
Carlin DA, Hapig-Ward S, Chan BW, Damrau N, Riley M, Caster RW, Bethards B, Siegel JB
Thermal stability and kinetic constants for 129 variants of a family 1 glycoside hydrolase reveal that enzyme activity and stability can be separately designed
May 22, 2017
PloS One
Accurate modeling of enzyme activity and stability is an important goal of the protein engineering community. However, studies seeking to evaluate current progress are limited by small data sets of quantitative kinetic constants and thermal stability measurements. Here, we report quantitative measurements of soluble protein expression in E. coli, thermal stability, and Michaelis-Menten constants (kcat, KM, and kcat/KM) for 129 designed mutants of a glycoside hydrolase. Statistical analyses reveal that functional Tm is independent of kcat, KM, and kcat/KM in this system, illustrating that an individual mutation can modulate these functional parameters independently. In addition, this data set is used to evaluate computational predictions of protein stability using the established Rosetta and FoldX algorithms. Predictions for both are found to correlate only weakly with experimental measurements, suggesting improvements are needed in the underlying algorithms.
The complex genetics of hypoplastic left heart syndrome
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Liu X, Yagi H, Saeed S, Bais AS, Gabriel GC,   . . . . . .   , Tsang M, Martin LJ, Woodrow Benson D, Aronow BJ, Lo CW
The complex genetics of hypoplastic left heart syndrome
May 22, 2017
Nature Genetics
Congenital heart disease (CHD) affects up to 1% of live births. Although a genetic etiology is indicated by an increased recurrence risk, sporadic occurrence suggests that CHD genetics is complex. Here, we show that hypoplastic left heart syndrome (HLHS), a severe CHD, is multigenic and genetically heterogeneous. Using mouse forward genetics, we report what is, to our knowledge, the first isolation of HLHS mutant mice and identification of genes causing HLHS. Mutations from seven HLHS mouse lines showed multigenic enrichment in ten human chromosome regions linked to HLHS. Mutations in Sap130 and Pcdha9, genes not previously associated with CHD, were validated by CRISPR-Cas9 genome editing in mice as being digenic causes of HLHS. We also identified one subject with HLHS with SAP130 and PCDHA13 mutations. Mouse and zebrafish modeling showed that Sap130 mediates left ventricular hypoplasia, whereas Pcdha9 increases penetrance of aortic valve abnormalities, both signature HLHS defects. These findings show that HLHS can arise genetically in a combinatorial fashion, thus providing a new paradigm for the complex genetics of CHD.
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Lu H, Galeano MCR, Ott E, Kaeslin G, Kausalya PJ,   . . . . . .   , Zerres K, Hildebrandt F, Roy S, Wicking C, Bergmann C
Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease
May 22, 2017
Nature Genetics
Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis.
Reevaluation of SNP heritability in complex human traits
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Speed D, Cai N, UCLEB Consortium, Johnson MR, Nejentsev S, Balding DJ
Reevaluation of SNP heritability in complex human traits
May 22, 2017
Nature Genetics
SNP heritability, the proportion of phenotypic variance explained by SNPs, has been reported for many hundreds of traits. Its estimation requires strong prior assumptions about the distribution of heritability across the genome, but current assumptions have not been thoroughly tested. By analyzing imputed data for a large number of human traits, we empirically derive a model that more accurately describes how heritability varies with minor allele frequency (MAF), linkage disequilibrium (LD) and genotype certainty. Across 19 traits, our improved model leads to estimates of common SNP heritability on average 43% (s.d. 3%) higher than those obtained from the widely used software GCTA and 25% (s.d. 2%) higher than those from the recently proposed extension GCTA-LDMS. Previously, DNase I hypersensitivity sites were reported to explain 79% of SNP heritability; using our improved heritability model, their estimated contribution is only 24%.
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
May 22, 2017   Nature Genetics Add nature.com free-link Cancel
Howson JMM, Zhao W, Barnes DR, Ho WK, Young R,   . . . . . .   , Nordestgaard BG, Assimes TL, Danesh J, Butterworth AS, Saleheen D
Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms
May 22, 2017
Nature Genetics
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10-8, in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.
Allele-specific expression reveals interactions between genetic variation and environment
May 22, 2017   Nature Methods Add nature.com free-link Cancel
Knowles DA, Davis JR, Edgington H, Raj A, Favé MJ, Zhu X, Potash JB, Weissman MM, Shi J, Levinson DF, Awadalla P, Mostafavi S, Montgomery SB, Battle A
Allele-specific expression reveals interactions between genetic variation and environment
May 22, 2017
Nature Methods
Identifying interactions between genetics and the environment (GxE) remains challenging. We have developed EAGLE, a hierarchical Bayesian model for identifying GxE interactions based on associations between environmental variables and allele-specific expression. Combining whole-blood RNA-seq with extensive environmental annotations collected from 922 human individuals, we identified 35 GxE interactions, compared with only four using standard GxE interaction testing. EAGLE provides new opportunities for researchers to identify GxE interactions using functional genomic data.
Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
May 17, 2017   Nature Add nature.com free-link Cancel
Hattori A, Tsunoda M, Konuma T, Kobayashi M, Nagy T, Glushka J, Tayyari F, McSkimming D, Kannan N, Tojo A, Edison AS, Ito T
Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia
May 17, 2017
Nature
Reprogrammed cellular metabolism is a common characteristic observed in various cancers. However, whether metabolic changes directly regulate cancer development and progression remains poorly understood. Here we show that BCAT1, a cytosolic aminotransferase for branched-chain amino acids (BCAAs), is aberrantly activated and functionally required for chronic myeloid leukaemia (CML) in humans and in mouse models of CML. BCAT1 is upregulated during progression of CML and promotes BCAA production in leukaemia cells by aminating the branched-chain keto acids. Blocking BCAT1 gene expression or enzymatic activity induces cellular differentiation and impairs the propagation of blast crisis CML both in vitro and in vivo. Stable-isotope tracer experiments combined with nuclear magnetic resonance-based metabolic analysis demonstrate the intracellular production of BCAAs by BCAT1. Direct supplementation with BCAAs ameliorates the defects caused by BCAT1 knockdown, indicating that BCAT1 exerts its oncogenic function through BCAA production in blast crisis CML cells. Importantly, BCAT1 expression not only is activated in human blast crisis CML and de novo acute myeloid leukaemia, but also predicts disease outcome in patients. As an upstream regulator of BCAT1 expression, we identified Musashi2 (MSI2), an oncogenic RNA binding protein that is required for blast crisis CML. MSI2 is physically associated with the BCAT1 transcript and positively regulates its protein expression in leukaemia. Taken together, this work reveals that altered BCAA metabolism activated through the MSI2-BCAT1 axis drives cancer progression in myeloid leukaemia.
Plant genetics: Spatial transcriptomics in plants
May 22, 2017   Nature Reviews. Genetics
Lieben L
Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in Obstructive Sleep Apnea
May 20, 2017   Chest
Schwab RJ, Leinwand SE, Bearn CB, Maislin G, Bhat Rao R, Nagaraja A, Wang S, Keenan BT
Digital Morphometrics: A New Upper Airway Phenotyping Paradigm in Obstructive Sleep Apnea
May 20, 2017
Chest
Obstructive sleep apnea (OSA) is associated with changes in pharyngeal anatomy. The goal of this study was to objectively and reproducibly quantify pharyngeal anatomy using digital morphometrics based on a laser ruler, and to assess differences between apneics and controls and associations with AHI (apnea-hypopnea index). This is the first study to use digital morphometrics to quantify intraoral risk factors for OSA. Digital photographs were obtained using an intraoral laser ruler and digital camera in 311 controls (mean AHI=4.2 events/hour) and 533 apneics (mean AHI=39.2 events/hour). The digital morphometric paradigm was validated and reproducible over time and camera distances. A larger modified Mallampati score and having a non-visible airway were associated with a higher AHI both unadjusted (p
Identification of key contributors in complex population structures
May 18, 2017   PloS One
Neuditschko M, Raadsma HW, Khatkar MS, Jonas E, Steinig EJ, Flury C, Signer-Hasler H, Frischknecht M, von Niederhäusern R, Leeb T, Rieder S
Identification of key contributors in complex population structures
May 18, 2017
PloS One
Evaluating the genetic contribution of individuals to population structure is essential to select informative individuals for genome sequencing, genotype imputation and to ascertain complex population structures. Existing methods for the selection of informative individuals for genomic imputation solely focus on the identification of key ancestors, which can lead to a loss of phasing accuracy of the reference population. Currently many methods are independently applied to investigate complex population structures. Based on the Eigenvalue Decomposition (EVD) of a genomic relationship matrix we describe a novel approach to evaluate the genetic contribution of individuals to population structure. We combined the identification of key contributors with model-based clustering and population network visualization into an integrated three-step approach, which allows identification of high-resolution population structures and substructures around such key contributors. The approach was applied and validated in four disparate datasets including a simulated population (5,100 individuals and 10,000 SNPs), a highly structured experimental sheep population (1,421 individuals and 44,693 SNPs) and two large complex pedigree populations namely horse (1,077 individuals and 38,124 SNPs) and cattle (2,457 individuals and 45,765 SNPs). In the simulated and experimental sheep dataset, our method, which is unsupervised, successfully identified all known key contributors. Applying our three-step approach to the horse and cattle populations, we observed high-resolution population substructures including the absence of obvious important key contributors. Furthermore, we show that compared to commonly applied strategies to select informative individuals for genotype imputation including the computation of marginal gene contributions (Pedig) and the optimization of genetic relatedness (Rel), the selection of key contributors provided the highest phasing accuracies within the selected reference populations. The presented approach opens new perspectives in the characterization and informed management of populations in general, and in areas such as conservation genetics and selective animal breeding in particular, where assessing the genetic contribution of influential and admixed individuals is crucial for research and management applications. As such, this method provides a valuable complement to common applied tools to visualize complex population structures and to select individuals for re-sequencing.
Transcriptomic analysis of salt stress responsive genes in Rhazya stricta
May 18, 2017   PloS One
Hajrah NH, Obaid AY, Atef A, Ramadan AM, Arasappan D,   . . . . . .   , Sabir JSM, Khiyami MA, Hall N, Bahieldin A, Jansen RK
Transcriptomic analysis of salt stress responsive genes in Rhazya stricta
May 18, 2017
PloS One
Rhazya stricta is an evergreen shrub that is widely distributed across Western and South Asia, and like many other members of the Apocynaceae produces monoterpene indole alkaloids that have anti-cancer properties. This species is adapted to very harsh desert conditions making it an excellent system for studying tolerance to high temperatures and salinity. RNA-Seq analysis was performed on R. stricta exposed to severe salt stress (500 mM NaCl) across four time intervals (0, 2, 12 and 24 h) to examine mechanisms of salt tolerance. A large number of transcripts including genes encoding tetrapyrroles and pentatricopeptide repeat (PPR) proteins were regulated only after 12 h of stress of seedlings grown in controlled greenhouse conditions. Mechanisms of salt tolerance in R. stricta may involve the upregulation of genes encoding chaperone protein Dnaj6, UDP-glucosyl transferase 85a2, protein transparent testa 12 and respiratory burst oxidase homolog protein b. Many of the highly-expressed genes act on protecting protein folding during salt stress and the production of flavonoids, key secondary metabolites in stress tolerance. Other regulated genes encode enzymes in the porphyrin and chlorophyll metabolic pathway with important roles during plant growth, photosynthesis, hormone signaling and abiotic responses. Heme biosynthesis in R. stricta leaves might add to the level of salt stress tolerance by maintaining appropriate levels of photosynthesis and normal plant growth as well as by the participation in reactive oxygen species (ROS) production under stress. We speculate that the high expression levels of PPR genes may be dependent on expression levels of their targeted editing genes. Although the results of PPR gene family indicated regulation of a large number of transcripts under salt stress, PPR actions were independent of the salt stress because their RNA editing patterns were unchanged.
Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU
May 18, 2017   PloS One
Durrer KE, Allen MS, Hunt von Herbing I
Genetically engineered probiotic for the treatment of phenylketonuria (PKU); assessment of a novel treatment in vitro and in the PAHenu2 mouse model of PKU
May 18, 2017
PloS One
Phenylketonuria (PKU) is a genetic disease characterized by the inability to convert dietary phenylalanine to tyrosine by phenylalanine hydroxylase. Given the importance of gut microbes in digestion, a genetically engineered microbe could potentially degrade some ingested phenylalanine from the diet prior to absorption. To test this, a phenylalanine lyase gene from Anabaena variabilis (AvPAL) was codon-optimized and cloned into a shuttle vector for expression in Lactobacillus reuteri 100-23C (pHENOMMenal). Functional expression of AvPAL was determined in vitro, and subsequently tested in vivo in homozygous PAHenu2 (PKU model) mice. Initial trials of two PAHenu2 homozygous (PKU) mice defined conditions for freeze-drying and delivery of bacteria. Animals showed reduced blood phe within three to four days of treatment with pHENOMMenal probiotic, and blood phe concentrations remained significantly reduced (P < 0.0005) compared to untreated controls during the course of experiments. Although pHENOMMenal probiotic could be cultured from fecal samples at four months post treatment, it could no longer be cultivated from feces at eight months post treatment, indicating eventual loss of the microbe from the gut. Preliminary screens during experimentation found no immune response to AvPAL. Collectively these studies provide data for the use of a genetically engineered probiotic as a potential treatment for PKU.
Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles
May 18, 2017   PloS One
Vanni VS, Somigliana E, Reschini M, Pagliardini L, Marotta E, Faulisi S, Paffoni A, Vigano' P, Vegetti W, Candiani M, Papaleo E
Top quality blastocyst formation rates in relation to progesterone levels on the day of oocyte maturation in GnRH antagonist IVF/ICSI cycles
May 18, 2017
PloS One
Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a "freeze-all" strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5-6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p
Lipid bodies accumulation in Leishmania infantum-infected C57BL/6 macrophages
May 18, 2017   Parasite Immunology
Rodríguez NE, Lockard RD, Turcotte EA, Araujo-Santos T, Bozza PT, Borges VM, Wilson ME
Lipid bodies accumulation in Leishmania infantum-infected C57BL/6 macrophages
May 18, 2017
Parasite Immunology
Lipid bodies (LBs) are intracellular accumulations of neutral lipids surrounded by a single membrane. These organelles are involved in the production of eicosanoids, which modulate immunity by either promoting or dampening inflammatory responses. Leishmania infantum, the etiological agent of visceral leishmaniasis in Brazil, is an intracellular parasite that causes disease by suppressing macrophage microbicidal responses. C57BL/6 mouse bone marrow-derived macrophages infected with L. infantum strain LcJ had higher numbers of LB+ cells (P 3μm) LBs were present inside parasitophorous vacuoles (PVs). These results contrast with those of L. infantum-infected BALB/c macrophages, in which the only LBs are derived from parasite, not macrophage origin. Increased LBs in C57BL/6 macrophages in close association with parasites would position host LBs where they could modulate L. infantum infection. These results imply a potential influence of the host genetics on the role of LBs in host-pathogen interactions. Overall, our data support a model in which the expression, and the role of LBs upon infection, ultimately depends of the specific combination of host-pathogen interactions. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Plasma and Serum Metabolite Association Networks: Comparability within and between Studies Using NMR and MS Profiling
May 18, 2017   Journal Of Proteome Research
Suarez-Diez M, Adam J, Adamski J, Chasapi SA, Luchinat C, Peters A, Prehn C, Santucci C, Spyridonidis A, Spyroulias GA, Tenori L, Wang-Sattler R, Saccenti E
Plasma and Serum Metabolite Association Networks: Comparability within and between Studies Using NMR and MS Profiling
May 18, 2017
Journal Of Proteome Research
Blood is one of the most used biofluids in metabolomics studies, and the serum and plasma fractions are routinely used as a proxy for blood itself. Here we investigated the association networks of an array of 29 metabolites identified and quantified via NMR in the plasma and serum samples of two cohorts of ∼1000 healthy blood donors each. A second study of 377 individuals was used to extract plasma and serum samples from the same individual on which a set of 122 metabolites were detected and quantified using FIA-MS/MS. Four different inference algorithms (ARANCE, CLR, CORR, and PCLRC) were used to obtain consensus networks. The plasma and serum networks obtained from different studies showed different topological properties with the serum network being more connected than the plasma network. On a global level, metabolite association networks from plasma and serum fractions obtained from the same blood sample of healthy people show similar topologies, and at a local level, some differences arise like in the case of amino acids.
Abstracts of the 52nd Workshop for Pediatric Research : Frankfurt, Germany. 27-28 October 2016
May 18, 2017   Molecular And Cellular Pediatrics
van den Bruck R, Weil PP, Ziegenhals T, Schreiner P, Juranek S,   . . . . . .   , Nonnenmacher L, Langhans J, Schneele L, Trenkler N, Debatin KM
Abstracts of the 52nd Workshop for Pediatric Research : Frankfurt, Germany. 27-28 October 2016
May 18, 2017
Molecular And Cellular Pediatrics
van den Bruck R, Weil PP, Ziegenhals T, Schreiner P, Juranek S, Gödde D, Vogel S, Schuster F, Orth V, Dörner J, Pembaur D, Röper M, Störkel S, Zirngibl H, Wirth S, Jenke ACW, Postberg J, Boy N, Heringer J, Haege G, Glahn EM, Hoffmann GF, Garbade SF, Burgard P, Kölker S, Chao CM, Yahya F, Moiseenko A, Shrestha A, Ahmadvand N, Quantius J, Wilhelm J, El-Agha E, Zimmer KP, Bellusci S, Staufner C, Kölker S, Prokisch H, Hoffmann GF, Seeliger S, Müller M, Hippe A, Steinkraus H, Wauer R, Lachmann B, Hofmann SR, Hedrich CM, Zierk J, Arzideh F, Haeckel R, Rascher W, Rauh M, Metzler M, Thieme S, Bandoła J, Richter C, Ryser M, Jamal A, Ashton MP, von Bonin M, Kuhn M, Hedrich CM, Bonifacio E, Berner R, Brenner S, Hammersen J, Has C, Naumann-Bartsch N, Stachel D, Kiritsi D, Söder S, Tardieu M, Metzler M, Bruckner-Tuderman L, Schneider H, Bohne F, Langer D, Cencic R, Eggermann T, Zechner U, Pelletier J, Zepp F, Enklaar T, Prawitt D, Pech M, Weckmann M, Heinsen FA, Franke A, Happle C, Dittrich AM, Hansen G, Fuchs O, von Mutius E, Oliver BG, Kopp MV, Paret C, Russo A, Theruvath J, Keller B, El Malki K, Lehmann N, Wingerter A, Neu MA, Aslihan GA, Wagner W, Sommer C, Pietsch T, Seidmann L, Faber J, Schreiner F, Ackermann M, Michalik M, Rother E, Bilkei-Gorzo A, Racz I, Bindila L, Lutz B, Dötsch J, Zimmer A, Woelfle J, Fischer HS, Ullrich TL, Bührer C, Czernik C, Schmalisch G, Stein R, Hofmann SR, Hagenbuchner J, Kiechl-Kohlendorfer U, Obexer P, Ausserlechner MJ, Loges NT, Frommer AT, Wallmeier J, Omran H, Öner-Sieben S, Gimpfl M, Rozman J, Irmler M, Beckers J, De Angelis MH, Roscher A, Wolf E, Ensenauer R, Nemes K, Frühwald M, Hasselblatt M, Siebert R, Kordes U, Kool M, Wang H, Hardy H, Refai O, Barwick KES, Zimmerman HH, Weis J, Baple EL, Crosby AH, Cirak S, Hellmuth C, Uhl O, Standl M, Heinrich J, Thiering E, Koletzko B, Blümel L, Kerl K, Picard D, Frühwald MC, Liebau MC, Reifenberger G, Borkhardt A, Hasselblatt M, Remke M, Tews D, Wabitsch M, Fischer-Posovszky P, Westhoff MA, Nonnenmacher L, Langhans J, Schneele L, Trenkler N, Debatin KM
Leveraging Human Genetics to Understand the Relation of LDL Cholesterol with Type 2 Diabetes
May 18, 2017   Clinical Chemistry
Ingelsson E, Knowles JW
Tea and coffee consumption in relation to DNA methylation in four European cohorts
May 23, 2017   Human Molecular Genetics
Ek WE, Tobi EW, Ahsan M, Lampa E, Ponzi E,   . . . . . .   , Vineis P, Lind L, Flanagan JM, Johansson Å, Epigenome-Wide Association study Consortium
Tea and coffee consumption in relation to DNA methylation in four European cohorts
May 23, 2017
Human Molecular Genetics
Lifestyle factors, such as food choices and exposure to chemicals, can alter DNA methylation and lead to changes in gene activity. Two such exposures with pharmacologically active components are coffee and tea consumption. Both coffee and tea has been suggested to play an important role in modulating disease-risk in humans by suppressing tumour progression, decreasing inflammation and influencing estrogen metabolism. These mechanisms may be mediated by changes in DNA methylation.To investigate if DNA methylation in blood is associated with coffee and tea consumption we performed a genome-wide DNA methylation study for coffee and tea consumption in four European cohorts (N = 3,096). DNA methylation was measured from whole blood at 421,695 CpG sites distributed throughout the genome and analysed in men and women both separately and together in each cohort. Meta-analyses of the results and additional regional-level analyses were performed.After adjusting for multiple testing, the meta-analysis revealed that two individual CpG-sites, mapping to DNAJC16 and TTC17, were differentially methylated in relation to tea consumption in women. No individual sites were associated in men or in the sex-combined analysis for tea or coffee. The regional analysis revealed that 28 regions were differentially methylated in relation to tea consumption in women. These regions contained genes known to interact with estradiol metabolism and cancer. No significant regions were found in the sex-combined and male-only analysis for either tea or coffee consumption. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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