| 51. |
- Frandsen, K. E. H., et al.
(författare)
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The molecular basis of polysaccharide cleavage by lytic polysaccharide monooxygenases
- 2016
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Ingår i: Nature Chemical Biology. - : Springer Science and Business Media LLC. - 1552-4450 .- 1552-4469. ; 12:4, s. 298-
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Tidskriftsartikel (refereegranskat)abstract
- Lytic polysaccharide monooxygenases (LPMOs) are copper-containing enzymes that oxidatively break down recalcitrant polysaccharides such as cellulose and chitin. Since their discovery, LPMOs have become integral factors in the industrial utilization of biomass, especially in the sustainable generation of cellulosic bioethanol. We report here a structural determination of an LPMO-oligosaccharide complex, yielding detailed insights into the mechanism of action of these enzymes. Using a combination of structure and electron paramagnetic resonance spectroscopy, we reveal the means by which LPMOs interact with saccharide substrates. We further uncover electronic and structural features of the enzyme active site, showing how LPMOs orchestrate the reaction of oxygen with polysaccharide chains.
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| 52. |
- Geldsetzer, Pascal, et al.
(författare)
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Depressive Symptoms and Their Relation to Age and Chronic Diseases Among Middle-Aged and Older Adults in Rural South Africa
- 2019
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Ingår i: The journals of gerontology. Series A, Biological sciences and medical sciences. - : OXFORD UNIV PRESS INC. - 1079-5006 .- 1758-535X. ; 74:6, s. 957-963
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Tidskriftsartikel (refereegranskat)abstract
- Background: Understanding how depression is associated with chronic conditions and sociodemographic characteristics can inform the design and effective targeting of depression screening and care interventions. In this study, we present some of the first evidence from sub-Saharan Africa on the association between depressive symptoms and a range of chronic conditions (diabetes, HIV, hypertension, and obesity) as well as sociodemographic characteristics. Methods: A questionnaire was administered to a population-based simple random sample of 5,059 adults aged 40 years and older in Agincourt, South Africa. Depressive symptoms were measured using a modified version of the eight-item Center for Epidemiological Studies-Depression screening tool. Diabetes was assessed using a capillary blood glucose measurement and HIV using a dried blood spot. Results: 17.0% (95% confidence interval: 15.9%-18.1%) of participants had at least three depressive symptoms. None of the chronic conditions were significantly associated with depressive symptoms in multivariable regressions. Older age was the strongest correlate of depressive symptoms with those aged 80 years and older having on average 0.63 (95% confidence interval: 0.40-0.86; p<.001) more depressive symptoms than those aged 40-49 years. Household wealth quintile and education were not significant correlates. Conclusions: This study provides some evidence that the positive associations of depression with diabetes, HIV, hypertension, and obesity that are commonly reported in high-income settings might not exist in rural South Africa. Our finding that increasing age is strongly associated with depressive symptoms suggests that there is a particularly high need for depression screening and treatment among the elderly adults in rural South Africa.
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| 53. |
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| 54. |
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| 55. |
- Ju, Young Seok, et al.
(författare)
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Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells.
- 2015
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 25:6, s. 814-824
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.
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| 56. |
- Kaufman, Bella, et al.
(författare)
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Olaparib Monotherapy in Patients With Advanced Cancer and a Germline BRCA1/2 Mutation.
- 2015
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 33:3, s. 134-244
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Tidskriftsartikel (refereegranskat)abstract
- Olaparib is an oral poly (ADP-ribose) polymerase inhibitor with activity in germline BRCA1 and BRCA2 (BRCA1/2) -associated breast and ovarian cancers. We evaluated the efficacy and safety of olaparib in a spectrum of BRCA1/2-associated cancers.
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| 57. |
- Martelotto, L. G., et al.
(författare)
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Genomic landscape of adenoid cystic carcinoma of the breast
- 2015
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Ingår i: Journal of Pathology. - : Wiley. - 0022-3417. ; 237:2, s. 179-189
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Tidskriftsartikel (refereegranskat)abstract
- Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin. Copyright (c) 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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| 58. |
- Nik-Zainal, Serena, et al.
(författare)
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Landscape of somatic mutations in 560 breast cancer whole-genome sequences
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 534:7605, s. 47-54
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Tidskriftsartikel (refereegranskat)abstract
- We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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| 59. |
- Peciulyte, Ausra, 1986, et al.
(författare)
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Redox processes acidify and decarboxylate steam-pretreated lignocellulosic biomass and are modulated by LPMO and catalase
- 2018
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Ingår i: Biotechnology for Biofuels. - : Springer Science and Business Media LLC. - 1754-6834 .- 1754-6834. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The bioconversion of lignocellulosic feedstocks to ethanol is being commercialised, but further process development is required to improve their economic feasibility. Efficient saccharification of lignocellulose to fermentable sugars requires oxidative cleavage of glycosidic linkages by lytic polysaccharide monooxygenases (LPMOs). However, a proper understanding of the catalytic mechanism of this enzyme class and the interaction with other redox processes associated with the saccharification of lignocellulose is still lacking. The in-use stability of LPMO-containing enzyme cocktails is increased by the addition of catalase implying that hydrogen peroxide (H2O2) is generated in the slurry during incubation. Therefore, we sought to characterize the effects of enzymatic and abiotic sources of H2O2on lignocellulose hydrolysis to identify parameters that could improve this process. Moreover, we studied the abiotic redox reactions of steam-pretreated wheat straw as a function of temperature and dry-matter (DM) content. Results: Abiotic reactions in pretreated wheat straw consume oxygen, release carbon dioxide (CO2) to the slurry, and decrease the pH. The magnitude of these reactions increased with temperature and with DM content. The presence of LPMO during saccharification reduced the amount of CO2liberated, while the effect on pH was insignificant. Catalase led to increased decarboxylation through an unknown mechanism. Both in situ-generated and added H2O2caused a decrease in pH. Conclusions: Abiotic redox processes similar to those that occur in natural water-logged environments also affect the saccharification of pretreated lignocellulose. Heating of the lignocellulosic material and adjustment of pH trigger rapid oxygen consumption and acidification of the slurry. In industrial settings, it will be of utmost importance to control these processes. LPMOs interact with the surrounding redox compounds and redirect abiotic electron flow from decarboxylating reactions to fuel the oxidative cleavage of glycosidic bonds in cellulose.
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| 60. |
- Rohr, Julia K., et al.
(författare)
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Performance of self-reported HIV status in determining true HIV status among older adults in rural South Africa : a validation study
- 2017
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Ingår i: Journal of the International AIDS Society. - 1758-2652. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: In South Africa, older adults make up a growing proportion of people living with HIV. HIV programmes are likely to reach older South Africans in home-based interventions where testing is not always feasible. We evaluate the accuracy of self-reported HIV status, which may provide useful information for targeting interventions or offer an alternative to biomarker testing.Methods: Data were taken from the Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa (HAALSI) baseline survey, which was conducted in rural Mpumalanga province, South Africa. A total of 5059 participants aged ≥40 years were interviewed from 2014 to 2015. Self-reported HIV status and dried bloodspots for HIV biomarker testing were obtained during at-home interviews. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for self-reported status compared to “gold standard” biomarker results. Log-binomial regression explored associations between demographic characteristics, antiretroviral therapy (ART) status and sensitivity of self-report.Results: Most participants (93%) consented to biomarker testing. Of those with biomarker results, 50.9% reported knowing their HIV status and accurately reported it. PPV of self-report was 94.1% (95% confidence interval (CI): 92.0–96.0), NPV was 87.2% (95% CI: 86.2–88.2), sensitivity was 51.2% (95% CI: 48.2–54.3) and specificity was 99.0% (95% CI: 98.7–99.4). Participants on ART were more likely to report their HIV-positive status, and participants reporting false-negatives were more likely to have older HIV tests.Conclusions: The majority of participants were willing to share their HIV status. False-negative reports were largely explained by lack of testing, suggesting HIV stigma is retreating in this setting, and that expansion of HIV testing and retesting is still needed in this population. In HIV interventions where testing is not possible, self-reported status should be considered as a routine first step to establish HIV status.
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| 61. |
- Rosenberg, Molly S., et al.
(författare)
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Sexual Behaviors and HIV Status : A Population-Based Study Among Older Adults in Rural South Africa
- 2017
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Ingår i: Journal of Acquired Immune Deficiency Syndromes. - 1525-4135 .- 1944-7884. ; 74:1, s. E9-E17
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To identify the unmet needs for HIV prevention among older adults in rural South Africa.Methods: We analyzed data from a population-based sample of 5059 men and women aged 40 years and older from the study Health and Aging in Africa: Longitudinal Studies of INDEPTH Communities (HAALSI), which was carried out in the Agincourt health and sociodemographic surveillance system in the Mpumalanga province of South Africa. We estimated the prevalence of HIV (laboratory-confirmed and self-reported) and key sexual behaviors by age and sex. We compared sexual behavior profiles across HIV status categories with and without age–sex standardization.Results: HIV prevalence was very high among HAALSI participants (23%, 95% confidence interval [CI]: 21 to 24), with no sex differences. Recent sexual activity was common (56%, 95% CI: 55 to 58) across all HIV status categories. Condom use was low among HIV-negative adults (15%, 95% CI: 14 to 17), higher among HIV-positive adults who were unaware of their HIV status (27%, 95% CI: 22 to 33), and dramatically higher among HIV-positive adults who were aware of their status (75%, 95% CI: 70 to 80). Casual sex and multiple partnerships were reported at moderate levels, with slightly higher estimates among HIV-positive compared to HIV-negative adults. Differences by HIV status remained after age–sex standardization.Conclusions: Older HIV-positive adults in an HIV hyperendemic community of rural South Africa report sexual behaviors consistent with high HIV transmission risk. Older HIV-negative adults report sexual behaviors consistent with high HIV acquisition risk. Prevention initiatives tailored to the particular prevention needs of older adults are urgently needed to reduce HIV risk in this and similar communities in sub-Saharan Africa.
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