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1.
Proc Natl Acad Sci U S A ; 116(43): 21484-21492, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31594846

RESUMO

The relative contributions of genetics and environment to temporal and geographic variation in human height remain largely unknown. Ancient DNA has identified changes in genetic ancestry over time, but it is not clear whether those changes in ancestry are associated with changes in height. Here, we directly test whether changes over the past 38,000 y in European height predicted using DNA from 1,071 ancient individuals are consistent with changes observed in 1,159 skeletal remains from comparable populations. We show that the observed decrease in height between the Early Upper Paleolithic and the Mesolithic is qualitatively predicted by genetics. Similarly, both skeletal and genetic height remained constant between the Mesolithic and Neolithic and increased between the Neolithic and Bronze Age. Sitting height changes much less than standing height-consistent with genetic predictions-although genetics predicts a small post-Neolithic increase that is not observed in skeletal remains. Geographic variation in stature is also qualitatively consistent with genetic predictions, particularly with respect to latitude. Finally, we hypothesize that an observed decrease in genetic heel bone mineral density in the Neolithic reflects adaptation to the decreased mobility indicated by decreased femoral bending strength. This study provides a model for interpreting phenotypic changes predicted from ancient DNA and demonstrates how they can be combined with phenotypic measurements to understand the relative contribution of genetic and developmentally plastic responses to environmental change.

2.
Sci Rep ; 9(1): 13851, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554822

RESUMO

The nickel (Ni)-specific chelator dimethylglyoxime (DMG) has been used for many years to detect, quantitate or decrease Ni levels in various environments. Addition of DMG at millimolar levels has a bacteriostatic effect on some enteric pathogens, including multidrug resistant (MDR) strains of Salmonella Typhimurium and Klebsiella pneumoniae. DMG inhibited activity of two Ni-containing enzymes, Salmonella hydrogenase and Klebsiella urease. Oral delivery of nontoxic levels of DMG to mice previously inoculated with S. Typhimurium led to a 50% survival rate, while 100% of infected mice in the no-DMG control group succumbed to salmonellosis. Pathogen colonization numbers from livers and spleens of mice were 10- fold reduced by DMG treatment of the Salmonella-infected mice. Using Nuclear Magnetic Resonance, we were able to detect DMG in the livers of DMG-(orally) treated mice. Inoculation of Galleria mellonella (wax moth) larvae with DMG prior to injection of either MDR K. pneumoniae or MDR S. Typhimurium led to 40% and 60% survival, respectively, compared to 100% mortality of larvae infected with either pathogen, but without prior DMG administration. Our results suggest that DMG-mediated Ni-chelation could provide a novel approach to combat enteric pathogens, including recalcitrant multi-drug resistant strains.

3.
Science ; 365(6456)2019 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-31467194

RESUMO

Twin and family studies have shown that same-sex sexual behavior is partly genetically influenced, but previous searches for specific genes involved have been underpowered. We performed a genome-wide association study (GWAS) on 477,522 individuals, revealing five loci significantly associated with same-sex sexual behavior. In aggregate, all tested genetic variants accounted for 8 to 25% of variation in same-sex sexual behavior, only partially overlapped between males and females, and do not allow meaningful prediction of an individual's sexual behavior. Comparing these GWAS results with those for the proportion of same-sex to total number of sexual partners among nonheterosexuals suggests that there is no single continuum from opposite-sex to same-sex sexual behavior. Overall, our findings provide insights into the genetics underlying same-sex sexual behavior and underscore the complexity of sexuality.

4.
Biomed Res Int ; 2019: 4715720, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31211138

RESUMO

Purpose: Children with neurological disorders, such as cerebral palsy (CP), have a high risk of developing scoliosis during growth. The fast progression of scoliosis implies in several cases frequent clinical and X-ray examinations. We present an ionizing radiation-free, noncontacting method to estimate the trajectory of the vertebral column and to potentially facilitate medical diagnosis in cases where an X-ray examination is not indicated. Methods: A body scanner and corresponding analysis software tools have been developed to get 3D surface scans of patient torsos and to analyze their spinal curvatures. The trajectory of the vertebral column has been deduced from the body contours at different transverse sectional planes along the vertical torso axis. In order to verify the present methods, we have analyzed twenty-five torso contours, extracted from computer tomography (CT) images of patients who had a CT scan for other medical reasons, but incidentally also showed a scoliosis. The software tools therefore process data from the body scanner as well as X-ray or CT images. Results: The methods presented show good results in the estimations of the lateral deviation of the spine for mild and moderate scoliosis. The partial mismatch for severe cases is associated with a less accurate estimation of the rotation of the vertebrae around the vertical body axis in these cases. In addition, distinct torso contour shapes, in the transverse sections, have been characterized according to the severity of the scoliosis. Conclusion: The hardware and software tools are a first step towards an ionizing radiation-free analysis of progression of scoliosis. However, further improvements of the analysis methods and tests on a larger number of data sets with diverse types of scoliosis are necessary, before its introduction into clinical application as a supplementary tool to conventional examinations.

5.
Elife ; 82019 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-30895926

RESUMO

Genetic predictions of height differ among human populations and these differences have been interpreted as evidence of polygenic adaptation. These differences were first detected using SNPs genome-wide significantly associated with height, and shown to grow stronger when large numbers of sub-significant SNPs were included, leading to excitement about the prospect of analyzing large fractions of the genome to detect polygenic adaptation for multiple traits. Previous studies of height have been based on SNP effect size measurements in the GIANT Consortium meta-analysis. Here we repeat the analyses in the UK Biobank, a much more homogeneously designed study. We show that polygenic adaptation signals based on large numbers of SNPs below genome-wide significance are extremely sensitive to biases due to uncorrected population stratification. More generally, our results imply that typical constructions of polygenic scores are sensitive to population stratification and that population-level differences should be interpreted with caution. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

6.
Am J Med Genet B Neuropsychiatr Genet ; 180(6): 439-447, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30708398

RESUMO

Major depressive disorder (MDD) is clinically heterogeneous with prevalence rates twice as high in women as in men. There are many possible sources of heterogeneity in MDD most of which are not measured in a sufficiently comparable way across study samples. Here, we assess genetic heterogeneity based on two fundamental measures, between-cohort and between-sex heterogeneity. First, we used genome-wide association study (GWAS) summary statistics to investigate between-cohort genetic heterogeneity using the 29 research cohorts of the Psychiatric Genomics Consortium (PGC; N cases = 16,823, N controls = 25,632) and found that some of the cohort heterogeneity can be attributed to ascertainment differences (such as recruitment of cases from hospital vs. community sources). Second, we evaluated between-sex genetic heterogeneity using GWAS summary statistics from the PGC, Kaiser Permanente GERA, UK Biobank, and the Danish iPSYCH studies but did not find convincing evidence for genetic differences between the sexes. We conclude that there is no evidence that the heterogeneity between MDD data sets and between sexes reflects genetic heterogeneity. Larger sample sizes with detailed phenotypic records and genomic data remain the key to overcome heterogeneity inherent in assessment of MDD.

7.
Int J Med Mushrooms ; 21(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30806251

RESUMO

Natural products are sources for exploratory development of new agents to combat the gastric pathogen Helicobacter pylori. Some edible fungi, such as the lion's mane mushroom, have been used for several thousand years to treat digestive diseases. Ethanol-based extractions to prepare Hericium erinaceus extracts were tested for growth inhibition ability of six different H. pylori strains at an extract concentration that did not inhibit Escherichia coli growth, and further for dose-dependent antibactericidal capacity on H. pylori. H. erinaceus extract exhibited similar growth inhibitory effects on all H. pylori strains tested, with a minimum inhibitory concentration of about 2 mg/mL. H. pylori survival in phosphate-buffered saline (PBS) was decreased 3 logs by 2 mg/mL extract addition. H. erinaceus extract inhibited H. pylori adhesion capacity to human gastric epithelial cell line (ATCC CRL-1739) (AGS), even when H. erinaceus extract was added at a concentration that affected neither H. pylori nor AGS viability. Interleukin-8 (IL-8, representing an immune response factor) in supernatants from AGS and 8-oxo-guanine (8-oxoG, a marker for oxidative DNA damage among the total host cell DNA) were measured from AGS cells exposed to H. erinaceus extract before H. pylori addition. The subsequent H. pylori-mediated immune response (IL-8 production) was significantly (P < 0.01) decreased by H. erinaceus extract; at 1.0 mg/mL extract addition, IL-8 expression returned to nearly background level (no H. pylori added). H. pylori infection of AGS caused a 3-fold increase in host 8-oxoG, but this increase was abolished by including 2 mg/mL H. erinaceus extract. Mouse colonization assays of C57BL mice were performed on homogenized stomachs 3 weeks after inoculating H. pylori into the animals; mice receiving the H. erinaceus extract had a mean H. pylori load of 6 × 104 CFU/g of stomach, about 1 log lower than the control (no extract) animals.


Assuntos
Agaricales/química , Produtos Biológicos/farmacologia , Etanol/química , Carpóforos/química , Helicobacter pylori/efeitos dos fármacos , Produtos Biológicos/química
8.
J Chromatogr A ; 1580: 30-48, 2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30429084

RESUMO

Ellipsoidal particles are investigated as packing media for liquid chromatography using high resolution fluid mechanics and Brownian dynamics simulations. The simulations are conducted with packed capillary columns, as well as beds with periodic boundary conditions (PBCs) to study transport in the absence of wall effects. The performance of ellipsoidal particles is evaluated over a range of aspect ratios. The definition of effective diameter used to compare sphere and ellipsoidal particle performance metrics is presented and discussed along with scaling relationships which are necessary to compare sphere and ellipsoidal particle packs. Ellipsoidal particle packs are found to be inferior to sphere packs using PBCs to study chromatographic dispersion. The separation impedance was calculated with PBCs and shown to be approximately the same with ellipsoidal particles as those of spheres. Efficiency of ellipsoidal packs, as measured by plate height, is lower than spherical particle packs and the pressure drop is higher than sphere packs when using PBCs. However, a smaller wall effect is shown for ellipsoidal particles when packing cylindrical capillaries. Radial variations in packing porosity and in flow within the wall region are smaller for ellipsoidal packings. The minimum reduced plate height and the separation impedance for the packed capillaries clearly demonstrate the advantages of ellipsoidal particles compared to spherical particles. This predicted performance advantage remains to be demonstrated in actual practice.

9.
Micromachines (Basel) ; 9(8)2018 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-30424342

RESUMO

Conventional manufacturing of microfluidic devices from glass substrates is a complex, multi-step process that involves different fabrication techniques and tools. Hence, it is time-consuming and expensive, in particular for the prototyping of microfluidic devices in low quantities. This article describes a laser-based process that enables the rapid manufacturing of enclosed micro-structures by laser micromachining and microwelding of two 1.1-mm-thick borosilicate glass plates. The fabrication process was carried out only with a picosecond laser (Trumpf TruMicro 5×50) that was used for: (a) the generation of microfluidic patterns on glass, (b) the drilling of inlet/outlet ports into the material, and (c) the bonding of two glass plates together in order to enclose the laser-generated microstructures. Using this manufacturing approach, a fully-functional microfluidic device can be fabricated in less than two hours. Initial fluid flow experiments proved that the laser-generated microstructures are completely sealed; thus, they show a potential use in many industrial and scientific areas. This includes geological and petroleum engineering research, where such microfluidic devices can be used to investigate single-phase and multi-phase flow of various fluids (such as brine, oil, and CO2) in porous media.

10.
Sci Rep ; 8(1): 14203, 2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30242194

RESUMO

Campylobacter concisus is an emerging human pathogen found throughout the entire human oral-gastrointestinal tract. The ability of C. concisus to colonize diverse niches of the human body indicates the pathogen is metabolically versatile. C. concisus is able to grow under both anaerobic conditions and microaerophilic conditions. Hydrogen (H2) has been shown to enhance growth and may even be required. Analysis of several C. concisus genome sequences reveals the presence of two sets of genes encoding for distinct hydrogenases: a H2-uptake-type ("Hyd") complex and a H2-evolving hydrogenase ("Hyf"). Whole cells hydrogenase assays indicate that the former (H2-uptake) activity is predominant in C. concisus, with activity among the highest we have found for pathogenic bacteria. Attempts to generate site-directed chromosomal mutants were partially successful, as we could disrupt hyfB, but not hydB, suggesting that H2-uptake, but not H2-evolving activity, is an essential respiratory pathway in C. concisus. Furthermore, the tetrathionate reductase ttrA gene was inactivated in various C. concisus genomospecies. Addition of tetrathionate to the medium resulted in a ten-fold increase in cell yield for the WT, while it had no effect on the ttrA mutant growth. To our knowledge, this is the first report of mutants in C. concisus.

11.
Microbiology ; 164(8): 1059-1068, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29906255

RESUMO

Nickel metabolism and trafficking in Helicobacter pylori is complex, perhaps more so than in any other pathogen. Along with nickel enzymes and their associated nickel-binding maturation machinery, H. pylori contains nickel storage proteins, Hpn and Hpnl. Through a combined crosslinking and enrichment approach, we show that Hpn/Hpnl interact with a wide array of partners; over 100 proteins were captured, including known nickel-enzyme maturation proteins, and other proteins outside known H. pylori nickel-associated proteins. The crosslinker binds to exposed amines, but there was no correlation between lysine content and the pulldown abundance of captured proteins. Phenotypic characterization of mutant strains (Δhpn, Δhpnl, or ΔhpnΔhpnl) was used to explore interactions. Nickel deprivation affected the hydrogenase activity of the ΔhpnΔhpnl strain much more severely than the wild-type (WT), whereas the activities of the single mutants were similar to WT. Leucyl aminopeptidase activity was affected in opposite ways in the mutant strains: Δhpn had a threefold decrease, while Δhpnl had a sevenfold increase, compared to the parent. Similar mutant strain analysis supported Hpn and Hpnl acting synergistically to suppress aliphatic amidase activity in a nickel-dependent manner. Recombinant amidase could bind a variety of divalent metals. Amidase activity was greatest in the mutant strains and was inhibited by exogenous nickel. The addition of pure storage protein to extracts from the mutants only restored the suppression of amidase activity for the mutant strain lacking that protein; both storage proteins are needed for amidase suppression. These results suggest that Hpn and Hpnl play more diverse roles than previously thought.

12.
J Bacteriol ; 2018 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-29866802

RESUMO

The well-studied catalytic role of urease, the Ni-dependent conversion of urea into carbon dioxide and ammonia, has been shown to protect Helicobacter pylori against the low pH environment of the stomach lumen. We hypothesized that the abundantly expressed urease protein can play another, non-catalytic role in combating oxidative stress via Met-residue mediated quenching of harmful oxidants. Three catalytically inactive urease mutant strains were constructed by single substitutions of Ni binding residues. The mutant versions synthesize normal levels of urease and the altered versions retain all methionine residues. The three site-directed urease mutants were able to better withstand a hypochlorous acid (HOCl) challenge than a ΔureAB deletion strain. The capacity of purified urease to protect whole cells via oxidant quenching was assessed by adding urease enzyme to non-growing HOCl-exposed cells. No wild type cells were recovered with oxidant alone, whereas urease addition significantly aided viability. These results suggest that urease can protect H. pylori against oxidative damage and that the protective ability is distinct from the well characterized catalytic role. In order to determine the capability of Msr to reduce oxidized Met residues in urease, purified H. pylori urease was exposed to HOCl and a previously-described Msr peptide repair mixture was added. Of the 25 methionine residues in urease, 11 were subject to both oxidation and to Msr-mediated repair, as identified by MS analysis; therefore the oxidant quenchable Met pool comprising urease can be recycled by the Msr repair system. Non-catalytic urease appears to play an important role in oxidant protection.Importance Chronic Helicobacter pylori infection can lead to gastric ulcers and gastric cancers. The enzyme urease contributes to the survival of the bacterium in the harsh environment of the stomach through increasing the local pH. In addition to combating acid, H. pylori must survive host-produced reactive oxygen species in order to persist in the gastric mucosa. We describe a cyclic amino acid based antioxidant role of urease, whereby oxidized methionine residues can be recycled by methionine sulfoxide reductase to again quench oxidants. This work expands our understanding of the role of an already-acknowledged pathogen virulence factor and specifically expands our knowledge of H. pylori survival mechanisms.

13.
Nat Commun ; 9(1): 989, 2018 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-29515099

RESUMO

Genomic prediction has the potential to contribute to precision medicine. However, to date, the utility of such predictors is limited due to low accuracy for most traits. Here theory and simulation study are used to demonstrate that widespread pleiotropy among phenotypes can be utilised to improve genomic risk prediction. We show how a genetic predictor can be created as a weighted index that combines published genome-wide association study (GWAS) summary statistics across many different traits. We apply this framework to predict risk of schizophrenia and bipolar disorder in the Psychiatric Genomics consortium data, finding substantial heterogeneity in prediction accuracy increases across cohorts. For six additional phenotypes in the UK Biobank data, we find increases in prediction accuracy ranging from 0.7% for height to 47% for type 2 diabetes, when using a multi-trait predictor that combines published summary statistics from multiple traits, as compared to a predictor based only on one trait.

14.
Mol Microbiol ; 108(4): 379-396, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29498770

RESUMO

Helicobacter pylori is anomalous among non nitrogen-fixing bacteria in containing an incomplete NIF system for Fe-S cluster assembly comprising two essential proteins, NifS (cysteine desulfurase) and NifU (scaffold protein). Although nifU deletion strains cannot be obtained via the conventional gene replacement, a NifU-depleted strain was constructed and shown to be more sensitive to oxidative stress compared to wild-type (WT) strains. The hp1492 gene, encoding a putative Nfu-type Fe-S cluster carrier protein, was disrupted in three different H. pylori strains, indicating that it is not essential. However, Δnfu strains have growth deficiency, are more sensitive to oxidative stress and are unable to colonize mouse stomachs. Moreover, Δnfu strains have lower aconitase activity but higher hydrogenase activity than the WT. Recombinant Nfu was found to bind either one [2Fe-2S] or [4Fe-4S] cluster/dimer, based on analytical, UV-visible absorption/CD and resonance Raman studies. A bacterial two-hybrid system was used to ascertain interactions between Nfu, NifS, NifU and each of 36 putative Fe-S-containing target proteins. Nfu, NifS and NifU were found to interact with 15, 6 and 29 putative Fe-S proteins respectively. The results indicate that Nfu, NifS and NifU play a major role in the biosynthesis and/or delivery of Fe-S clusters in H. pylori.

15.
Schizophr Res ; 2018 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-29409757

RESUMO

Schizophrenia is a disorder with a high heritability. Patients as well as their first degree relatives display lower levels of performance in a number of cognitive domains compared to subjects without genetic risk. Several studies could link these aberrations to single genetic variants, however, only recently, polygenic risk scores as proxies for genetic risk have been associated with cognitive domains and their neural correlates. In the present study, a sample of healthy subjects (n=137) performed a letter version of the n-back task while scanned with 3-T fMRI. All subjects were genotyped with the PsychChip and polygenic risk scores were calculated based on the PGC2 schizophrenia GWAS results. Polygenic risk for schizophrenia was associated with a lower degree of brain activation in prefrontal areas during the 3-back compared to the 0-back baseline condition. Furthermore, polygenic risk was associated with lower levels of brain activation in the right inferior frontal gyrus during the 3-back compared to a 2-back condition. Polygenic risk leads to a shift in the underlying activation pattern to the left side, thus resembling results reported in patients with schizophrenia. The data may point to polygenic risk for schizophrenia being associated with brain function in a cognitive task known to be impaired in patients and their relatives.

16.
Org Lett ; 20(4): 897-900, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29380605

RESUMO

A chemical strategy was developed wherein a single trigger sets in motion a three-reaction cascade leading to the release of more than one drug-component in sequence with the generation of a fluorescent side product for easy monitoring. As a proof of concept, codelivery of CO with the antibiotic metronidazole was demonstrated.


Assuntos
Monóxido de Carbono/química , Corantes Fluorescentes , Estrutura Molecular , Pró-Fármacos
17.
Nat Commun ; 9(1): 224, 2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29335400

RESUMO

Health risk factors such as body mass index (BMI) and serum cholesterol are associated with many common diseases. It often remains unclear whether the risk factors are cause or consequence of disease, or whether the associations are the result of confounding. We develop and apply a method (called GSMR) that performs a multi-SNP Mendelian randomization analysis using summary-level data from genome-wide association studies to test the causal associations of BMI, waist-to-hip ratio, serum cholesterols, blood pressures, height, and years of schooling (EduYears) with common diseases (sample sizes of up to 405,072). We identify a number of causal associations including a protective effect of LDL-cholesterol against type-2 diabetes (T2D) that might explain the side effects of statins on T2D, a protective effect of EduYears against Alzheimer's disease, and bidirectional associations with opposite effects (e.g., higher BMI increases the risk of T2D but the effect of T2D on BMI is negative).


Assuntos
Índice de Massa Corporal , Colesterol/sangue , Doença/genética , Estudo de Associação Genômica Ampla/métodos , Doença de Alzheimer/sangue , Doença de Alzheimer/genética , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Doença/etiologia , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único , Fatores de Risco
18.
PLoS One ; 12(8): e0183260, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28809946

RESUMO

The nickel-containing enzymes of Helicobacter pylori, urease and hydrogenase, are essential for efficient colonization in the human stomach. The insertion of nickel into urease and hydrogenase is mediated by the accessory protein HypA. HypA contains an N-terminal nickel-binding site and a dynamic structural zinc-binding site. The coordination of nickel and zinc within HypA is known to be critical for urease maturation and activity. Herein, we test the hydrogenase activity of a panel of H. pylori mutant strains containing point mutations within the nickel- and zinc-binding sites. We found that the residues that are important for hydrogenase activity are those that were similarly vital for urease activity. Thus, the zinc and metal coordination sites of HypA play similar roles in urease and hydrogenase maturation. In other pathogenic bacteria, deletion of hydrogenase leads to a loss in acid resistance. Thus, the acid resistance of two strains of H. pylori containing a hydrogenase deletion was also tested. These mutant strains demonstrated wild-type levels of acid resistance, suggesting that in H. pylori, hydrogenase does not play a role in acid resistance.


Assuntos
Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Helicobacter pylori/enzimologia , Hidrogenase/química , Hidrogenase/metabolismo , Sítios de Ligação , Helicobacter pylori/metabolismo , Concentração de Íons de Hidrogênio , Níquel/metabolismo , Ligação Proteica , Urease/química , Urease/metabolismo , Zinco/metabolismo
19.
DNA Repair (Amst) ; 57: 161-170, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28800560

RESUMO

Bacterial MutS2 proteins, consisting of functional domains for ATPase, DNA-binding, and nuclease activities, play roles in DNA recombination and repair. Here we observe a mechanism for generating MutS2 expression diversity in the human pathogen Helicobacter pylori, and identify a unique MutS2 domain responsible for specific DNA-binding. H. pylori strains differ in mutS2 expression due to variations in the DNA upstream sequence containing short sequence repeats. Based on Western blots, mutS2 in some strains appears to be co-translated with the upstream gene, but in other strains (e.g. UA948) such translational coupling does not occur. Accordingly, strain UA948 had phenotypes similar to its ΔmutS2 derivative, whereas expression of MutS2 at a separate locus in UA948 (the genetically complemented strain) displayed a lower mutation rate and lower transformation frequency than did ΔmutS2. A series of truncated HpMutS2 proteins were purified and tested for their specific abilities to bind 8-oxoG-containing DNA (GO:C) and Holiday Junction structures (HJ). The specific DNA binding domain was localized to an area adjacent to the Smr nuclease domain, and it encompasses 30-amino-acid-residues containing a "KPPKNKFKPPK" motif. Gel shift assays and competition assays supported that a truncated version of HpMutS2-C12 (∼12kDa protein containing the specific DNA-binding domain) has much greater capacity to bind to HJ or GO:C DNA than to normal double stranded DNA. By studying the in vivo roles of the separate domains of HpMutS2, we observed that the truncated versions were unable to complement the ΔmutS2 strain, suggesting the requirement for coordinated function of all the domains in vivo.


Assuntos
Reparo do DNA , DNA Bacteriano/metabolismo , Guanosina/análogos & derivados , Helicobacter pylori/metabolismo , Recombinação Homóloga , Proteína MutS de Ligação de DNA com Erro de Pareamento/metabolismo , Dano ao DNA , DNA Bacteriano/química , DNA Cruciforme , Guanosina/metabolismo , Proteína MutS de Ligação de DNA com Erro de Pareamento/genética , Biossíntese de Proteínas , Domínios Proteicos
20.
J Psychiatr Res ; 94: 148-155, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28715705

RESUMO

Lower levels of circulating iron have been associated with depression. Our objective was to investigate the phenotypic and genetic relationship between measures of circulating levels of iron (serum iron, transferrin, transferrin saturation, and ferritin) and depressive symptoms. Data were available from ongoing studies at QIMR Berghofer Medical Research Institute (QIMRB), including twin adolescents (mean age 15.1 years, standard deviation (SD) 3.2 years), and twin adults (mean age 23.2 years, SD 2.2 years). In the adolescent cohort, there were 3416 participants from 1688 families. In the adult cohort there were 9035 participants from 4533 families. We estimated heritabilities of, and phenotypic and genetic correlations between, traits. We conducted analyses that linked results from published large-scale genome-wide association studies (including iron and Major Depressive Disorder) with our study samples using single SNP and multi-SNP genetic risk score analyses, and LD score regression analyses. In both cohorts, measures of iron, transferrin, transferrin saturation, and log 10 of ferritin (L10Fer) were all highly heritable, while depressive measures were moderately heritable. In adolescents, depression measures were higher in those in the middle 10th versus top 10th percentile of transferrin saturation measures (p = 0.002). Genetic profile risk scores of the iron measures were not significantly associated with depression in study participants. LD score analyses showed no significant genetic relationship between iron and depression. Genetic factors strongly influence iron measures in adolescents and adults. Using several different strategies we find no evidence for a genetic contribution to the relationship between blood measures of iron and measures of depression.


Assuntos
Transtorno Depressivo Maior/sangue , Transtorno Depressivo Maior/genética , Ferritinas/sangue , Predisposição Genética para Doença , Ferro/sangue , Sistema de Registros/estatística & dados numéricos , Transferrina/análise , Adolescente , Adulto , Austrália/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Queensland/epidemiologia , Adulto Jovem
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