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| 4. |
- Abe, O, et al.
(författare)
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Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials
- 2005
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Ingår i: The Lancet. - 1474-547X. ; 365:9472, s. 1687-1717
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Tidskriftsartikel (refereegranskat)abstract
- Background Quinquennial overviews (1985-2000) of the randomised trials in early breast cancer have assessed the 5-year and 10-year effects of various systemic adjuvant therapies on breast cancer recurrence and survival. Here, we report the 10-year and 15-year effects. Methods Collaborative meta-analyses were undertaken of 194 unconfounded randomised trials of adjuvant chemotherapy or hormonal therapy that began by 1995. Many trials involved CMF (cyclophosphamide, methotrexate, fluorouracil), anthracycline-based combinations such as FAC (fluorouracil, doxombicin, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide), tamoxifen, or ovarian suppression: none involved taxanes, trastuzumab, raloxifene, or modem aromatase inhibitors. Findings Allocation to about 6 months of anthracycline-based polychemotherapy (eg, with FAC or FEC) reduces the annual breast cancer death rate by about 38% (SE 5) for women younger than 50 years of age when diagnosed and by about 20% (SE 4) for those of age 50-69 years when diagnosed, largely irrespective of the use of tamoxifen and of oestrogen receptor (ER) status, nodal status, or other tumour characteristics. Such regimens are significantly (2p=0 . 0001 for recurrence, 2p<0 . 00001 for breast cancer mortality) more effective than CMF chemotherapy. Few women of age 70 years or older entered these chemotherapy trials. For ER-positive disease only, allocation to about 5 years of adjuvant tamoxifen reduces the annual breast cancer death rate by 31% (SE 3), largely irrespective of the use of chemotherapy and of age (<50, 50-69, &GE; 70 years), progesterone receptor status, or other tumour characteristics. 5 years is significantly (2p<0 . 00001 for recurrence, 2p=0 . 01 for breast cancer mortality) more effective than just 1-2 years of tamoxifen. For ER-positive tumours, the annual breast cancer mortality rates are similar during years 0-4 and 5-14, as are the proportional reductions in them by 5 years of tamoxifen, so the cumulative reduction in mortality is more than twice as big at 15 years as at 5 years after diagnosis. These results combine six meta-analyses: anthracycline-based versus no chemotherapy (8000 women); CMF-based versus no chemotherapy (14 000); anthracycline-based versus CMF-based chemotherapy (14 000); about 5 years of tamoxifen versus none (15 000); about 1-2 years of tamoxifen versus none (33 000); and about 5 years versus 1-2 years of tamoxifen (18 000). Finally, allocation to ovarian ablation or suppression (8000 women) also significantly reduces breast cancer mortality, but appears to do so only in the absence of other systemic treatments. For middle-aged women with ER-positive disease (the commonest type of breast cancer), the breast cancer mortality rate throughout the next 15 years would be approximately halved by 6 months of anthracycline-based chemotherapy (with a combination such as FAC or FEC) followed by 5 years of adjuvant tamoxifen. For, if mortality reductions of 38% (age <50 years) and 20% (age 50-69 years) from such chemotherapy were followed by a further reduction of 31% from tamoxifen in the risks that remain, the final mortality reductions would be 57% and 45%, respectively (and, the trial results could well have been somewhat stronger if there had been full compliance with the allocated treatments). Overall survival would be comparably improved, since these treatments have relatively small effects on mortality from the aggregate of all other causes. Interpretation Some of the widely practicable adjuvant drug treatments that were being tested in the 1980s, which substantially reduced 5-year recurrence rates (but had somewhat less effect on 5-year mortality rates), also substantially reduce 15-year mortality rates. Further improvements in long-term survival could well be available from newer drugs, or better use of older drugs.
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- Micah, Angela E., et al.
(författare)
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Tracking development assistance for health and for COVID-19 : a review of development assistance, government, out-of-pocket, and other private spending on health for 204 countries and territories, 1990-2050
- 2021
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Ingår i: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 398:10308, s. 1317-1343
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Forskningsöversikt (refereegranskat)abstract
- Background The rapid spread of COVID-19 renewed the focus on how health systems across the globe are financed, especially during public health emergencies. Development assistance is an important source of health financing in many low-income countries, yet little is known about how much of this funding was disbursed for COVID-19. We aimed to put development assistance for health for COVID-19 in the context of broader trends in global health financing, and to estimate total health spending from 1995 to 2050 and development assistance for COVID-19 in 2020. Methods We estimated domestic health spending and development assistance for health to generate total health-sector spending estimates for 204 countries and territories. We leveraged data from the WHO Global Health Expenditure Database to produce estimates of domestic health spending. To generate estimates for development assistance for health, we relied on project-level disbursement data from the major international development agencies' online databases and annual financial statements and reports for information on income sources. To adjust our estimates for 2020 to include disbursements related to COVID-19, we extracted project data on commitments and disbursements from a broader set of databases (because not all of the data sources used to estimate the historical series extend to 2020), including the UN Office of Humanitarian Assistance Financial Tracking Service and the International Aid Transparency Initiative. We reported all the historic and future spending estimates in inflation-adjusted 2020 US$, 2020 US$ per capita, purchasing-power parity-adjusted US$ per capita, and as a proportion of gross domestic product. We used various models to generate future health spending to 2050. Findings In 2019, health spending globally reached $8. 8 trillion (95% uncertainty interval [UI] 8.7-8.8) or $1132 (1119-1143) per person. Spending on health varied within and across income groups and geographical regions. Of this total, $40.4 billion (0.5%, 95% UI 0.5-0.5) was development assistance for health provided to low-income and middle-income countries, which made up 24.6% (UI 24.0-25.1) of total spending in low-income countries. We estimate that $54.8 billion in development assistance for health was disbursed in 2020. Of this, $13.7 billion was targeted toward the COVID-19 health response. $12.3 billion was newly committed and $1.4 billion was repurposed from existing health projects. $3.1 billion (22.4%) of the funds focused on country-level coordination and $2.4 billion (17.9%) was for supply chain and logistics. Only $714.4 million (7.7%) of COVID-19 development assistance for health went to Latin America, despite this region reporting 34.3% of total recorded COVID-19 deaths in low-income or middle-income countries in 2020. Spending on health is expected to rise to $1519 (1448-1591) per person in 2050, although spending across countries is expected to remain varied. Interpretation Global health spending is expected to continue to grow, but remain unequally distributed between countries. We estimate that development organisations substantially increased the amount of development assistance for health provided in 2020. Continued efforts are needed to raise sufficient resources to mitigate the pandemic for the most vulnerable, and to help curtail the pandemic for all. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.
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| 10. |
- Ercan, Ayse Bahar, et al.
(författare)
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Clinical and biological landscape of constitutional mismatch-repair deficiency syndrome: an International Replication Repair Deficiency Consortium cohort study.
- 2024
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Ingår i: The Lancet Oncology. - 1470-2045. ; 25:5, s. 668-682
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Tidskriftsartikel (refereegranskat)abstract
- Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare and aggressive cancer predisposition syndrome. Because a scarcity of data on this condition contributes to management challenges and poor outcomes, we aimed to describe the clinical spectrum, cancer biology, and impact of genetics on patient survival in CMMRD.In this cohort study, we collected cross-sectional and longitudinal data on all patients with CMMRD, with no age limits, registered with the International Replication Repair Deficiency Consortium (IRRDC) across more than 50 countries. Clinical data were extracted from the IRRDC database, medical records, and physician-completed case record forms. The primary objective was to describe the clinical features, cancer spectrum, and biology of the condition. Secondary objectives included estimations of cancer incidence and of the impact of the specific mismatch-repair gene and genotype on cancer onset and survival, including after cancer surveillance and immunotherapy interventions.We analysed data from 201 patients (103 males, 98 females) enrolled between June 5, 2007 and Sept 9, 2022. Median age at diagnosis of CMMRD or a related cancer was 8·9 years (IQR 5·9-12·6), and median follow-up from diagnosis was 7·2 years (3·6-14·8). Endogamy among minorities and closed communities contributed to high homozygosity within countries with low consanguinity. Frequent dermatological manifestations (117 [93%] of 126 patients with complete data) led to a clinical overlap with neurofibromatosis type 1 (35 [28%] of 126). 339 cancers were reported in 194 (97%) of 201 patients. The cumulative cancer incidence by age 18 years was 90% (95% CI 80-99). Median time between cancer diagnoses for patients with more than one cancer was 1·9 years (IQR 0·8-3·9). Neoplasms developed in 15 organs and included early-onset adult cancers. CNS tumours were the most frequent (173 [51%] cancers), followed by gastrointestinal (75 [22%]), haematological (61 [18%]), and other cancer types (30 [9%]). Patients with CNS tumours had the poorest overall survival rates (39% [95% CI 30-52] at 10 years from diagnosis; log-rank p<0·0001 across four cancer types), followed by those with haematological cancers (67% [55-82]), gastrointestinal cancers (89% [81-97]), and other solid tumours (96% [88-100]). All cancers showed high mutation and microsatellite indel burdens, and pathognomonic mutational signatures. MLH1 or MSH2 variants caused earlier cancer onset than PMS2 or MSH6 variants, and inferior survival (overall survival at age 15 years 63% [95% CI 55-73] for PMS2, 49% [35-68] for MSH6, 19% [6-66] for MLH1, and 0% for MSH2; p<0·0001). Frameshift or truncating variants within the same gene caused earlier cancers and inferior outcomes compared with missense variants (p<0·0001). The greater deleterious effects of MLH1 and MSH2 variants as compared with PMS2 and MSH6 variants persisted despite overall improvements in survival after surveillance or immune checkpoint inhibitor interventions.The very high cancer burden and unique genomic landscape of CMMRD highlight the benefit of comprehensive assays in timely diagnosis and precision approaches toward surveillance and immunotherapy. These data will guide the clinical management of children and patients who survive into adulthood with CMMRD.The Canadian Institutes for Health Research, Stand Up to Cancer, Children's Oncology Group National Cancer Institute Community Oncology Research Program, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Harry and Agnieszka Hall, Meagan's Walk, BRAINchild Canada, The LivWise Foundation, St Baldrick Foundation, Hold'em for Life, and Garron Family Cancer Center.
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| 11. |
- Barack, Leor, et al.
(författare)
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Black holes, gravitational waves and fundamental physics : a roadmap
- 2019
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Ingår i: Classical and quantum gravity. - : IOP Publishing. - 0264-9381 .- 1361-6382. ; 36:14
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Forskningsöversikt (refereegranskat)abstract
- The grand challenges of contemporary fundamental physics dark matter, dark energy, vacuum energy, inflation and early universe cosmology, singularities and the hierarchy problem all involve gravity as a key component. And of all gravitational phenomena, black holes stand out in their elegant simplicity, while harbouring some of the most remarkable predictions of General Relativity: event horizons, singularities and ergoregions. The hitherto invisible landscape of the gravitational Universe is being unveiled before our eyes: the historical direct detection of gravitational waves by the LIGO-Virgo collaboration marks the dawn of a new era of scientific exploration. Gravitational-wave astronomy will allow us to test models of black hole formation, growth and evolution, as well as models of gravitational-wave generation and propagation. It will provide evidence for event horizons and ergoregions, test the theory of General Relativity itself, and may reveal the existence of new fundamental fields. The synthesis of these results has the potential to radically reshape our understanding of the cosmos and of the laws of Nature. The purpose of this work is to present a concise, yet comprehensive overview of the state of the art in the relevant fields of research, summarize important open problems, and lay out a roadmap for future progress. This write-up is an initiative taken within the framework of the European Action on 'Black holes, Gravitational waves and Fundamental Physics'.
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| 13. |
- Das, Anirban, et al.
(författare)
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Combined immunotherapy improves outcome for replication repair deficient (RRD) high-grade glioma failing anti-PD1 monotherapy: A report from the International RRD Consortium.
- 2024
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Ingår i: Cancer discovery. - 2159-8290. ; 14:2, s. 258-273
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Tidskriftsartikel (refereegranskat)abstract
- Immune-checkpoint inhibition (ICI) is effective for replication-repair deficient, high-grade gliomas (RRD-HGG). Clinical/biologic impact of immune-directed approaches after failing ICI-monotherapy are unknown. We performed an international study on 75 patients treated with anti-PD1; 20 are progression-free (median follow-up: 3.7-years). After 2nd-progression/recurrence (n=55), continuing ICI-based salvage prolonged survival to 11.6-months (n=38; p<0.001), particularly for those with extreme mutation burden (p=0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and immune-microenvironment. Response to re-irradiation was explained by an absence of deleterious post-radiation indel signatures (ID8). Increased CTLA4-expression over time, and subsequent CTLA4-inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to reinvigoration of peripheral immune and radiological responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/ synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology.
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| 15. |
- Hoffman, Tove, et al.
(författare)
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Alkhurma Hemorrhagic Fever Virus RNA in Hyalomma rufipes Ticks Infesting Migratory Birds, Europe and Asia Minor
- 2018
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Ingår i: Emerging Infectious Diseases. - Atlanta, United States : U.S. Department of Health and Human Services * Centers for Disease Control and Prevention. - 1080-6040 .- 1080-6059. ; 24:5, s. 879-882
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Tidskriftsartikel (refereegranskat)abstract
- Alkhurma hemorrhagic fever virus RNA was detected in immature Hyalomma rufipes ticks infesting northward migratory birds caught in the North Mediterranean Basin. This finding suggests a role for birds in the ecology of the Alkhurma hemorrhagic fever virus and a potential mechanism for dissemination to novel regions. Increased surveillance is warranted.
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| 16. |
- Hoffman, Tove, et al.
(författare)
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Association between guilds of birds in the African-Western Palaearctic region and the tick species Hyalomma rufipes, one of the main vectors of Crimean-Congo hemorrhagic fever virus
- 2021
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Ingår i: One Health. - : Elsevier. - 2352-7714. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionThe ecology of the vertebrate host contributes to the geographical range expansion of ticks. In this study, we investigated which tick taxa that infest and are dispersed by birds along African-Western Palaearctic flyways during northward migration, and whether bird ecology was associated with tick taxa.Materials and methodsTicks were collected from birds trapped at bird observatories in Spain, Italy, Greece, and Israel during the spring migration of 2014 and 2015, using mist nets. The tick-infested bird species were classified into guilds, using different combinations of the variables: migration distance, wintering region, foraging behaviour, and winter habitat. Ticks were molecularly determined to genus and species level by sequencing fragments of the 12S ribosomal DNA (rDNA) gene and by phylogenetic inference, using the Maximum Likelihood algorithm. Data were analysed using descriptive measures, graphs, Chi2 tests, the Tukey-Kramer test, and a parametric linear model (generalized linear model) in order to analyse and adjust for characteristics in the bird guilds and their relationship to collected tick taxa.ResultsMost (84.2%) of the 10,209 trapped birds were long-distance migrants, of which 2.4% were infested by ticks. The most common tick species was Hyalomma rufipes (77.7%; 447/575), a known vector and reservoir of Crimean-Congo hemorrhagic fever virus. Bird guilds containing only long-distance migrants with wintering areas in Africa were associated with the tick species H. rufipes (p < 0.0001). Furthermore, bird winter habitat was associated with H. rufipes (p = 0.003); with bird species overwintering in open habitat (p = 0.014) and wetlands (p = 0.046) having significantly more H. rufipes as compared to birds with a winter habitat comprising forest and shrubs (p = 0.82).ConclusionsWith climate change, the likelihood of establishment of permanent Hyalomma populations in central and northern Europe is increasing. Thus, surveillance programs for monitoring the risk of introduction and establishment of H. rufipes in the Western-Palaearctic should be established. Our study suggests that migratory bird species wintering in African open habitats and wetlands are good candidates for monitoring potential introduction.
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| 17. |
- Hoffman, Tove, et al.
(författare)
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Association between guilds of birds in the African-Western Palaearctic region and the tick species Hyalomma rufipes, one of the main vectors of Crimean-Congo hemorrhagic fever virus.
- 2022
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Ingår i: Microorganisms. - : MDPI AG. - 2076-2607. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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| 18. |
- Hoffman, Tove, et al.
(författare)
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Co-occurrence of Francisella and spotted fever group Rickettsia in avian-associated Hyalomma rufipes
- 2022
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The migratory behaviour of wild birds aids in the geographical spread of ticks and their microorganisms. Ticks are known to harbor both pathogenic and symbiotic bacteria - such as species of the genera Francisella, Rickettsia,and Midichloria - and multiple bacterial species may occur within them. Francisella occurs in different tick taxa andconsists of closely related pathogenic and non-pathogenic species. Spotted fever group Rickettsia are transmitted to humans by different tick genera and are emerging human pathogens in Europe. The aims of this study were to investigate dispersal of Francisella as well as co-occurrence of Francisella and spotted fever group Rickettsia in ticks infesting northward migrating birds in the African-Western Palaearctic region.Materials and methods: Birds were trapped using mist nets at bird observatories in Spain, Italy, Greece, and Israel during their spring migration of 2014 and 2015. Ticks were screened for the genus Francisella, the species Francisella tularensis, and spotted fever group Rickettsia by microfluidic qPCR. Ticks with putative positive results for F. tularensiswere subjected to confirmation analyses, metagenomics analysis, enrichment, and whole genome sequencing.Results: There was a high prevalence of Francisella species (76.7%) and co-occurrence of Francisella species and spotted fever group Rickettsia (50.6%) in the tick species Hyalomma rufipes. Two H. rufipes yielded putative positive test results for the human pathogen F. tularensis during initial screening. Metagenomics analysis revealed presence of Francisella sp., Rickettsia sp., and Midichloria sp. DNA in the two H. rufipes ticks. The levels of Rickettsia and Midichloria DNA were relatively high while the level of Francisella DNA was low and required enrichment for the construction of metagenome-assembled genomes. Phylogenetic inference and calculations of the average nucleotide identity (ANI) indicated that: i) the Francisella genomes belonged to the Francisella-like endosymbiont (FLE) group in Clade 1 of Francisella and had highest sequence identity to an FLE found in Ornithodoros moubata (ANI: 96.7/97.0%), ii) the Rickettsia genomes had highest resemblance to Rickettsia aeschlimannii (ANI: 98.8 - 99.9%), and iii) the Midichloria genomes resembled Midichloria mitochondrii (ANI: 91.5 - 92.3%).Conclusions: The results of this study suggest ticks containing Francisella species, FLEs, and spotted fever groupRickettsia are dispersed by northbound migratory birds in the African-Western Palaearctic and suggest H. rufipes may not be involved in the transmission of F. tularensis in the study region. Future studies should aim at confirming the prevalence of Francisella spp. and spotted fever group Rickettsia in H. rufipes, in addition to focusing on the influence of FLEs on H. rufipes and their interaction with pathogenic and symbiotic bacteria of the genera Rickettsia and Midichloria.
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| 19. |
- Hoffman, Tove, et al.
(författare)
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Co-Occurrence of Francisella, Spotted Fever Group Rickettsia, and Midichloria in Avian-Associated Hyalomma rufipes
- 2022
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Ingår i: Microorganisms. - : MDPI. - 2076-2607. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- The migratory behavior of wild birds contributes to the geographical spread of ticks and their microorganisms. In this study, we aimed to investigate the dispersal and co-occurrence of Francisella and spotted fever group Rickettsia (SFGR) in ticks infesting birds migrating northward in the African-Western Palaearctic region (AWPR). Birds were trapped with mist nests across the Mediterranean basin during the 2014 and 2015 spring migration. In total, 575 ticks were collected from 244 birds. We screened the ticks for the species Francisella tularensis, the genus Francisella, and SFGR by microfluidic real-time PCR. Confirmatory analyses and metagenomic sequencing were performed on tick samples that putatively tested positive for F. tularensis during initial screenings. Hyalomma rufipes was the most common tick species and had a high prevalence of Francisella, including co-occurrence of Francisella and SFGR. Metagenomic analysis of total DNA extracted from two H. rufipes confirmed the presence of Francisella, Rickettsia, and Midichloria. Average nucleotide identity and phylogenetic inference indicated the highest identity of the metagenome-assembled genomes to a Francisella-like endosymbiont (FLE), Rickettsia aeschlimannii, and Midichloria mitochondrii. The results of this study suggest that (i) FLE- and SFGR-containing ticks are dispersed by northbound migratory birds in the AWPR, (ii) H. rufipes likely is not involved in transmission of F. tularensis in the AWPR, and (iii) a dual endosymbiosis of FLEs and Midichloria may support some of the nutritional requirements of H. rufipes.
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| 20. |
- Neymotin, Samuel A., et al.
(författare)
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I-h Tunes Theta/Gamma Oscillations and Cross-Frequency Coupling In an In Silico CA3 Model
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:10, s. e76285-
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Tidskriftsartikel (refereegranskat)abstract
- I-h channels are uniquely positioned to act as neuromodulatory control points for tuning hippocampal theta (4-12 Hz) and gamma (25 Hz) oscillations, oscillations which are thought to have importance for organization of information flow. contributes to neuronal membrane resonance and resting membrane potential, and is modulated by second messengers. We investigated oscillatory control using a multiscale computer model of hippocampal CA3, where each cell class (pyramidal, basket, and oriens-lacunosum moleculare cells), contained type-appropriate isoforms of. Our model demonstrated that modulation of pyramidal and basket allows tuning theta and gamma oscillation frequency and amplitude. Pyramidal also controlled cross-frequency coupling (CFC) and allowed shifting gamma generation towards particular phases of the theta cycle, effected via 's ability to set pyramidal excitability. Our model predicts that in vivo neuromodulatory control of allows flexibly controlling CFC and the timing of gamma discharges at particular theta phases.
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| 21. |
- Segal-Raz, Hava, et al.
(författare)
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ATM-mediated phosphorylation of polynucleotide kinase/phosphatase is required for effective DNA double-strand break repair
- 2011
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Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 12:7, s. 713-719
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Tidskriftsartikel (refereegranskat)abstract
- The cellular response to double-strand breaks (DSBs) in DNA is a complex signalling network, mobilized by the nuclear protein kinase ataxia-telangiectasia mutated (ATM), which phosphorylates many factors in the various branches of this network. A main question is how ATM regulates DSB repair. Here, we identify the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) as an ATM target. PNKP phosphorylates 5'-OH and dephosphorylates 3'-phosphate DNA ends that are formed at DSB termini caused by DNA-damaging agents, thereby regenerating legitimate ends for further processing. We establish that the ATM phosphorylation targets on human PNKP-Ser 114 and Ser 126-are crucial for cellular survival following DSB induction and for effective DSB repair, being essential for damage-induced enhancement of the activity of PNKP and its proper accumulation at the sites of DNA damage. These findings show a direct functional link between ATM and the DSB-repair machinery.
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