| 131. |
- Wilson, Rachel M., et al.
(author)
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Hydrogenation of organic matter as a terminal electron sink sustains high CO2 : CH4 production ratios during anaerobic decomposition
- 2017
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In: Organic Geochemistry. - : Elsevier BV. - 0146-6380 .- 1873-5290. ; 112, s. 22-32
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Journal article (peer-reviewed)abstract
- Once inorganic electron acceptors are depleted, organic matter in anoxic environments decomposes by hydrolysis, fermentation, and methanogenesis, requiring syntrophic interactions between microorganisms to achieve energetic favorability. In this classic anaerobic food chain, methanogenesis represents the terminal electron accepting (TEA) process, ultimately producing equimolar CO2 and CH4 for each molecule of organic matter degraded. However, CO2:CH4 production in Sphagnum-derived, mineral-poor, cellulosic peat often substantially exceeds this 1:1 ratio, even in the absence of measureable inorganic TEAs. Since the oxidation state of C in both cellulose-derived organic matter and acetate is 0, and CO2 has an oxidation state of +4, if CH4 (oxidation state -4) is not produced in equal ratio, then some other compound(s) must balance CO2 production by receiving 4 electrons. Here we present evidence for ubiquitous hydrogenation of diverse unsaturated compounds that appear to serve as organic TEAs in peat, thereby providing the necessary electron balance to sustain CO2:CH4 > 1. While organic electron acceptors have previously been proposed to drive microbial respiration of organic matter through the reversible reduction of quinone moieties, the hydrogenation mechanism that we propose, by contrast, reduces CAC double bonds in organic matter thereby serving as (1) a terminal electron sink, (2) a mechanism for degrading complex unsaturated organic molecules, (3) a potential mechanism to regenerate electron-accepting quinones, and, in some cases, (4) a means to alleviate the toxicity of unsaturated aromatic acids. This mechanism for CO2 generation without concomitant CH4 production has the potential to regulate the global warming potential of peatlands by elevating CO2:CH4 production ratios.
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| 132. |
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| 133. |
- Østergaard, Søren D, et al.
(author)
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Associations between Potentially Modifiable Risk Factors and Alzheimer Disease : A Mendelian Randomization Study.
- 2015
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In: PLoS Medicine. - : Public Library of Science. - 1549-1277 .- 1549-1676. ; 12:6
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Journal article (peer-reviewed)abstract
- BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR).METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses.CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.
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| 134. |
- Bao, Jie J., et al.
(author)
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Analytic gradients for compressed multistate pair-density functional theory
- 2022
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In: Molecular Physics. - : Taylor & Francis Group. - 0026-8976 .- 1362-3028. ; 120:19-20
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Journal article (peer-reviewed)abstract
- Photochemical reactions often involve states that are closely coupled due to near degeneracies, for example by proximity to conical intersections. Therefore, a multistate method is used to accurately describe these states; for example, ordinary perturbation theory is replaced by quasidegenerate perturbation theory. Multiconfiguration pair-density functional theory (MC-PDFT) provides an efficient way to approximate the full dynamical correlation energy of strongly correlated systems, and we recently proposed compressed multistate pair-density functional theory (CMS-PDFT) to treat closely coupled states. In the present paper, we report the implementation of analytic gradients for CMS-PDFT in both OpenMolcas and PySCF, and we illustrate the use of these gradients by applying the method to the excited states of formaldehyde and phenol.
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| 135. |
- Dillner, Joakim, et al.
(author)
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Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial.
- 2010
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In: BMJ: British Medical Journal. - : BMJ. - 1756-1833 .- 0959-8138 .- 1468-5833. ; 341
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Journal article (peer-reviewed)abstract
- OBJECTIVES: To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). DESIGN: Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months' follow-up. SETTING: Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. PARTICIPANTS: 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. INTERVENTION: Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. MAIN OUTCOME MEASURES: Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. RESULTS: In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. CONCLUSIONS: Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. TRIAL REGISTRATIONS: NCT00092521 and NCT00092534.
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| 136. |
- Goes, Fernando S, et al.
(author)
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Exome Sequencing of Familial Bipolar Disorder.
- 2016
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In: JAMA psychiatry. - : American Medical Association (AMA). - 2168-6238 .- 2168-622X. ; 73:6, s. 590-7
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Journal article (peer-reviewed)abstract
- Complex disorders, such as bipolar disorder (BD), likely result from the influence of both common and rare susceptibility alleles. While common variation has been widely studied, rare variant discovery has only recently become feasible with next-generation sequencing.
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| 137. |
- Hall, Laurie A, et al.
(author)
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Characterizing dispersal patterns in a threatened seabird with limited genetic structure.
- 2009
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In: Molecular ecology. - 1365-294X.
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Journal article (peer-reviewed)abstract
- Abstract Genetic assignment methods provide an appealing approach for characterizing dispersal patterns on ecological time scales, but require sufficient genetic differentiation to accurately identify migrants and a large enough sample size of migrants to, for example, compare dispersal between sexes or age classes. We demonstrate that assignment methods can be rigorously used to characterize dispersal patterns in a marbled murrelet (Brachyramphus marmoratus) population from central California that numbers approximately 600 individuals and is only moderately differentiated (F(ST) approximately 0.03) from larger populations to the north. We used coalescent simulations to select a significance level that resulted in a low and approximately equal expected number of type I and II errors and then used this significance level to identify a population of origin for 589 individuals genotyped at 13 microsatellite loci. The proportion of migrants in central California was greatest during winter when 83% of individuals were classified as migrants compared to lower proportions during the breeding (6%) and post-breeding (8%) seasons. Dispersal was also biased toward young and female individuals, as is typical in birds. Migrants were rarely members of parent-offspring pairs, suggesting that they contributed few young to the central California population. A greater number of migrants than expected under equilibrium conditions, a lack of individuals with mixed ancestry, and a small number of potential source populations (two), likely allowed us to use assignment methods to rigorously characterize dispersal patterns for a population that was larger and less differentiated than typically thought required for the identification of migrants.
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| 138. |
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| 139. |
- Huusko, Johanna M, et al.
(author)
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Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
- 2018
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In: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 14:7
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Journal article (peer-reviewed)abstract
- Preterm birth is a leading cause of morbidity and mortality in infants. Genetic and environmental factors play a role in the susceptibility to preterm birth, but despite many investigations, the genetic basis for preterm birth remain largely unknown. Our objective was to identify rare, possibly damaging, nucleotide variants in mothers from families with recurrent spontaneous preterm births (SPTB). DNA samples from 17 Finnish mothers who delivered at least one infant preterm were subjected to whole exome sequencing. All mothers were of northern Finnish origin and were from seven multiplex families. Additional replication samples of European origin consisted of 93 Danish sister pairs (and two sister triads), all with a history of a preterm delivery. Rare exonic variants (frequency <1%) were analyzed to identify genes and pathways likely to affect SPTB susceptibility. We identified rare, possibly damaging, variants in genes that were common to multiple affected individuals. The glucocorticoid receptor signaling pathway was the most significant (p<1.7e-8) with genes containing these variants in a subgroup of ten Finnish mothers, each having had 2-4 SPTBs. This pathway was replicated among the Danish sister pairs. A gene in this pathway, heat shock protein family A (Hsp70) member 1 like (HSPA1L), contains two likely damaging missense alleles that were found in four different Finnish families. One of the variants (rs34620296) had a higher frequency in cases compared to controls (0.0025 vs. 0.0010, p = 0.002) in a large preterm birth genome-wide association study (GWAS) consisting of mothers of general European ancestry. Sister pairs in replication samples also shared rare, likely damaging HSPA1L variants. Furthermore, in silico analysis predicted an additional phosphorylation site generated by rs34620296 that could potentially affect chaperone activity or HSPA1L protein stability. Finally, in vitro functional experiment showed a link between HSPA1L activity and decidualization. In conclusion, rare, likely damaging, variants in HSPA1L were observed in multiple families with recurrent SPTB.
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| 140. |
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