ALBERT

Beschreibung: Systems of activator–inhibitor reaction–diffusion equations posed on an infinite line are studied using a variety of analytical and numerical methods. A canonical form is considered, which contains all known models with simple cubic autocatalytic nonlinearity and arbitrary constant and linear kinetics. Restricting attention to models that have a unique homogeneous equilibrium, this class includes the classical Schnakenberg and Brusselator models, as well as other systems proposed in the literature to model morphogenesis. Such models are known to feature Turing instability, when activator diffuses more slowly than inhibitor, leading to stable spatially periodic patterns. Conversely in the limit of small feed rates, semi-strong interaction asymptotic analysis shows existence of isolated spike-like patterns. This paper describes the broad bifurcation structures that connect these two regimes. A certain universal two-parameter state diagram is revealed in which the Turing bifurcation becomes sub-critical, leading to the onset of homoclinic snaking. This regime then morphs into the spike regime, with the outer-fold being predicted by the semi-strong asymptotics. A rescaling of parameters and field concentrations shows how this state diagram can be studied independently of the diffusion rates. Temporal dynamics is found to strongly depend on the diffusion ratio though. A Hopf bifurcation occurs along the branch of stable spikes, which is subcritical for small diffusion ratio, leading to collapse to the homogeneous state. As the diffusion ratio increases, this bifurcation typically becomes supercritical and interacts with the homoclinic snaking and also with a supercritical homogeneous Hopf bifurcation, leading to complex spatio-temporal dynamics. The details are worked out for a number of different models that fit the theory using a mixture of weakly nonlinear analysis, semi-strong asymptotics and different numerical continuation algorithms.

Beschreibung: Dynamic topological logic ($extsf{DTL}$) is a multi-modal logic that was introduced for reasoning about dynamic topological systems, i.e. structures of the form $langle{mathfrak{X}, f} angle $, where $mathfrak{X}$ is a topological space and $f$ is a continuous function on it. The problem of finding a complete and natural axiomatization for this logic in the original tri-modal language has been open for more than one decade. In this paper, we give a natural axiomatization of $extsf{DTL}$ and prove its strong completeness with respect to the class of all dynamic topological systems. Our proof system is infinitary in the sense that it contains an infinitary derivation rule with countably many premises and one conclusion. It should be remarked that $extsf{DTL}$ is semantically non-compact, so no finitary proof system for this logic could be strongly complete. Moreover, we provide an infinitary axiomatic system for the logic ${extsf{DTL}}_{mathcal{A}}$, i.e. the $extsf{DTL}$ of Alexandrov spaces, and show that it is strongly complete with respect to the class of all dynamical systems based on Alexandrov spaces.

Beschreibung: Recent studies show decreasing prostate-specific antigen utilization and increasing incidence of metastatic prostate cancer in the United States after national recommendations against screening in 2012. Yet whether the increasing incidence of metastatic prostate cancer is consistent in magnitude with the expected impact of decreased screening is unknown. We compared observed incidence of metastatic prostate cancer from the Surveillance, Epidemiology, and End Results program and published effects of continued historical screening and discontinued screening starting in 2013 projected by two models of disease natural history, screening, and diagnosis. The observed rate of new metastatic prostate cancer cases in 2017 was 44%-60% of the projected increase under discontinued screening relative to continued screening. Thus, the observed increase in incident metastatic prostate cancer is consistent with the expected impact of reduced screening. Although this comparison does not establish a causal relationship, it highlights the plausible role of decreased screening in the observed trend.

Beschreibung: Background Few studies have examined gene-specific associations with contralateral and/or second breast cancer (SBC). Methods The frequency of pathogenic/likely pathogenic (P/LP) variants in clinically-actionable genes (BRCA1, BRCA2, PTEN, TP53, CHEK2, CDH1, ATM, PALB2, NBN, and NF1) was compared between women with a primary breast cancer (PBC) and SBC who underwent multi-gene panel testing at a single diagnostic testing laboratory. Race/ethnicity-specific logistic regression burden tests adjusted for age at diagnosis of first breast cancer, histology, presence of first- or second-degree relatives with breast cancer, and prior testing for BRCA1/2 genes, were used to test for associations with SBC. All statistical tests were two-sided. Results The study was comprised of 75,550 women with PBC and 7,728 with SBC. Median time between breast cancers for SBC was 11 (IQR=6,17) years. Restricting to women tested for all actionable genes (n = 60,310), there were 4,231 (7.8%) carriers of P/LP variants in actionable genes among the controls (PBC) compared to 652 (11.1%) women with SBC (p〈 .001). Among Caucasians, exclusive of Ashkenazi Jewish women, those carrying a P/LP variant in a clinically actionable gene were 1.44 (95% CI: 1.30-1.60) times as likely to have SBC than non-carriers, after accounting for potential confounders. Among African American and Hispanic women, a P/LP variant in a clinically actionable gene was 1.88 (1.36-2.56) and 1.66 (1.02-2.58) times as likely to be associated with SBC respectively (p

Beschreibung: A fundamental aspect of mitochondria is that they possess DNA and protein translation machinery. Mitochondrial DNA encodes 22 tRNAs that translate mitochondrial mRNAs to 13 polypeptides of respiratory complexes. Various chemical modifications have been identified in mitochondrial tRNAs via complex enzymatic processes. A growing body of evidence has demonstrated that these modifications are essential for translation by regulating tRNA stability, structure and mRNA binding, and can be dynamically regulated by the metabolic environment. Importantly, the hypomodification of mitochondrial tRNA due to pathogenic mutations in mitochondrial tRNA genes or nuclear genes encoding modifying enzymes can result in life-threatening mitochondrial diseases in humans. Thus, the mitochondrial tRNA modification is a fundamental mechanism underlying the tight regulation of mitochondrial translation and is essential for life. In this review, we focus on recent findings on the physiological roles of 5-taurinomethyl modification (herein referred as taurine modification) in mitochondrial tRNAs. We summarize the findings in human patients and animal models with a deficiency of taurine modifications and provide pathogenic links to mitochondrial diseases. We anticipate that this review will help understand the complexity of mitochondrial biology and disease.

Beschreibung: My central interest is decision making in the presence of epistemic uncertainty. A method appropriate for both specialized inquiries and everyday reasoning is based on credal logic, which employs multivalent degrees of belief rather than traditional probability theory. It accounts for epistemic uncertainty as unallocated belief. It holds that, when facing real uncertainty, if a person believes a and believes b, then the person believes a and b together. This brand of multivalent logic underlies and justifies how legal decision makers and the rest of us find facts in a world infused with epistemic uncertainty. Indeed, this article closes by showing the equivalence of multivalent logic and inference to the best explanation. By demonstrating this similarity in reasoning, I aim to shore up our faith in the logic of traditional legal reasoning.

Beschreibung: ZFP36L1 is an RNA-binding protein responsible for mRNA decay in the cytoplasm. ZFP36L1 has also been suggested as a nuclear-cytoplasmic shuttling protein because it contains a potential nuclear localization signal and a nuclear export signal. However, it remains unclear how the nuclear localization of ZFP36L1 is controlled. In this study, we provide evidence that the nuclear accumulation of ZFP36L1 protein is modulated in a cell cycle-dependent manner. ZFP36L1 protein accumulation in fractionated nuclei was particularly prominent in cells arrested at G1-/S-phase boundary, while it was downregulated in S-phase cells, and eventually disappeared in G2-phase nuclei. Moreover, forced nuclear targeting of ZFP36L1 revealed marked downregulation of this protein in S- and G2-phase cells, suggesting that ZFP36L1 can be eliminated in the nucleus. The C-terminal serine-rich cluster of ZFP36L1 is critical for the regulation of its nuclear accumulation because truncation of this probable disordered region enhanced the nuclear localization of ZFP36L1, increased its stability and abolished its cell cycle-dependent fluctuations. These findings provide the first hints to the question of how ZFP36L1 nuclear accumulation is controlled during the course of the cell cycle.

Beschreibung: The theory of comparative propensity, championed by the late Mike Redmayne, has been an influential theory underpinning normative models of the probative value of evidence of previous convictions in criminal trials. It purports to generalize an approximate probative value by means of a Bayesian model in which the likelihood of an innocent person having a criminal record is calculated by reference to general population statistics, and the hard evidence underpinning the prior probability is treated as unknown. The theory has been criticized on the ground that it fails to take account of bias against past offenders in the selection of cases for prosecution. This article analyses the model and these criticisms and concludes that both the model and the criticisms are flawed because they fail to address the evidence on which the prior odds are based. We find that, not only are such mathematical models unsound, but they can only be ‘repaired’ by making assumptions about the typical case which run counter to the legal presumption of innocence. Analysing the flaws in these models, however, does provide some insight into issues affecting the value of prior convictions evidence.

Beschreibung: For several decades, legal and scientific scholars have argued that conclusions from forensic examinations should be supported by statistical data and reported within a probabilistic framework. Multiple models have been proposed to quantify and express the probative value of forensic evidence. Unfortunately, the use of statistics to perform inferences in forensic science adds a layer of complexity that most forensic scientists, court offices and lay individuals are not armed to handle. Many applications of statistics to forensic science rely on ad hoc strategies and are not scientifically sound. The opacity of the technical jargon that is used to describe these probabilistic models and their results, and the complexity of the techniques involved make it very difficult for the untrained user to separate the wheat from the chaff. This series of article is intended to help forensic scientists and lawyers recognize limitations and issues in tools proposed to interpret the results of forensic examinations. This article focuses on the tool proposed by the Latent Print Branch of the U.S. Defense Forensic Science Center (DFSC) and called FRStat. In this article, I explore the compatibility of the results outputted by FRStat with the language used by the DFCS to report the conclusions of their fingerprint examinations, as well as the appropriateness of the statistical modelling underpinning the tool and the validation of its performance.

Beschreibung: In the so-called rare type match problem, the discrete characteristics of a crime stain have not been observed in the set of background material. To assess the strength of evidence, two competing statistical hypotheses need to be considered. The formulation of the hypotheses depends on which identification of source question is of interest (Ommen, 2017, Approximate statistical solutions to the forensic identification of source problem. (Phd thesis). South Dakota State University). Assuming that the evidence has been generated according to the beta-binomial model, two quantifications of the value of evidence can be found in the literature, but no clear indication is given when to use either of these. When the likelihood ratio is used to quantify the value of evidence, an estimate is needed for the frequency of the discrete characteristics. The central discussion is about whether or not one of the traces needs to be added to the background material when determining this estimate. In this article it is shown, using fully Bayesian methods, that one of the values of evidence from the literature corresponds to the so-called ‘identification of common source’ problem and the other to the ‘identification of specific source’ problem (Ommen, 2017, Approximate statistical solutions to the forensic identification of source problem. (Phd thesis). South Dakota State University). This means that the question whether or not one of the traces needs to be added to the background material reduces to the question whether a common source or specific source problem is under consideration. The distinction between the two values is especially important for the rare type match problem, since the values of evidence differ most in this situation.

Beschreibung: A proposed rule announced by the Office of Federal Contract Compliance describing the way statistical tests will be used in compliance reviews led to the Chamber of Commerce filing a formal Comment. The comment raises several statistical issues, including the proper analysis of stratified data and the effect of large samples on tests of significance. The Chamber correctly pointed out that simple pooling of the data into one large sample can lead to misleading conclusions, so an appropriate analysis, combining the results of statistical analyses of the individual strata into an overall estimate and statistical test is described. Both the proposal and Comment state that practical significance should be considered but do not provide a clear definition of the term, although various definitions are referred to. Two alternative approaches to evaluating the practical significance are described. One assesses the financial impact of the disparity on a typical wage earner, while the second considers the number of employees affected by the disparity and estimates the effect of the disparity on their earnings during their expected time of employment.