Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of ...recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation).
Nesta tese estudamos alguns aspectos de um modelo de percolação de longo alcance em Zd, d 2. Esse modelo é uma variação do modelo de percolação independente de sítios em Zd, onde cada sítio está ...ocupado ou vazio de maneira independente com probabilidade
p e 1 p respectivamente, p 2 0; 1. Num primeiro momento, consideramos o problema de percolação de palavras no grafo Ld
K = (Zd;K n=1En), onde En é o conjunto de elos paralelos a
algum eixo coordenado e de comprimento n 2 N e uma palavra é um elemento 2 f0; 1gN. Obtemos os seguintes resultados:
8p 2 (0; 1), existe uma constante K = K(p), tal que todas as palavras são vistas em Ld K quase certamente. Obtemos a escala correta da constante K(p) quando p vai para zero, a m de que todas as palavras sejam vistas quase certamente. Obtemos um resultado parcial para a escala da constante K(p) quando p vai para zero, quando o evento de interesse é ver quase todas as palavras. Em um segundo momento, estudamos o comportamento da probabilidade de percolação
Gk(p) e do ponto crítico pc(Gk) em um modelo de percolação independente de sítios em Gk = (Zd; E1 Ek). Obtemos o seguinte resultado: lim k!1 pc(Gk) = pc(Z2d). O resultado acima é generalizado para modelos cujos elos de longo alcance tem vários comprimentos.
O problema da ruína tem sido amplamente investigado sob diferentes suposições para o processo estocástico que modela as reservas de uma companhia de seguros. O foco desta dissertação consiste em ...estudar uma das mais importantes partes da matemática atuarial, a qual é reconhecida como Teoria da Ruína, dando ênfase ao cálculo da probabilidade de ruína de uma seguradora com o capital sujeito a investimento a uma taxa de juros constante. Supõe-se que as indenizações pagas pela seguradora têm distribuição do tipo cauda leve, o que na prática significa que nenhuma delas é grande o suficiente para afetar o resultado total significativamente. Este estudo começa com a descrição do modelo de risco sem investimentos fazendo-se, em particular, uma descrição minuciosa do modelo clássico de Cramér-Lundberg, o qual descreve, de maneira simples, a evolução do capital de uma companhia de seguros. Em seguida apresenta-se o modelo de risco com investimento, o qual descreve o capital de uma companhia de seguros que recebe juros de suas reservas a uma taxa constante no tempo. Feito isto, passa-se ao modelo de difusão para a reserva de uma seguradora. Salienta-se que este tópico será visto com um cuidado maior que os demais, sendo analisado em todos os detalhes. Considera-se um processo de risco com investimento das reservas, de forma que o fluxo de caixa e a taxa acumulada de juros são aproximados por processos de difusão com coeficientes dependendo do tempo e do atual saldo financeiro. Estuda-se uma equação diferencial parcial (ordinária) para a probabilidade de ruína em tempo finito (infinito). Nesta dissertação investiga-se o regime de validade desta aproximação comparando a solução numérica da referida equação diferencial parcial com os valores obtidos por simulação das probabilidades de ruína em tempo finito para o modelo de risco com investimento, para diferentes tipos de distribuição das indenizações. Realiza-se também o mesmo tipo de comparação para a probabilidade de ruína em tempo infinito. Neste caso, a solução da equação diferencial ordinária é exata e uma técnica de mudança de medida deve ser realizada a fim de realizar as simulações. Constata-se que a qualidade das aproximações depende dos parâmetros do modelo. Um objeto de estudo para o futuro seria encontrar uma relação entre os parâmetros, a qual defina em quais situações a aproximação por difusão é satisfatória.
Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two
) variants with a recessive kidney disease risk, ...named G1 and G2, occur at high frequency. APOL1 is a trypanolytic protein that confers innate resistance to most African trypanosomes, but not
or
which cause human African trypanosomiasis. In this case-control study, we test the prevailing hypothesis that these
variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa. We demonstrate a five-fold dominant protective association for G2 against
infection. Furthermore, we report unpredicted strong opposing associations with
disease outcome. G2 associates with faster progression of
trypanosomiasis, while G1 associates with asymptomatic carriage and undetectable parasitemia. These results implicate both forms of human African trypanosomiasis in the selection and persistence of otherwise detrimental
kidney disease variants.
Highlights • Surveys the feature description methods, and the learning algorithms employed. • Also surveys the ECG signal preprocessing and the heartbeat segmentation techniques. • Description of ...databases used for methods evaluation indicated by the AAMI standard. • Discussion of limitations and drawbacks of the methods in the literature. • Concluding remarks and future challenges are also pointed out.
Measures of overlap of labelled regions of images, such as the Dice and Tanimoto coefficients, have been extensively used to evaluate image registration and segmentation algorithms. Modern studies ...can include multiple labels defined on multiple images yet most evaluation schemes report one overlap per labelled region, simply averaged over multiple images. In this paper, common overlap measures are generalized to measure the total overlap of ensembles of labels defined on multiple test images and account for fractional labels using fuzzy set theory. This framework allows a single "figure-of-merit" to be reported which summarises the results of a complex experiment by image pair, by label or overall. A complementary measure of error, the overlap distance, is defined which captures the spatial extent of the nonoverlapping part and is related to the Hausdorff distance computed on grey level images. The generalized overlap measures are validated on synthetic images for which the overlap can be computed analytically and used as similarity measures in nonrigid registration of three-dimensional magnetic resonance imaging (MRI) brain images. Finally, a pragmatic segmentation ground truth is constructed by registering a magnetic resonance atlas brain to 20 individual scans, and used with the overlap measures to evaluate publicly available brain segmentation algorithms
Ranolazine, an anti-anginal drug, is a late Na+ channel current blocker that is also believed to attenuate fatty acid oxidation and mitochondrial respiratory complex I activity, especially during ...ischemia. In this study, we investigated if ranolazine's protective effect against cardiac ischemia/reperfusion (IR) injury is mediated at the mitochondrial level and specifically if respiratory complex I (NADH Ubiquinone oxidoreductase) function is protected. We treated isolated and perfused guinea pig hearts with ranolazine just before 30min ischemia and then isolated cardiac mitochondria at the end of 30min ischemia and/or 30min ischemia followed by 10min reperfusion. We utilized spectrophotometric and histochemical techniques to assay complex I activity, Western blot analysis for complex I subunit NDUFA9, electron paramagnetic resonance for activity of complex I Fe–S clusters, enzyme linked immuno sorbent assay (ELISA) for determination of protein acetylation, native gel histochemical staining for respiratory supercomplex assemblies, and high pressure liquid chromatography for cardiolipin integrity; cardiac function was measured during IR. Ranolazine treated hearts showed higher complex I activity and greater detectable complex I protein levels compared to untreated IR hearts. Ranolazine treatment also led to more normalized electron transfer via Fe–S centers, supercomplex assembly and cardiolipin integrity. These improvements in complex I structure and function with ranolazine were associated with improved cardiac function after IR. However, these protective effects of ranolazine are not mediated by a direct action on mitochondria, but rather indirectly via cytosolic mechanisms that lead to less oxidation and better structural integrity of complex I.
► Mitochondrial complex I is a major target of cardiac ischemia/reperfusion (IR) injury. ► IR injury caused specific biophysical, biochemical and molecular changes in complex I. ► A cardio-protective drug, ranolazine, was found to indirectly reduce complex I damage. ► Cardiac function after IR injury can be improved by indirectly reducing complex I dysfunction.
Phenotypic plasticity is important in adaptation and shapes the evolution of organisms. However, we understand little about what aspects of the genome are important in facilitating plasticity. ...Eusocial insect societies produce plastic phenotypes from the same genome, as reproductives (queens) and nonreproductives (workers). The greatest plasticity is found in the simple eusocial insect societies in which individuals retain the ability to switch between reproductive and nonreproductive phenotypes as adults. We lack comprehensive data on the molecular basis of plastic phenotypes. Here, we sequenced genomes, microRNAs (miRNAs), and multiple transcriptomes and methylomes from individual brains in a wasp (Polistes canadensis) and an ant (Dinoponera quadriceps) that live in simple eusocial societies. In both species, we found few differences between phenotypes at the transcriptional level, with little functional specialization, and no evidence that phenotype-specific gene expression is driven by DNA methylation or miRNAs. Instead, phenotypic differentiation was defined more subtly by nonrandom transcriptional network organization, with roles in these networks for both conserved and taxon-restricted genes. The general lack of highly methylated regions or methylome patterning in both species may be an important mechanism for achieving plasticity among phenotypes during adulthood. These findings define previously unidentified hypotheses on the genomic processes that facilitate plasticity and suggest that the molecular hallmarks of social behavior are likely to differ with the level of social complexity.
In their stormy response to Nancy MacLean's book Democracy in Chains, some academics on the libertarian right have conducted a concerted defense of Nobel Laureate James Buchanan's credentials as an ...anti-racist, or at least a non-racist. An odd component of their argument is a claim of innocence by association: the peripatetic South African economist and Mont Pelerin Society founding member William Harold Hutt was against apartheid; Buchanan was a friend and supporter of Hutt; therefore, Buchanan could not have been abetting segregationists with his support for public funding of segregated private schools. At the core of this chain of argument is the inference that Hutt's opposition to apartheid proves that Hutt himself was committed to racial equality. However, just as there were white supremacists who opposed slavery in the United States, we demonstrate Hutt was a white supremacist who opposed apartheid in South Africa. We document how Hutt embraced notions of black inferiority, even in The Economics of the Colour Bar, his most ferocious attack on apartheid. Whether or not innocence by association is a sound defense of anyone's ideology or conduct, Hutt, himself, was not innocent of white supremacy.
Palmitoleic acid (POA, 16:1n-7) is a lipokine that has potential nutraceutical use to treat non-alcoholic fatty liver disease. We tested the effects of POA supplementation (daily oral gavage, ...300 mg/Kg, 15 days) on murine liver inflammation induced by a high fat diet (HFD, 59% fat, 12 weeks). In HFD-fed mice, POA supplementation reduced serum insulin and improved insulin tolerance compared with oleic acid (OA, 300 mg/Kg). The livers of POA-treated mice exhibited less steatosis and inflammation than those of OA-treated mice with lower inflammatory cytokine levels and reduced toll-like receptor 4 protein content. The anti-inflammatory effects of POA in the liver were accompanied by a reduction in liver macrophages (LM, CD11c+; F4/80+; CD86+), an effect that could be triggered by peroxisome proliferator activated receptor (PPAR)-γ, a lipogenic transcription factor upregulated in livers of POA-treated mice. We also used HFD-fed mice with selective deletion of PPAR-γ in myeloid cells (PPAR-γ KOLyzCre+) to test whether the beneficial anti-inflammatory effects of POA are dependent on macrophages PPAR-γ. POA-mediated improvement of insulin tolerance was tightly dependent on myeloid PPAR-γ, while POA anti-inflammatory actions including the reduction in liver inflammatory cytokines were preserved in mice bearing myeloid cells deficient in PPAR-γ. This overlapped with increased CD206+ (M2a) cells and downregulation of CD86+ and CD11c+ liver macrophages. Moreover, POA supplementation increased hepatic AMPK activity and decreased expression of the fatty acid binding scavenger receptor, CD36. We conclude that POA controls liver inflammation triggered by fat accumulation through induction of M2a macrophages independently of myeloid cell PPAR-γ.
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•Palmitoleic acid (POA) supplementation reduced serum insulin and improved insulin tolerance;•Livers of POA-treated mice exhibited less steatosis and inflammation;•POA lowered the liver M1 macrophages population and the expression of inflammation-related immune-cell markers;•POA increased PPAR-γ, a transcription factor that regulates anti-inflammatory effects in macrophages;•However, POA reduced liver inflammation even in mice that lack PPAR-γ expression in myeloid cells;•POA controls liver inflammation through induction of M2a macrophages independently of PPAR-γ in myeloid cells.
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