| 1. |
- Blokland, G. A. M., et al.
(författare)
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Sex-Dependent Shared and Nonshared Genetic Architecture Across Mood and Psychotic Disorders
- 2022
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Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 91:1, s. 102-117
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Tidskriftsartikel (refereegranskat)abstract
- Background: Sex differences in incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across disorders suggest possible shared sex-dependent genetic risk. Methods: We conducted the largest to date genome-wide genotype-by-sex (G×S) interaction of risk for these disorders using 85,735 cases (33,403 SCZ, 19,924 BIP, and 32,408 MDD) and 109,946 controls from the PGC (Psychiatric Genomics Consortium) and iPSYCH. Results: Across disorders, genome-wide significant single nucleotide polymorphism–by-sex interaction was detected for a locus encompassing NKAIN2 (rs117780815, p = 3.2 × 10−8), which interacts with sodium/potassium-transporting ATPase (adenosine triphosphatase) enzymes, implicating neuronal excitability. Three additional loci showed evidence (p < 1 × 10−6) for cross-disorder G×S interaction (rs7302529, p = 1.6 × 10−7; rs73033497, p = 8.8 × 10−7; rs7914279, p = 6.4 × 10−7), implicating various functions. Gene-based analyses identified G×S interaction across disorders (p = 8.97 × 10−7) with transcriptional inhibitor SLTM. Most significant in SCZ was a MOCOS gene locus (rs11665282, p = 1.5 × 10−7), implicating vascular endothelial cells. Secondary analysis of the PGC-SCZ dataset detected an interaction (rs13265509, p = 1.1 × 10−7) in a locus containing IDO2, a kynurenine pathway enzyme with immunoregulatory functions implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant G×S interaction of genes regulating vascular endothelial growth factor receptor signaling in MDD (false discovery rate-corrected p < .05). Conclusions: In the largest genome-wide G×S analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development and immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway levels. © 2021 Society of Biological Psychiatry
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| 2. |
- Munn-Chernoff, M. A., et al.
(författare)
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Shared genetic risk between eating disorder- and substance-use-related phenotypes: Evidence from genome-wide association studies
- 2021
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Ingår i: Addiction Biology. - : Wiley. - 1355-6215 .- 1369-1600. ; 26:1
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Tidskriftsartikel (refereegranskat)abstract
- Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r(g)], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from similar to 2400 to similar to 537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r(g) = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r(g) = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r(g) = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r(gs) = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors.
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| 5. |
- Kirnbauer, A., et al.
(författare)
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Mechanical properties and thermal stability of reactively sputtered multi-principal-metal Hf-Ta-Ti-V-Zr nitrides
- 2020
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Ingår i: Surface & Coatings Technology. - : ELSEVIER SCIENCE SA. - 0257-8972 .- 1879-3347. ; 389
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Tidskriftsartikel (refereegranskat)abstract
- Crystalline (Hf,Ta,Ti,V,Zr)N nitride thin films, with a high-entropy metal-sublattice, were synthesized at 440 degrees C by reactive magnetron sputtering using an equimolar Hf-Ta-Ti-V-Zr-compound target. The coatings are single-phase fcc structured mono-nitrides for N-2/(Ar + N-2) flow-rate-ratios (f(N2)) between 30 and 45%. For higher f(N2) a small fraction of a second phase (next to the fcc matrix) can be detected by X-ray diffraction (XRD) and selected area electron diffraction (SAED). All coatings studied (prepared with f(N2) between 30 and 60%) show similar chemical compositions and hardness (H) values between 30.0 and 34.0 GPa with indentation moduli of similar to 460 GPa. Atom probe tomography (APT) indicates a homogenous distribution of all elements within our fcc-(Hf,Ta,Ti,V,Zr)N even after vacuum-annealing at 1300 degrees C. While H decreased from 32.5 to 28.1 GPa by this annealing treatment, the coating is still single-phase fcc structured with a defect density (expressed by XRD and SAED features, transmission electron microscopy contrast, and grain sizes) comparable to the as-deposited state. Only after vacuum-annealing at 1500 degrees C, XRD and APT reveal the formation of hexagonal structured (Ta,V)(2)N. The onset of nitrogen-loss - detected by thermogravimetric analysis - is similar to 1350 degrees C. Based on our results we can conclude that the sluggish diffusion within our fcc-(Hf,Ta,Ti,V,Zr)N warrants the single-phase fcc structure up to 1300 degrees C, although ab initio based calculations would suggest the lower-entropy products [fcc-(Hf,Zr)N, fcc-(Ta,V)N, and fcc-TiN] and [fcc-(Hf,Zr)N and fcc-(Ta,Ti,V)N] to be energetically more stable up to 1302 K.
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| 7. |
- Alturki, M, et al.
(författare)
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Biochemical characterisation of carious dentine zones using Raman spectroscopy.
- 2021
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Ingår i: Journal of dentistry. - : Elsevier BV. - 1879-176X .- 0300-5712. ; 105
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Tidskriftsartikel (refereegranskat)abstract
- Carious tissue discrimination in clinical operative caries management relies traditionally on the subjective hardness of carious dentine. Biochemical alterations within the lesion have the potential to discriminate the lesion zones objectively. This study aimed to determine the correlation between the biochemical proportions of amide I and phosphate moieties as these are the most prominent peaks found in dentine with the Knoop microhardness of carious dentine zones, using non-contact Raman spectroscopy. The null hypothesis investigated was that there was no correlation between Raman peak ratios, amide I: phosphateν1, and the Knoop microhardness within specific zones of a carious lesion.423 scan points from 20 carious dentine lesion samples examined using high-resolution Raman spectroscopy. The peak ratio of the characteristic vibration mode of amide I (1650 cm-1) and phosphate (960 cm-1) bands were calculated, following a straight line path through the lesion to the pulp and correlated to corresponding Knoop microhardness measurements.Using logistic regression analysis, clear correlations were found between the Knoop microhardness and Raman peak ratio cut-off values between caries-infected and caries-affected dentine (81.5 % sensitivity / 92.7 % specificity), with a lower specificity (2.7 %) found between caries-affected and sound dentine.This study concluded that non-contact Raman spectroscopy can be used in vitro to discriminate objectively between the different zones of a carious dentine lesion at high resolution, using the Raman peak ratios, amide I : phosphate ν1.Specific biochemical alterations have the potential to be used in-vitro and in-vivo to identify the end-point of selective carious lesion excavation.
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| 8. |
- Alturki, M., et al.
(författare)
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Chemo-mechanical characterization of carious dentine using Raman microscopy and Knoop microhardness
- 2020
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Ingår i: Royal Society Open Science. - : The Royal Society. - 2054-5703. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- One of the aims in the clinical operative management of dental carious lesions is to remove selectively the highly infected and structurally denatured dentine tissue, while retaining the deeper, repairable affected and intact, healthy tissues for long-term mechanical strength. The present study examined the correlation of chemical functional groups and the microhardness through the different depths of a carious lesion using Raman spectroscopy and Knoop microhardness testing. The null hypothesis investigated was that there was no correlation between Raman peak ratios (amide I : phosphate (nu 1)) and equivalent Knoop microhardness measurements. Ten freshly extracted human permanent teeth with carious dentine lesions were sectioned and examined using high-resolution Raman microscopy. The ratio of absorbency at the amide I and phosphate bands were calculated from 139 scan points through the depth of the lesions and correlated with 139 juxtaposed Knoop microhardness indentations. The results indicated a high correlation (p < 0.01) between the peak ratio and the equivalent Knoop hardness within carious dentine lesions. This study concluded that Raman spectroscopy can be used as a non-invasive analytical technology for in vitro studies to discriminate the hardness of carious dentine layers using the peak ratio as an alternative to the invasive, mechanical Knoop hardness test.
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| 9. |
- Alturki, M., et al.
(författare)
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In Vitro Analysis of Organic Ester Functional Groups in Carious Dentine
- 2022
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Ingår i: Applied Sciences (Switzerland). - : MDPI AG. - 2076-3417. ; 12:3
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Tidskriftsartikel (refereegranskat)abstract
- Background: With the implementation of minimally invasive selective caries removal protocols to treat cavitated, deep carious dentine lesions, there is a need to investigate specific biochemical moiety distributions to help characterise and distinguish between infected (contaminated) and affected (demineralised) zones within the dentine lesion. The present in vitro investigation aimed to compare the distribution of ester functional groups (1740 cm−1) within carious dentine tissue (infected and affected dentine). The null hypothesis stipulated that there are no differences in ester function intensity/distribution within carious dentine lesions. Materials and Methods: From a total of five extracted human molar teeth with carious dentine lesions, 246 points from 10 sections of carious dentine were examined using high‐resolution Raman spectroscopy and characterised into infected, affected and sound dentine. The peak intensity of the characteristic vibration mode of the ester function was calculated from sample scans. Results: Analyses indicated a statistically significant difference in the spectroscopic vibration bands of esters between the infected and affected dentine zones. Conclusion: The ester functional group is higher in intensity in the caries‐infected dentine zone compared to the affected tissue. This finding could be used to develop an objective indicator for the selective operative management of carious dentine. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
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| 10. |
- Koller, Timm O, et al.
(författare)
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Structural basis for HflXr-mediated antibiotic resistance in Listeria monocytogenes
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 50:19, s. 11285-11300
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Tidskriftsartikel (refereegranskat)abstract
- HflX is a ubiquitous bacterial GTPase that splits and recycles stressed ribosomes. In addition to HflX, Listeria monocytogenes contains a second HflX homolog, HflXr. Unlike HflX, HflXr confers resistance to macrolide and lincosamide antibiotics by an experimentally unexplored mechanism. Here, we have determined cryo-EM structures of L. monocytogenes HflXr-50S and HflX-50S complexes as well as L. monocytogenes 70S ribosomes in the presence and absence of the lincosamide lincomycin. While the overall geometry of HflXr on the 50S subunit is similar to that of HflX, a loop within the N-terminal domain of HflXr, which is two amino acids longer than in HflX, reaches deeper into the peptidyltransferase center. Moreover, unlike HflX, the binding of HflXr induces conformational changes within adjacent rRNA nucleotides that would be incompatible with drug binding. These findings suggest that HflXr confers resistance using an allosteric ribosome protection mechanism, rather than by simply splitting and recycling antibiotic-stalled ribosomes.
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