The bottom-up approach of the Nationally Determined Contributions (NDCs) in the Paris Agreement has led countries to self-determine their greenhouse gas (GHG) emission reduction targets. The planned ...‘ratcheting-up’ process, which aims to ensure that the NDCs comply with the overall goal of limiting global average temperature increase to well below 2 °C or even 1.5 °C, will most likely include some evaluation of ‘fairness’ of these reduction targets. In the literature, fairness has been discussed around equity principles, for which many different effort-sharing approaches have been proposed. In this research, we analysed how country-level emission targets and carbon budgets can be derived based on such criteria. We apply novel methods directly based on the global carbon budget, and, for comparison, more commonly used methods using GHG mitigation pathways. For both, we studied the following approaches: equal cumulative per capita emissions, contraction and convergence, grandfathering, greenhouse development rights and ability to pay. As the results critically depend on parameter settings, we used the wide authorship from a range of countries included in this paper to determine default settings and sensitivity analyses. Results show that effort-sharing approaches that (i) calculate required reduction targets in carbon budgets (relative to baseline budgets) and/or (ii) take into account historical emissions when determining carbon budgets can lead to (large) negative remaining carbon budgets for developed countries. This is the case for the equal cumulative per capita approach and especially the greenhouse development rights approach. Furthermore, for developed countries, all effort-sharing approaches except grandfathering lead to more stringent budgets than cost-optimal budgets, indicating that cost-optimal approaches do not lead to outcomes that can be regarded as fair according to most effort-sharing approaches.
Asthma is a complex disease with sex-specific differences in prevalence. Candidate gene studies have suggested that genotype-by-sex interaction effects on asthma risk exist, but this has not yet been ...explored at a genome-wide level. We aimed to identify sex-specific asthma risk alleles by performing a genome-wide scan for genotype-by-sex interactions in the ethnically diverse participants in the EVE Asthma Genetics Consortium. We performed male- and female-specific genome-wide association studies in 2653 male asthma cases, 2566 female asthma cases and 3830 non-asthma controls from European American, African American, African Caribbean and Latino populations. Association tests were conducted in each study sample, and the results were combined in ancestry-specific and cross-ancestry meta-analyses. Six sex-specific asthma risk loci had P-values < 1 × 10(-6), of which two were male specific and four were female specific; all were ancestry specific. The most significant sex-specific association in European Americans was at the interferon regulatory factor 1 (IRF1) locus on 5q31.1. We also identify a Latino female-specific association in RAP1GAP2. Both of these loci included single-nucleotide polymorphisms that are known expression quantitative trait loci and have been associated with asthma in independent studies. The IRF1 locus is a strong candidate region for male-specific asthma susceptibility due to the association and validation we demonstrate here, the known role of IRF1 in asthma-relevant immune pathways and prior reports of sex-specific differences in interferon responses.
Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was ...aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.
There has been considerable effort focused on developing efficient programs for tagging single-nucleotide polymorphisms (SNPs). Many of these programs do not account for potential reduced genomic ...coverage resulting from genotyping failures nor do they preferentially select SNPs based on functionality, which may be more likely to be biologically important.
We have developed a user-friendly and efficient software program, Snagger, as an extension to the existing open-source software, Haploview, which uses pairwise r2 linkage disequilibrium between single nucleotide polymorphisms (SNPs) to select tagSNPs. Snagger distinguishes itself from existing SNP selection algorithms, including Tagger, by providing user options that allow for: (1) prioritization of tagSNPs based on certain characteristics, including platform-specific design scores, functionality (i.e., coding status), and chromosomal position, (2) efficient selection of SNPs across multiple populations, (3) selection of tagSNPs outside defined genomic regions to improve coverage and genotyping success, and (4) picking of surrogate tagSNPs that serve as backups for tagSNPs whose failure would result in a significant loss of data. Using HapMap genotype data from ten ENCODE regions and design scores for the Illumina platform, we show similar coverage and design score distribution and fewer total tagSNPs selected by Snagger compared to the web server Tagger.
Snagger improves upon current available tagSNP software packages by providing a means for researchers to select tagSNPs that reliably capture genetic variation across multiple populations while accounting for significant genotyping failure risk and prioritizing on SNP-specific characteristics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Paleoseismology of the Hyde Fault, Otago, New Zealand Griffin, Jonathan D.; Stirling, Mark W.; Barrell, David J.A. ...
New Zealand journal of geology and geophysics,
10/2022, Letnik:
65, Številka:
4
Journal Article
Recenzirano
Odprti dostop
We present the first paleoseismic investigation of the Hyde Fault, one of a series of north-east striking reverse faults within the Otago range and basin province in southern New Zealand. Surface ...traces of the fault and associated geomorphology were mapped using a lidar digital elevation model and field investigations. Trenches were excavated at two sites across fault scarps on alluvial fan surfaces. The trenches revealed stratigraphic evidence for four surface-rupturing earthquakes. Optically stimulated luminescence dating constrains the timing of these events to around 47.2 ka (37.5-56.7 ka at 95% confidence), 34.6 ka (24.7-46.4 ka), 23.5 ka (19.7-27.3 ka) and 10.5 ka (7.9-13.1 ka). We obtain a mean inter-event time of 12.4 kyr (2.3-23.9 kyr at 95% confidence) and the slip rate is estimated to be 0.22 mm/yr (0.15-0.3 mm/yr). We do not find evidence to suggest that earthquake recurrence on the Hyde Fault is episodic, in contrast to other well-studied faults within Otago, suggesting diverse recurrence styles may co-exist in the same fault system. This poses challenges for characterising the seismic hazard potential of faults in the region, particularly when paleoearthquake records are limited to the most recent few events.
Biomarkers predictive of inflammatory events post-vaccination could accelerate vaccine development. Within the BIOVACSAFE framework, we conducted three identically designed, placebo-controlled ...inpatient/outpatient clinical studies (NCT01765413/NCT01771354/NCT01771367). Six antiviral vaccination strategies were evaluated to generate training data-sets of pre-/post-vaccination vital signs, blood changes and whole-blood gene transcripts, and to identify putative biomarkers of early inflammation/reactogenicity that could guide the design of subsequent focused confirmatory studies. Healthy adults (N = 123; 20-21/group) received one immunization at Day (D)0. Alum-adjuvanted hepatitis B vaccine elicited vital signs and inflammatory (CRP/innate cells) responses that were similar between primed/naive vaccinees, and low-level gene responses. MF59-adjuvanted trivalent influenza vaccine (ATIV) induced distinct physiological (temperature/heart rate/reactogenicity) response-patterns not seen with non-adjuvanted TIV or with the other vaccines. ATIV also elicited robust early (D1) activation of IFN-related genes (associated with serum IP-10 levels) and innate-cell-related genes, and changes in monocyte/neutrophil/lymphocyte counts, while TIV elicited similar but lower responses. Due to viral replication kinetics, innate gene activation by live yellow-fever or varicella-zoster virus (YFV/VZV) vaccines was more suspended, with early IFN-associated responses in naïve YFV-vaccine recipients but not in primed VZV-vaccine recipients. Inflammatory responses (physiological/serum markers, innate-signaling transcripts) are therefore a function of the vaccine type/composition and presence/absence of immune memory. The data reported here have guided the design of confirmatory Phase IV trials using ATIV to provide tools to identify inflammatory or reactogenicity biomarkers.
Radiation therapy is a major component of cancer treatment pathways worldwide. The main aim of this treatment is to achieve tumor control through the delivery of ionizing radiation while preserving ...healthy tissues for minimal radiation toxicity. Because radiation therapy relies on accurate localization of the target and surrounding tissues, imaging plays a crucial role throughout the treatment chain. In the treatment planning phase, radiological images are essential for defining target volumes and organs-at-risk, as well as providing elemental composition (e.g., electron density) information for radiation dose calculations. At treatment, onboard imaging informs patient setup and could be used to guide radiation dose placement for sites affected by motion. Imaging is also an important tool for treatment response assessment and treatment plan adaptation. MRI, with its excellent soft tissue contrast and capacity to probe functional tissue properties, holds great untapped potential for transforming treatment paradigms in radiation therapy. The MR in Radiation Therapy ISMRM Study Group was established to provide a forum within the MR community to discuss the unmet needs and fuel opportunities for further advancement of MRI for radiation therapy applications. During the summer of 2021, the study group organized its first virtual workshop, attended by a diverse international group of clinicians, scientists, and clinical physicists, to explore our predictions for the future of MRI in radiation therapy for the next 25 years. This article reviews the main findings from the event and considers the opportunities and challenges of reaching our vision for the future in this expanding field.
Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations ...in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3-Kinase/Akt, RTK-RAS, TGFβ signaling, p53 and β-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty-nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy.
Display omitted
•Alteration map of 10 signaling pathways across 9,125 samples from 33 cancer types•Reusable, curated pathway templates that include a catalogue of driver genes•57% of tumors have at least one potentially actionable alteration in these pathways•Co-occurrence of actionable alterations suggests combination therapy opportunities
An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.
Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole ...Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.
Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large ...datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%–85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD-L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors.
Display omitted
•PanSoftware applied to PanCancer data identified 299 cancer driver genes•Driver genes and mutations are shared across anatomical origins and cell types•In silico discovery of ∼3,400 driver mutations coupled with experimental validation•57% of tumors harbor potentially actionable oncogenic events
A comprehensive analysis of oncogenic driver genes and mutations in >9,000 tumors across 33 cancer types highlights the prevalence of clinically actionable cancer driver events in TCGA tumor samples.
PDF
