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| 2. |
- Stanaway, Jeffrey D., et al.
(författare)
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Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017
- 2018
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Ingår i: The Lancet. - 1474-547X .- 0140-6736. ; 392:10159, s. 1923-1994
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Tidskriftsartikel (refereegranskat)abstract
- Background The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017 comparative risk assessment (CRA) is a comprehensive approach to risk factor quantification that offers a useful tool for synthesising evidence on risks and risk-outcome associations. With each annual GBD study, we update the GBD CRA to incorporate improved methods, new risks and risk-outcome pairs, and new data on risk exposure levels and risk- outcome associations. Methods We used the CRA framework developed for previous iterations of GBD to estimate levels and trends in exposure, attributable deaths, and attributable disability-adjusted life-years (DALYs), by age group, sex, year, and location for 84 behavioural, environmental and occupational, and metabolic risks or groups of risks from 1990 to 2017. This study included 476 risk-outcome pairs that met the GBD study criteria for convincing or probable evidence of causation. We extracted relative risk and exposure estimates from 46 749 randomised controlled trials, cohort studies, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. Using the counterfactual scenario of theoretical minimum risk exposure level (TMREL), we estimated the portion of deaths and DALYs that could be attributed to a given risk. We explored the relationship between development and risk exposure by modelling the relationship between the Socio-demographic Index (SDI) and risk-weighted exposure prevalence and estimated expected levels of exposure and risk-attributable burden by SDI. Finally, we explored temporal changes in risk-attributable DALYs by decomposing those changes into six main component drivers of change as follows: (1) population growth; (2) changes in population age structures; (3) changes in exposure to environmental and occupational risks; (4) changes in exposure to behavioural risks; (5) changes in exposure to metabolic risks; and (6) changes due to all other factors, approximated as the risk-deleted death and DALY rates, where the risk-deleted rate is the rate that would be observed had we reduced the exposure levels to the TMREL for all risk factors included in GBD 2017.
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| 3. |
- Adhikari, Deepak, et al.
(författare)
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Inhibitory phosphorylation of Cdk1 mediates prolonged prophase I arrest in female germ cells and is essential for female reproductive lifespan
- 2016
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Ingår i: Cell Research. - : Springer Science and Business Media LLC. - 1001-0602 .- 1748-7838. ; 26, s. 1212-1225
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Tidskriftsartikel (refereegranskat)abstract
- © 2016 IBCB, SIBS, CAS. A unique feature of female germ cell development in mammals is their remarkably long arrest at the prophase of meiosis I, which lasts up to 50 years in humans. Both dormant and growing oocytes are arrested at prophase I and completely lack the ability to resume meiosis. Here, we show that the prolonged meiotic arrest of female germ cells is largely achieved via the inhibitory phosphorylation of Cdk1 (cyclin-dependent kinase 1). In two mouse models where we have introduced mutant Cdk1 T14AY15F which cannot be inhibited by phosphorylation (Cdk1AF) in small meiotically incompetent oocytes, the prophase I arrest is interrupted, leading to a premature loss of female germ cells. We show that in growing oocytes, Cdk1AF leads to premature resumption of meiosis with condensed chromosomes and germinal vesicle breakdown followed by oocyte death, whereas in dormant oocytes, Cdk1AF leads to oocyte death directly, and both situations damage the ovarian reserve that maintains the female reproductive lifespan, which should be around 1 year in mice. Furthermore, interruption of the inhibitory phosphorylation of Cdk1 results in DNA damage, which is accompanied by induction of the Chk2 (checkpoint kinase 2)-p53/p63-dependent cell death pathway, which eventually causes global oocyte death. Together, our data demonstrate that the phosphorylation-mediated suppression of Cdk1 activity is one of the crucial factors that maintain the lengthy prophase arrest in mammalian female germ cells, which is essential for preserving the germ cell pool and reproductive lifespan in female mammals.
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| 4. |
- Block, Keith I., et al.
(författare)
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Designing a broad-spectrum integrative approach for cancer prevention and treatment
- 2015
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Ingår i: Seminars in Cancer Biology. - : Academic Press. - 1044-579X .- 1096-3650. ; 35, s. S276-S304
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Forskningsöversikt (refereegranskat)abstract
- Targeted therapies and the consequent adoption of "personalized" oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity "broadspectrum" therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested, many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered. (C) 2015 The Authors. Published by Elsevier Ltd.
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| 5. |
- Campmier, Mark Joseph, et al.
(författare)
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Seasonally optimized calibrations improve low-cost sensor performance: long-term field evaluation of PurpleAir sensors in urban and rural India
- 2023
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Ingår i: Atmospheric Measurement Techniques. - 1867-1381 .- 1867-8548. ; 16:19, s. 4357-4374
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Tidskriftsartikel (refereegranskat)abstract
- Lower-cost air pollution sensors can fill critical air quality data gaps in India, which experiences very high fine particulate matter (PM2.5) air pollution but has sparse regulatory air monitoring. Challenges for low-cost PM2.5 sensors in India include high-aerosol mass concentrations and pronounced regional and seasonal gradients in aerosol composition. Here, we report on a detailed long-time performance evaluation of a popular sensor, the Purple Air PA-II, at multiple sites in India. We established three distinct sites in India across land use categories and population density extremes (in urban Delhi and rural Hamirpur in north India and urban Bengaluru in south India), where we collocated the PA-II model with reference beta attenuation monitors. We evaluated the performance of uncalibrated sensor data, and then developed, optimized, and evaluated calibration models using a comprehensive feature selection process with a view to reproducibility in the Indian context. We assessed the seasonal and spatial transferability of sensor calibration schemes, which is especially important in India because of the paucity of reference instrumentation. Without calibration, the PA-II was moderately correlated with the reference signal (R2Combining double low line 0.55-0.74) but was inaccurate (NRMSE ≥ 40 %). Relative to uncalibrated data, parsimonious annual calibration models improved the PurpleAir (PA) model performance at all sites (cross-validated NRMSE 20 %-30 %; R2Combining double low line 0.82-0.95), and greatly reduced seasonal and diurnal biases. Because aerosol properties and meteorology vary regionally, the form of these long-term models differed among our sites, suggesting that local calibrations are desirable when possible. Using a moving-window calibration, we found that using seasonally specific information improves performance relative to a static annual calibration model, while a short-term calibration model generally does not transfer reliably to other seasons. Overall, we find that the PA-II model can provide reliable PM2.5 data with better than ±25 % precision and accuracy when paired with a rigorous calibration scheme that accounts for seasonality and local aerosol composition.
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| 6. |
- Dai, Y. L., et al.
(författare)
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Asynchronous embryonic germ cell development leads to a heterogeneity of postnatal ovarian follicle activation and may influence the timing of puberty onset in mice
- 2022
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Ingår i: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Ovarian follicles, which are the basic units of female reproduction, are composed of oocytes and surrounding somatic (pre) granulosa cells (GCs). A recent study revealed that signaling in somatic preGCs controlled the activation (initial recruitment) of follicles in the adult ovaries, but it is also known that there are two waves of follicle with age-related heterogeneity in their developmental dynamics in mammals. Although this heterogeneity was proposed to be crucial for female reproduction, our understanding of how it arises and its significance is still elusive. Results In the current study, by deleting the key secreted factor KIT ligand from preGCs and analyzing the follicle cell developmental dynamics, we revealed distinct patterns of activation and growth associated with the two waves of follicles in mouse ovary. Our results confirmed that activation of adult wave follicles is initiated by somatic preGCs and dependent on the KIT ligand. By contrast, activation of first wave follicles, which are awakened from germ cells before follicle formation, can occur in the absence of preGC-secreted KIT ligand in postnatal ovaries and appears to be oocyte-initiated. We also found that the asynchronous activity of phosphatidylinositol 3 kinases (PI3K) signaling and meiotic process in embryonic germ cells lead to the follicle heterogeneity in postnatal ovaries. In addition, we supplied evidence that the time sequence of embryonic germ cell development and its related first wave follicle growth are correlated to the time of puberty onset in females. Conclusion Taken together, our study provides evidence that asynchronous development of embryonic oocytes leads to the heterogeneity of postnatal ovarian follicle activation and development, and affects the timing of onset of puberty in females.
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| 7. |
- Olahova, M., et al.
(författare)
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POLRMT mutations impair mitochondrial transcription causing neurological disease
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- While >300 disease-causing variants have been identified in the mitochondrial DNA (mtDNA) polymerase gamma, no mitochondrial phenotypes have been associated with POLRMT, the RNA polymerase responsible for transcription of the mitochondrial genome. Here, we characterise the clinical and molecular nature of POLRMT variants in eight individuals from seven unrelated families. Patients present with global developmental delay, hypotonia, short stature, and speech/intellectual disability in childhood; one subject displayed an indolent progressive external ophthalmoplegia phenotype. Massive parallel sequencing of all subjects identifies recessive and dominant variants in the POLRMT gene. Patient fibroblasts have a defect in mitochondrial mRNA synthesis, but no mtDNA deletions or copy number abnormalities. The in vitro characterisation of the recombinant POLRMT mutants reveals variable, but deleterious effects on mitochondrial transcription. Together, our in vivo and in vitro functional studies of POLRMT variants establish defective mitochondrial transcription as an important disease mechanism. POLRMT is key for transcription of the mitochondrial genome, yet has not been implicated in mitochondrial disease to date. Here, the authors identify mutations in POLRMT in individuals with mitochondrial disease-related phenotypes and characterise underlying defects in mitochondrial transcription.
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| 8. |
- Singh, Meenakshi
(författare)
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Pathogenic mechanisms affecting mitochondrial DNA replication and transcription
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mitochondria are cytoplasmic organelles fundamental to life and health. In mitochondria, energy from the food we eat is converted into adenosine triphosphate (ATP), which in turn is used as a source of chemical energy to drive a multitude of cellular reactions. Owing to its endosymbiotic origin, the mitochondrion contains its own genetic material, a circular double-stranded DNA molecule (mtDNA) of about 16.6 kb. The mitochondrial genome contains 37 genes, which code for 13 protein components of the oxidative phosphorylation system, 2 ribosomal RNAs that are required for mitochondrial ribosome biogenesis, and a set of 22 transfer RNAs. The enzymatic systems needed to replicate and transcribe mtDNA are distinct from those present in the nucleus. The objective of this thesis is to characterize pathogenic mechanisms affecting mtDNA replication and transcription in human cells. In collaboration with clinical colleagues, we report that mutations in the gene coding for mitochondrial RNA polymerase (POLRMT) can cause mitochondrial dysfunction and neurological disease. Using in vitro biochemistry and cell biology approaches, we find that the identified mutations cause deleterious effects on mitochondrial transcription, which in turn impair biogenesis of the oxidative phosphorylation system. Mammalian mitochondria lack systems for ribonucleotide excision repair and mtDNA therefore contains relatively high levels of embedded ribonucleotides, which can be even higher in patients suffering from genetic disorders associated with imbalanced nucleotide pools. We demonstrate that embedded ribonucleotides can cause problems for the transcribing POLRMT, causing premature termination of mitochondrial transcription. We suggest that these effects can contribute to the phenotypes associated with nucleotide pool disorders. Others have demonstrated that nucleoside analogues used to treat retroviral infections can cause a progressive accumulation of somatic mtDNA mutations. We investigated the effects of two nucleoside analogues commonly used to treat childhood cancer, 5-Fluorouracil (5-FU) and 6-Thioguanine (6-TG). Using a reconstituted mtDNA replication system, with highly purified components, we demonstrate that both 5-FU and 6-TG impair the activity of mitochondrial DNA polymerase in vitro. We also find that these compounds can cause mtDNA replication stalling in cells. Taken together, our data suggest that 5-FU and 6-TG have the potential to cause mutations, but future studies of mtDNA isolated from patients treated with these compounds are required to validate this idea.
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| 9. |
- Singh, Meenakshi, et al.
(författare)
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Ribonucleotides embedded in template DNA impair mitochondrial RNA polymerase progression
- 2022
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 50:2, s. 989-999
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Tidskriftsartikel (refereegranskat)abstract
- Human mitochondria lack ribonucleotide excision repair pathways, causing misincorporated ribonucleotides (rNMPs) to remain embedded in the mitochondrial genome. Previous studies have demonstrated that human mitochondrial DNA polymerase γ can bypass a single rNMP, but that longer stretches of rNMPs present an obstacle to mitochondrial DNA replication. Whether embedded rNMPs also affect mitochondrial transcription has not been addressed. Here we demonstrate that mitochondrial RNA polymerase elongation activity is affected by a single, embedded rNMP in the template strand. The effect is aggravated at stretches with two or more consecutive rNMPs in a row and cannot be overcome by addition of the mitochondrial transcription elongation factor TEFM. Our findings lead us to suggest that impaired transcription may be of functional relevance in genetic disorders associated with imbalanced nucleotide pools and higher levels of embedded rNMPs. © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.
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