Mitochondrial topoisomerase IB (TOP1MT) is a nuclear-encoded topoisomerase, exclusively localized to mitochondria, which resolves topological stress generated during mtDNA replication and ...transcription. Here, we report that TOP1MT is overexpressed in cancer tissues and demonstrate that TOP1MT deficiency attenuates tumor growth in human and mouse models of colon and liver cancer. Due to their mitochondrial dysfunction, TOP1MT-KO cells become addicted to glycolysis, which limits synthetic building blocks and energy supply required for the proliferation of cancer cells in a nutrient-deprived tumor microenvironment. Mechanistically, we show that TOP1MT associates with mitoribosomal subunits, ensuring optimal mitochondrial translation and assembly of oxidative phosphorylation complexes that are critical for sustaining tumor growth. The TOP1MT genomic signature profile, based on Top1mt-KO liver cancers, is correlated with enhanced survival of hepatocellular carcinoma patients. Our results highlight the importance of TOP1MT for tumor development, providing a potential rationale to develop TOP1MT-targeted drugs as anticancer therapies.
Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current ...classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides.
Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed.
We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA.
The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.
Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European ...Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.
Flood estimation and flood management have traditionally been the domain of hydrologists, water resources engineers and statisticians, and disciplinary approaches abound. Dominant views have been ...shaped; one example is the catchment perspective: floods are formed and influenced by the interaction of local, catchment-specific characteristics, such as meteorology, topography and geology. These traditional views have been beneficial, but they have a narrow framing. In this paper we contrast traditional views with broader perspectives that are emerging from an improved understanding of the climatic context of floods. We come to the following conclusions: (1) extending the traditional system boundaries (local catchment, recent decades, hydrological/hydraulic processes) opens up exciting possibilities for better understanding and improved tools for flood risk assessment and management. (2) Statistical approaches in flood estimation need to be complemented by the search for the causal mechanisms and dominant processes in the atmosphere, catchment and river system that leave their fingerprints on flood characteristics. (3) Natural climate variability leads to time-varying flood characteristics, and this variation may be partially quantifiable and predictable, with the perspective of dynamic, climate-informed flood risk management. (4) Efforts are needed to fully account for factors that contribute to changes in all three risk components (hazard, exposure, vulnerability) and to better understand the interactions between society and floods. (5) Given the global scale and societal importance, we call for the organization of an international multidisciplinary collaboration and data-sharing initiative to further understand the links between climate and flooding and to advance flood research.
Rapidly attending towards potentially harmful stimuli to prevent possible damage to the body is a critical component of adaptive behavior. Research suggests that individuals display an attentional ...bias, i.e., preferential allocation of attention, for consciously perceived bodily sensations that signal potential threat, like itch or pain. Evidence is not yet clear whether an attentional bias also exists for stimuli that have been presented for such a short duration that they do not enter the stream of consciousness. This study investigated whether a preconscious attentional bias towards itch-related pictures exists in 127 healthy participants and whether this can be influenced by priming with mild itch-related stimuli compared to control stimuli. Mild itch was induced with von Frey monofilaments and scratching sounds, while control stimuli where of matched modalities but neutral. Attentional bias was measured with a subliminal pictorial dot-probe task. Moreover, we investigated how attentional inhibition of irrelevant information and the ability to switch between different tasks, i.e., cognitive flexibility, contribute to the emergence of an attentional bias. Attentional inhibition was measured with a Flanker paradigm and cognitive flexibility was measured with a cued-switching paradigm. Contrary to our expectations, results showed that participants attention was not biased towards the itch-related pictures, in facts, attention was significantly drawn towards the neutral pictures. In addition, no effect of the itch-related priming was observed. Finally, this effect was not influenced by participants' attentional inhibition and cognitive flexibility. Therefore, we have no evidence for a preconscious attentional bias towards itch stimuli. The role of preconscious attentional bias in patients with chronic itch should be investigated in future studies.
Aims/hypothesis
In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia ...telangiectasia mutated (
ATM
) gene in multiple additional populations.
Methods
Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS,
n
= 929) and the Rotterdam Study (
n
= 182) from the Netherlands, and the CARDS Trial (
n
= 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA
1c
reduction and treatment success, defined as the ability to reach the treatment target of an HbA
1c
≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed.
Results
In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58,
p
= 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39,
p
= 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49,
p
= 0.016 and OR 1.25, 95% CI 1.33, 1.38,
p
= 7.8 × 10
−6
, respectively).
Conclusions/interpretation
A gene variant near
ATM
is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), ...both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.
Global importance of large-diameter trees Lutz, James A.; Furniss, Tucker J.; Johnson, Daniel J. ...
Global ecology and biogeography,
July 2018, Letnik:
27, Številka:
7/8
Journal Article
Recenzirano
Odprti dostop
Aim: To examine the contribution of large-diameter trees to biomass, stand structure, and species richness across forest biomes. Location: Global. Time period: Early 21st century. Major taxa studied: ...Woody plants. Methods: We examined the contribution of large trees to forest density, richness and biomass using a global network of 48 large (from 2 to 60 ha) forest plots representing 5,601,473 stems across 9,298 species and 210 plant families. This contribution was assessed using three metrics: the largest 1% of trees ≥ 1 cm diameter at breast height (DBH), all trees ≥ 60 cm DBH, and those rank-ordered largest trees that cumulatively comprise 50% of forest biomass. Results: Averaged across these 48 forest plots, the largest 1% of trees ≥ 1 cm DBH comprised 50% of aboveground live biomass, with hectare-scale standard deviation of 26%. Trees ≥ 60 cm DBH comprised 41% of aboveground live tree biomass. The size of the largest trees correlated with total forest biomass (r2 = .62, p < .001). Large-diameter trees in high biomass forests represented far fewer species relative to overall forest richness (r2 = .45, p < .001). Forests with more diverse large-diameter tree communities were comprised of smaller trees (r2 = .33, p < .001). Lower large-diameter richness was associated with large-diameter trees being individuals of more common species (r2 = .17, p = .002). The concentration of biomass in the largest 1% of trees declined with increasing absolute latitude (r2 = .46, p < .001), as did forest density (r2 = .31, p < .001). Forest structural complexity increased with increasing absolute latitude (r2 = .26, p < .001). Main conclusions: Because large-diameter trees constitute roughly half of the mature forest biomass worldwide, their dynamics and sensitivities to environmental change represent potentially large controls on global forest carbon cycling. We recommend managing forests for conservation of existing large-diameter trees or those that can soon reach large diameters as a simple way to conserve and potentially enhance ecosystem services.
Efficiently reducing natural hazard risks requires a thorough understanding of the costs of natural hazards. Current methods to assess these costs employ a variety of terminologies and approaches for ...different types of natural hazards and different impacted sectors. This may impede efforts to ascertain comprehensive and comparable cost figures. In order to strengthen the role of cost assessments in the development of integrated natural hazard management, a review of existing cost assessment approaches was undertaken. This review considers droughts, floods, coastal and Alpine hazards, and examines different cost types, namely direct tangible damages, losses due to business interruption, indirect damages, intangible effects, and the costs of risk mitigation. This paper provides an overview of the state-of-the-art cost assessment approaches and discusses key knowledge gaps. It shows that the application of cost assessments in practice is often incomplete and biased, as direct costs receive a relatively large amount of attention, while intangible and indirect effects are rarely considered. Furthermore, all parts of cost assessment entail considerable uncertainties due to insufficient or highly aggregated data sources, along with a lack of knowledge about the processes leading to damage and thus the appropriate models required. Recommendations are provided on how to reduce or handle these uncertainties by improving data sources and cost assessment methods. Further recommendations address how risk dynamics due to climate and socio-economic change can be better considered, how costs are distributed and risks transferred, and in what ways cost assessment can function as part of decision support.
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