| 1. |
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| 2. |
- Egholm, M., et al.
(författare)
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PNA HYBRIDIZES TO COMPLEMENTARY OLIGONUCLEOTIDES OBEYING THE WATSON-CRICK HYDROGEN-BONDING RULES
- 1993
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 365:6446, s. 566-568
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Tidskriftsartikel (refereegranskat)abstract
- DNA ANALOGUES are currently being intensely investigated owing to their potential as gene-targeted drugs1-3. Furthermore, their properties and interaction with DNA and RNA could provide a better understanding of the structural features of natural DNA that determine its unique chemical, biological and genetic properties3,4. We recently designed a DNA analogue, PNA, in which the backbone is structurally homomorphous with the deoxyribose backbone and consists of N-(2-aminoethyl)glycine units to which the nucleobases are attached5-9. We showed that PNA oligomers containing solely thymine and cytosine can hybridize to complementary oligonucleotides, presumably by forming Watson-Crick-Hoogsteen (PNA)2-DNA triplexes, which are much more stable than the corresponding DNA-DNA duplexes5-7, and bind to double-stranded DNA by strand displacement5,8. We report here that PNA containing all four natural nucleobases hybridizes to complementary oligonucleotides obeying the Watson-Crick base-pairing rules, and thus is a true DNA mimic in terms of base-pair recognition.
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| 3. |
- Andersen, J. L., et al.
(författare)
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Pleistocene Evolution of a Scandinavian Plateau Landscape
- 2018
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Ingår i: Journal of Geophysical Research - Earth Surface. - 2169-9003 .- 2169-9011. ; 123:12, s. 3370-3387
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Tidskriftsartikel (refereegranskat)abstract
- The origins and Pleistocene evolution of plateau landscapes along passive continental margins of the North Atlantic have been debated for more than a century. A key question in this debate concerns whether glacial and periglacial surface processes have substantially eroded plateau areas during late Cenozoic climatic cooling or whether the plateaus have mainly been protected from erosion by cold-based and largely nonerosive ice sheets. Here we investigate the Pleistocene evolution of a prominent plateau landscape in Reinheimen National Park, southern Norway. We estimate erosion rates across the plateau via inverse modeling of 141 new cosmogenic Be-10 and Al-26 measurements in regolith profiles and bedrock. We combine these results with sedimentological analyses of the regolith. In the vicinity of Reinheimen's regolith-covered summits, the combination of uniformly slow erosion (<10m/Myr) and near-parabolic slope geometry suggests long-term equilibrium with the presently active periglacial mass-wasting processes. Outside summit areas, erosion is faster (up to >50m/Myr), possibly due to episodic glacial erosion. Despite some indications of chemical alteration, such as grusic saprolite and small amounts of secondary minerals, the fine regolith comprises low clay/silt ratios and is dominated by primary minerals with no sign of dissolution. Together with our modeled erosion rates, this indicates that the regolith cover formed, and continues to develop, during the cold climate of the Late Pleistocene. Plain Language Summary Plateaus dissected by steep-sided valleys and fjords are common landscape elements within the mountains bordering the North Atlantic. Most of these plateaus have likely experienced millions of years of near-freezing temperatures and were repeatedly covered by ice sheets during recent glacial periods. Yet the imprint of cold-climate erosion processes on the plateau landscape evolution remains poorly understood. Here we investigate the Pleistocene evolution of an extensive Scandinavian plateau landscape in Reinheimen National Park, southern Norway. We measure cosmogenic nuclides within the surficial layers of rock and sediment on the plateau. The concentration of these cosmogenic nuclides reflects the erosion of the plateau landscape and thereby the impact of recent cold-climate surface processes. We find that erosion has influenced the plateaus within the latest glacial cycles. In the vicinity of the highest, sediment-clad summits, the plateau shape is determined by processes related to freezing and thawing of rocks and sediment, while the influence of erosion by glaciers and streams increases further downslope.
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| 4. |
- Egholm, Julie W.M., et al.
(författare)
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Perioperative alcohol cessation intervention for postoperative complications
- 2018
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Ingår i: Cochrane Database of Systematic Reviews. - 1361-6137. ; 2018:11
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Forskningsöversikt (refereegranskat)abstract
- Background: Risky consumption of alcohol is a global problem. More than 3.3 million deaths annually are associated with risky use of alcohol, and global alcohol consumption continues to increase. People who have high alcohol consumption often require planned and emergency surgical procedures. Risky drinking is associated with increased postoperative complications such as infections, cardiopulmonary complications, and bleeding episodes. Alcohol causes disorders of the liver, pancreas, and nervous system. Stopping consumption of alcohol can normalize these organ systems to some degree and may reduce the occurrence of complications after surgery. This review was first published in 2012 and was updated in 2018. Objectives: To assess the effects of perioperative alcohol cessation interventions on rates of postoperative complications and alcohol consumption. Search methods: We searched the following databases up until 21 September 2018: Cochrane Central Register of Controlled Trials (CENTRAL), in the Cochrane Library; MEDLINE; Embase; CINAHL via EBSCOhost; and two trials registers. We scanned the reference lists and citations of included trials and any identified relevant systematic reviews for further references to additional trials. When necessary, we contacted trial authors to ask for additional information. Selection criteria: We included all randomized controlled trials (RCTs) that evaluated the effects of perioperative alcohol cessation interventions on postoperative complications and alcohol consumption. We included participants with risky consumption of alcohol who were undergoing all types of elective or acute surgical procedures under general or regional anaesthesia or sedation, who were offered a perioperative alcohol cessation intervention or no intervention. We defined 'risky drinking' as alcohol consumption equivalent to more than 3 alcoholic units (AU)/d or 21 AU/week (with 1 AU containing 12 grams of ethanol) with or without symptoms of alcohol abuse or dependency. This corresponds to the amount of alcohol associated with increased postoperative complication rates in most clinical studies. Data collection and analysis: We used guidance provided in the Cochrane Handbook for Systematic Reviews of Interventions. We presented main outcomes as dichotomous variables in a meta-analysis. When data were available, we conducted subgroup and sensitivity analyses to explore the risk of bias. Primary outcome measures were postoperative complications and in-hospital and 30-day mortality. Secondary outcomes were successful quitting at the end of the programme, postoperative alcohol use, and length of hospital stay. We assessed the quality of evidence using the GRADE approach. Main results: We included in this updated review one new study (70 participants), resulting in a total of three RCTs (140 participants who drank 3 to 40 AU/d). All three studies were of moderate to good quality. All studies evaluated the effects of intensive alcohol cessation interventions, including pharmacological strategies for alcohol withdrawal symptoms, patient education, and relapse prophylaxis. We identified one ongoing study. Overall, 53 of the 122 participants from three studies who underwent surgery developed any type of postoperative complication that required treatment. Of 61 participants in the intervention groups, 20 had complications, compared with 33 of 61 participants in the control groups (risk ratio (RR) 0.62, 95% confidence interval (CI) 0.40 to 0.96). Results show differences between the three clinical studies regarding outcome measurement and intensity of the interventions. However, all alcohol cessation programmes were intensive and included pharmacological therapy. The overall quality of evidence for this outcome is moderate. In-hospital and 30-day postoperative mortality rates were low in the three studies. Researchers reported one death among 61 participants in the intervention groups, and three deaths among 61 participants in the control groups (RR 0.47, 95% CI 0.07 to 2.96). The quality of evidence for this outcome is low. Investigators describe more successful quitters at the end of the intervention programme than among controls. Forty-one out of 70 participants in the intervention groups successfully quit drinking compared with only five out of 70 participants in the control groups (RR 8.22, 95% CI 1.67 to 40.44). The quality of evidence for this outcome is moderate. All three studies reported postoperative alcohol consumption (grams of alcohol/week) at the end of the programme as median and range values; therefore it was not possible to estimate the mean and the standard deviation (SD). We performed no meta-analysis. All three studies reported length of stay, and none of these studies described a significant difference in length of stay. Data were insufficient for review authors to perform a meta-analysis. No studies reported on the prevalence of participants without risky drinking in the longer term. Authors' conclusions: This systematic review assessed the efficacy of perioperative alcohol cessation interventions for postoperative complications and alcohol consumption. All three studies showed a significant reduction in the number of participants who quit drinking alcohol during the intervention period. Intensive alcohol cessation interventions offered for four to eight weeks to participants undergoing all types of surgical procedures to achieve complete alcohol cessation before surgery probably reduced the number of postoperative complications. Data were insufficient for review authors to assess their effects on postoperative mortality. No studies reported an effect on length of stay, and no studies addressed the prevalence of risky drinking in the longer term. Included studies were few and reported small sample sizes; therefore one should be careful about drawing firm conclusions based on these study results. All three studies were conducted in Denmark, and most participants were men. The included participants may represent a selective group, as they could have been more motivated and/or more interested in participating in clinical research or otherwise different, and effects may have been overestimated for both intervention and control groups in these studies. Trial results indicate that these studies are difficult to perform, that strong research competencies are necessary for future studies, and that further evaluation of perioperative alcohol cessation interventions in high-quality randomized controlled trials is needed. Once published and assessed, the one 'ongoing' study identified may alter the conclusions of this review.
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| 5. |
- Hyrup, B., et al.
(författare)
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STRUCTURE-ACTIVITY STUDIES OF THE BINDING OF MODIFIED PEPTIDE NUCLEIC-ACIDS (PNAS) TO DNA
- 1994
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 116:18, s. 7964-7970
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Tidskriftsartikel (refereegranskat)abstract
- Peptide nucleic acid (PNA) oligomers where one of the repeating backbone units is extended with a methylene group to either N-(2-aminoethyl)-beta-alanine or N-(3-aminopropyl)glycine were prepared. Alternatively, the linker to the nucleobase was extended from methylenecarbonyl to ethylenecarbonyl. The thermal stability of the hybrids between these PNA oligomers and complementary DNA oligonucleotides was significantly lower than that of the corresponding complexes involving unmodified PNA. However, the sequence selectivity was retained. Thymidyl decamers with all N-(2-aminoethyl)-beta-alanine or N-(3-aminopropyl)glycine backbones were prepared and shown to be unable to hybridize to the complementary (dA)(10) oligonucleotides, whereas a PNA decamer containing only ethylenecarbonyl linkers between the nucleobases and the N-(2-aminoethyl)glycine backbone showed weak but sequence-specific affinity for complementary DNA. All hybrids involving homopyrimidine PNA oligomers exhibited (PNA)(2)/DNA stoichiometry, whereas mixed-sequence PNA oligomers formed PNA/DNA duplexes. The preferred binding direction between the modified PNA and DNA in the duplex motifs was antiparallel, as previously reported for complexes involving unmodified PNA.
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| 6. |
- Jansen, J. D., et al.
(författare)
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Erosion rates in Fennoscandia during the past million years
- 2019
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Ingår i: Quaternary Science Reviews. - : Elsevier BV. - 0277-3791. ; 207, s. 37-48
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Tidskriftsartikel (refereegranskat)abstract
- The widespread existence of cosmogenic nuclides accumulated in bedrock prior to the last glaciation demonstrates the limited erosional efficacy of the most recent Fennoscandian and Laurentide ice sheets. Yet the deeper history of erosion in these landscapes repeatedly blanketed by ice remains essentially unknown. Here we present the first comprehensive ice sheet-wide analysis of cosmogenic 10Be data (n = 953) from the Fennoscandian landscape. We find 64% of all sampled bedrock surfaces contain 10Be inheritance, including >85% of blockfields and tors, and >50% of ice-carved terrain, in addition to 27% of ice-transported boulders. Recent ice sheets scoured landscapes well beyond glacial troughs and nuclide inventories reveal a patchy legacy of erosional effectiveness that diminishes at high elevations, such that 89% (n = 55) of bedrock samples retain inheritance above 1600 m. We exploit this widespread nuclide inheritance in a Markov chain Monte Carlo-based inversion model to estimate long-term erosion rates and surface exposure histories from 113 paired 10Be–26Al bedrock samples. Nuclide inventories with or without inheritance convey equally important information about the erosional effectiveness of the last ice sheet. We define cosmogenic nuclide memory as the residence time of bedrock samples inside the nuclide-production window (≤2 m depth) where ∼ 80% of the total nuclide production occurs. The cosmogenic nuclide memory is set by mean erosion rate and varies from ∼10 ka for samples eroded >2 m during the last glaciation to > 1-Ma for the slowest erosion rates. We find that mean erosion rates are well constrained compared to the ratio of exposure to burial. The inclusion of bedrock erosion in our computations thwarts the capacity to constrain surface exposure history or identify former nunataks from paired 10Be–26Al data. Ice-carved surfaces reflect diverse erosion histories that are not straightforward to interpret from surficial morphology alone. Relative to the ∼10 mm/kyr benchmark for polar ice masses, we report point-based mean erosion rates that vary by more than three orders of magnitude, with glacial troughs and areal-scour terrain eroding at ∼1 to >100 mm/kyr, blockfields at 0.8–16 mm/kyr, and tors at 0.8–7.7 mm/kyr (5th–95th percentiles). © 2019 Elsevier Ltd
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| 7. |
- Kim, Seog K., et al.
(författare)
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RIGHT-HANDED TRIPLEX FORMED BETWEEN PEPTIDE NUCLEIC-ACID PNA-T(8) AND POLY(DA) SHOWN BY LINEAR AND CIRCULAR-DICHROISM SPECTROSCOPY
- 1993
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 1520-5126 .- 0002-7863. ; 115:15, s. 6477-6481
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Tidskriftsartikel (refereegranskat)abstract
- The binding of an eightmer of peptide nucleic acid, H-T8-Lys-NH2 (=PNA-T8), to a polynucleotide, poly(dA), was studied by flow linear dichroism (LD) and circular dichroism (CD) spectroscopy. Whereas the single stranded DNA, due to its high flexibility, does not display any measurable LD signal when subjected to shear flow, the complex with PNA does. A titration shows that saturation occurs at a stoichiometry of two PNA thymine bases per DNA adenine base, indicating the formation of a triplex PNA2-DNA complex. The persistence length of the adduct remains small up to relatively high stoichiometries (above 1:1 T:A) indicating that no significant amounts of PNA:DNA duplex are formed. Instead triplex stretches seem to form surrounded by flexible parts of single stranded poly(dA). Upon approaching the stoichiometry 2:1 of T:A the LD increases dramatically demonstrating that the stiffness of the PNA-DNA triplex arises from base-base contacts preventing bending of the chain. It is also inferred that the main stiffness of duplex DNA very probably has a similar origin and is not primarily a result of the increased phosphate-phosphate repulsion. Circular dichroism spectra support the conclusion that a triplex is formed as the only PNA-DNA complex and that it is a right-handed helix. The wavelength dependence of the reduced linear dichroism shows that the inclination of the bases from perpendicularity relative to the helix axis is small. The base conformation of the poly(dA)[PNA-T8]2 triplex is very similar to that of the conventional poly(dA)[poly(dT)]2 triplex.
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| 8. |
- Margeridon-Thermet, S, et al.
(författare)
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Ultra-deep pyrosequencing of hepatitis B virus quasispecies from nucleoside and nucleotide reverse-transcriptase inhibitor (NRTI)-treated patients and NRTI-naive patients
- 2009
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Ingår i: Journal of Infectious Diseases. - : University of Chicago Press. - 0022-1899 .- 1537-6613. ; 199:9, s. 1275-1285
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Tidskriftsartikel (refereegranskat)abstract
- The dynamics of emerging nucleoside and nucleotide reverse-transcriptase inhibitor (NRTI) resistance in hepatitis B virus (HBV) are not well understood because standard dideoxynucleotide direct polymerase chain reaction (PCR) sequencing assays detect drug-resistance mutations only after they have become dominant. To obtain insight into NRTI resistance, we used a new sequencing technology to characterize the spectrum of low-prevalence NRTI-resistance mutations in HBV obtained from 20 plasma samples from 11 NRTI-treated patients and 17 plasma samples from 17 NRTI-naive patients, by using standard direct PCR sequencing and ultra-deep pyrosequencing (UDPS). UDPS detected drug-resistance mutations that were not detected by PCR in 10 samples from 5 NRTI-treated patients, including the lamivudine-resistance mutation V173L (in 5 samples), the entecavir-resistance mutations T184S (in 2 samples) and S202G (in 1 sample), the adefovir-resistance mutation N236T (in 1 sample), and the lamivudine and adefovir-resistance mutations V173L, L180M, A181T, and M204V (in 1 sample). G-to-A hypermutation mediated by the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like family of cytidine deaminases was estimated to be present in 0.6% of reverse-transcriptase genes. Genotype A coinfection was detected by UDPS in each of 3 patients in whom genotype G virus was detected by direct PCR sequencing. UDPS detected low-prevalence HBV variants with NRTI-resistance mutations, G-to-A hypermutation, and low-level dual genotype infection with a sensitivity not previously possible.
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| 9. |
- Wittung, Pernilla, 1968, et al.
(författare)
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DNA-LIKE DOUBLE HELIX FORMED BY PEPTIDE NUCLEIC-ACID
- 1994
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 368:6471, s. 561-563
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Tidskriftsartikel (refereegranskat)abstract
- ALTHOUGH the importance of the nucleobases in the DNA double helix is well understood, the evolutionary significance of the deoxyribose phosphate backbone and the contribution of this chemical entity to the overall helical structure and stability of the double helix is not so clear. Peptide nucleic acid (PNA)1-7 is a DNA analogue with a backbone consisting of N-(2-aminoethyl)glycine units (Fig. 1) which has been shown to mimic DNA in forming Watson-Crick complementary duplexes with normal DNA7. Using circular dichroism spectroscopy we show here that two complementary PNA strands can hybridize to one another to form a helical duplex. There is a seeding of preferred chirality which is induced by the presence of an L- (or D-) lysine residue attached at the carboxy terminus of the PNA strand. These results indicate that a (deoxy)ribose phosphate backbone is not an essential requirement for the formation of double helical DNA-like structures in solution.
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