The paper investigates contribution of doubly fed induction generator (DFIG) to system frequency responses. Impact of different governor settings and system inertia are investigated. Three distinct ...cases are simulated in order to illustrate the influence of DFIG penetration on frequency regulation. Provision of inertial response by DFIG through artificial speed coupling is also presented. The effects of the inertial response on the machine behavior and its significance for frequency regulation are discussed. The influence of converter current limits and auxiliary loop parameters on the inertial response are illustrated and a novel control algorithm is developed for extracting maximum energy from the turbine in a stable manner. The results of the study are illustrated on the example of an isolated power system consisting of a diesel generator and a DFIG.
This paper explores and compares the performance of alternative voltage control strategies applied to doubly fed induction generator (DFIG). Different combinations of reactive power control of rotor- ...and grid-side converters are investigated for voltage-control purposes. Simulations are performed using detailed models built in DIgSILENT PowerFactory in order to illustrate the influence of controllers on transient stability and steady-state operation of the DFIG-based wind plant. This paper also proposes appropriate control strategies for different sets of network operating conditions and topologies. Operational limits, such as current margins and pulse-width modulation limits, are also taken into account.
There has been a fast growing demand for the application of doubly fed induction generators (DFIG) in wind power plants in recent years. They have in particular dominated the market in last two ...years. DFIG is an ideal candidate to satisfy the requirements of the recently proposed challenging grid codes. However, many uncertainties still exist or at least there are no published reports regarding validated comprehensive DFIG models. This paper attempts to clarify the existing ambiguities in modelling of DFIG under various operating conditions using the power system analysis package DIgSILENT PowerFactory. This paper uses available DFIG models and investigates/demonstrates the influence of various model parameters and simplifications (for both mechanical and electrical subsystems) on DFIG-based wind plant transient responses. It further explores and compares the performance of different crowbar protection and rotor side converter restart schemes. Realistic operational limits, such as current margins and PWM modulation limits, are taken into account in all simulations.
Multi-locus Inherited Neoplasia Allele Syndrome (MINAS) refers to individuals with germline pathogenic variants in two or more cancer susceptibility genes(CSGs). With increased use of exome/genome ...sequencing it would be predicted that detection of MINAS would become more frequent. Here we review recent progress in knowledge of MINAS. A systematic literature search for reports of individuals with germline pathogenic variants in 2 or more of 94 CSGs was performed. In addition, participants with multiple primary tumours who underwent genome sequencing as part of the Rare Disease arm of the UK 100,000 Genomes Project were interrogated to detect additional cases. We identified 385 MINAS cases (211 reported in the last 5 years, 6 from 100,000 genomes participants). Most (287/385) cases contained at least one pathogenic variant in either BRCA1 or BRCA2. 108/385 MINAS cases had multiple primary tumours at presentation and a subset of cases presented unusual multiple tumour phenotypes. We conclude that, as predicted, increasing numbers of individuals with MINAS are being have been reported but, except for individuals with BRCA1/BRCA2 MINAS, individual CSG combinations are generally rare. In many cases it appears that the clinical phenotype is that which would be expected from the effects of the constituent CSG variants acting independently. However, in some instances the presence of unusual tumour phenotypes and/or multiple primary tumours suggests that there may be complex interactions between the relevant MINAS CSGs. Systematic reporting of MINAS cases in a MINAS database (e.g. https://databases.lovd.nl/shared/diseases/04296 ) will facilitate more accurate prognostic predictions for specific CSG combinations.
The aim of this study was to investigate the relationship of AEG-1 and p53 with the prognostic parameters of renal cell carcinoma (RCC). In this study, 50 paraffin blocks were histopathologically ...diagnosed at the Department of Pathology of the Medical Hospital of Duzce University, between 2005 and 2011. The cases consisted of 24 clear cell (CC) and 26 non-clear cell (NCC) RCC subtypes as follows: 24 (48%) clear cell RCC, 12 (24%) papillary RCC, 4 (8%) multilocular cystic RCC and 10 (20%) chromophobe RCC; none had sarcomatoid changes. By immunohistochemical analysis we investigated AEG-1 and p53 expression in carcinomas of the kidney, and by statistical analysis determined their relationship with clinicopathological parameters. Significant relationships were found between increasing tumor diameter and the increase of p53 (p = 0.028). In addition, p53 was significantly related to renal sinus invasion (p = 0.05) and Fuhrman grade (p = 0.026). There was a significant relationship between increased AEG-1 staining scores and CC and NCC carcinoma subtypes (p = 0.032), tumor capsule invasion (p = 0.01) and lymphovascular invasion (p = 0.015). There was also a significant correlation between tumor size and capsule and lymphovascular invasion (p = 0.02). We concluded that high AEG-1 and p53 expression correlates with the prognostic parameters in RCC patients, and in addition may be associated with tumor progression.
The objective of this study was to employ ensemble clustering and tree-based risk model approaches to identify interactions between clinicogenomic features for colorectal cancer using the 100,000 ...Genomes Project.
Among the 2211 patients with colorectal cancer (mean age of diagnosis: 67.7; 59.7% male), 16.3%, 36.3%, 39.0% and 8.4% had stage 1, 2, 3 and 4 cancers, respectively. Almost every patient had surgery (99.7%), 47.4% had chemotherapy, 7.6% had radiotherapy and 1.4% had immunotherapy. On average, tumour mutational burden (TMB) was 18 mutations/Mb and 34.4%, 31.3% and 25.7% of patients had structural or copy number mutations in KRAS, BRAF and NRAS, respectively. In the fully adjusted Cox model, patients with advanced cancer stage 3 hazard ratio (HR) = 3.2; p < 0.001; stage 4 HR = 10.2; p < 0.001 and those who had immunotherapy (HR = 1.8; p < 0.04) or radiotherapy (HR = 1.5; p < 0.02) treatment had a higher risk of dying. The ensemble clustering approach generated four distinct clusters where patients in cluster 2 had the best survival outcomes (1-year: 98.7%; 2-year: 96.7%; 3-year: 93.0%) while patients in cluster 3 (1-year: 87.9; 2-year: 70.0%; 3-year: 53.1%) had the worst outcomes. Kaplan-Meier analysis and log rank test revealed that the clusters were separated into distinct prognostic groups (p < 0.0001). Survival tree or recursive partitioning analyses were performed to further explore risk groups within each cluster. Among patients in cluster 2, for example, interactions between cancer stage, grade, radiotherapy, TMB, BRAF mutation status were identified. Patients with stage 4 cancer and TMB ≥ 1.6 mutations/Mb had 4 times higher risk of dying relative to the baseline hazard in that cluster.
Various species of the intestinal microbiota have been associated with the development of colorectal cancer
, but it has not been demonstrated that bacteria have a direct role in the occurrence of ...oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin
. This compound is believed to alkylate DNA on adenine residues
and induces double-strand breaks in cultured cells
. Here we expose human intestinal organoids to genotoxic pks
E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We ...performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.
Several strands of evidence question the dogma that human mitochondrial DNA (mtDNA) is inherited exclusively down the maternal line, most recently in three families where several individuals harbored ...a 'heteroplasmic haplotype' consistent with biparental transmission. Here we report a similar genetic signature in 7 of 11,035 trios, with allelic fractions of 5-25%, implying biparental inheritance of mtDNA in 0.06% of offspring. However, analysing the nuclear whole genome sequence, we observe likely large rare or unique nuclear-mitochondrial DNA segments (mega-NUMTs) transmitted from the father in all 7 families. Independently detecting mega-NUMTs in 0.13% of fathers, we see autosomal transmission of the haplotype. Finally, we show the haplotype allele fraction can be explained by complex concatenated mtDNA-derived sequences rearranged within the nuclear genome. We conclude that rare cryptic mega-NUMTs can resemble paternally mtDNA heteroplasmy, but find no evidence of paternal transmission of mtDNA in humans.
AbstractObjectiveTo determine whether whole genome sequencing can be used to define the molecular basis of suspected mitochondrial disease.DesignCohort study.SettingNational Health Service, England, ...including secondary and tertiary care.Participants345 patients with suspected mitochondrial disorders recruited to the 100 000 Genomes Project in England between 2015 and 2018.InterventionShort read whole genome sequencing was performed. Nuclear variants were prioritised on the basis of gene panels chosen according to phenotypes, ClinVar pathogenic/likely pathogenic variants, and the top 10 prioritised variants from Exomiser. Mitochondrial DNA variants were called using an in-house pipeline and compared with a list of pathogenic variants. Copy number variants and short tandem repeats for 13 neurological disorders were also analysed. American College of Medical Genetics guidelines were followed for classification of variants.Main outcome measureDefinite or probable genetic diagnosis.ResultsA definite or probable genetic diagnosis was identified in 98/319 (31%) families, with an additional 6 (2%) possible diagnoses. Fourteen of the diagnoses (4% of the 319 families) explained only part of the clinical features. A total of 95 different genes were implicated. Of 104 families given a diagnosis, 39 (38%) had a mitochondrial diagnosis and 65 (63%) had a non-mitochondrial diagnosis.ConclusionWhole genome sequencing is a useful diagnostic test in patients with suspected mitochondrial disorders, yielding a diagnosis in a further 31% after exclusion of common causes. Most diagnoses were non-mitochondrial disorders and included developmental disorders with intellectual disability, epileptic encephalopathies, other metabolic disorders, cardiomyopathies, and leukodystrophies. These would have been missed if a targeted approach was taken, and some have specific treatments.
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