PIP degron proteins, substrates of CRL4Cdt2, and not PIP boxes, interfere with DNA polymerase η and κ focus formation on UV damage

International audienceProliferating cell nuclear antigen (PCNA) is a well-known scaffold for many DNA replication and repair proteins, but how the switch between partners is regulated is currently unclear. Interaction with PCNA occurs via a domain known as a PCNA-Interacting Protein motif (PIP box). More recently, an additional specialized PIP box has been described, the « PIP degron », that targets PCNA-interacting proteins for proteasomal degradation via the E3 ubiquitin ligase CRL4(Cdt2). Here we provide evidence that CRL4(Cdt2)-dependent degradation of PIP degron proteins plays a role in the switch of PCNA partners during the DNA damage response by facilitating accumulation of translesion synthesis DNA polymerases into nuclear foci. We show that expression of a nondegradable PIP degron (Cdt1) impairs both Pol η and Pol κ focus formation on ultraviolet irradiation and reduces cell viability, while canonical PIP box-containing proteins have no effect. Furthermore, we identify PIP degron-containing peptides from several substrates of CRL4(Cdt2) as efficient inhibitors of Pol η foci formation. By site-directed mutagenesis we show that inhibition depends on a conserved threonine residue that confers high affinity for PCNA-binding. Altogether these findings reveal an important regulative role for the CRL4(Cdt2) pathway in the switch of PCNA partners on DNA damage

Strain in epitaxial MnSi films on Si(111) in the thick film limit studied by polarization-dependent extended x-ray absorption fine structure

We report a study of the strain state of epitaxial MnSi films on Si(111) substrates in the thick film limit (100-500~\AA) as a function of film thickness using polarization-dependent extended x-ray absorption fine structure (EXAFS). All films investigated are phase-pure and of high quality with a sharp interface between MnSi and Si. The investigated MnSi films are in a thickness regime where the magnetic transition temperature $T_\mathrm{c}$ assumes a thickness-independent enhanced value of $\geq$43~K as compared with that of bulk MnSi, where $T_\mathrm{c} \approx 29~{\rm K}$. A detailed refinement of the EXAFS data reveals that the Mn positions are unchanged, whereas the Si positions vary along the out-of-plane [111]-direction, alternating in orientation from unit cell to unit cell. Thus, for thick MnSi films, the unit cell volume is essentially that of bulk MnSi --- except in the vicinity of the interface with the Si substrate (thin film limit). In view of the enhanced magnetic transition temperature we conclude that the mere presence of the interface, and its specific characteristics, strongly affects the magnetic properties of the entire MnSi film, even far from the interface. Our analysis provides invaluable information about the local strain at the MnSi/Si(111) interface. The presented methodology of polarization dependent EXAFS can also be employed to investigate the local structure of other interesting interfaces.Comment: 11 pages, 10 figure

The plastic number and its generalized polynomial

The polynomial $X^{3}-X-1$ has a unique positive root known as plastic number, which is denoted by $\rho$ and is approximately equal to $1.32471795$. In this note we study the zeroes of the generalized polynomial $X^{k}-\sum_{j=0}^{k-2}X^{j}$ for $k\geq 3$ and prove that its unique positive root $\lambda_{k}$ tends to the golden ratio $\phi=\frac{1+\sqrt{5}}{2}$ as $k \to \infty$. We also derive bounds on $\lambda_{k}$ in terms of Fibonacci numbers.Comment: Publisher's pdf versio

Long range antiferromagnetic order of formally nonmagnetic Eu3 Van Vleck ions observed in multiferroic Eu1 xYxMnO3

We report on resonant magnetic x ray scattering and absorption spectroscopy studies of exchange coupled antiferromagnetic ordering of Eu3 magnetic moments in multiferroic Eu1 amp; 8722;xYxMnO3 in the absence of an external magnetic field. The observed resonant spectrum is characteristic of a magnetically ordered 7F1 state that mirrors the Mn magnetic ordering, due to exchange coupling between the Eu 4f and Mn 3d spins. Here, we observe long range magnetic order generated by exchange coupling of magnetic moments of formally nonmagnetic Van Vleck ions, which is a step further towards the realization of exotic phases induced by exchange coupling in systems entirely composed of non magnetic ion

Estimation of Recurrence of Colorectal Adenomas with Dependent Censoring Using Weighted Logistic Regression

In colorectal polyp prevention trials, estimation of the rate of recurrence of adenomas at the end of the trial may be complicated by dependent censoring, that is, time to follow-up colonoscopy and dropout may be dependent on time to recurrence. Assuming that the auxiliary variables capture the dependence between recurrence and censoring times, we propose to fit two working models with the auxiliary variables as covariates to define risk groups and then extend an existing weighted logistic regression method for independent censoring to each risk group to accommodate potential dependent censoring. In a simulation study, we show that the proposed method results in both a gain in efficiency and reduction in bias for estimating the recurrence rate. We illustrate the methodology by analyzing a recurrent adenoma dataset from a colorectal polyp prevention trial

Expert-Augmented Machine Learning

Machine Learning is proving invaluable across disciplines. However, its success is often limited by the quality and quantity of available data, while its adoption by the level of trust that models afford users. Human vs. machine performance is commonly compared empirically to decide whether a certain task should be performed by a computer or an expert. In reality, the optimal learning strategy may involve combining the complementary strengths of man and machine. Here we present Expert-Augmented Machine Learning (EAML), an automated method that guides the extraction of expert knowledge and its integration into machine-learned models. We use a large dataset of intensive care patient data to predict mortality and show that we can extract expert knowledge using an online platform, help reveal hidden confounders, improve generalizability on a different population and learn using less data. EAML presents a novel framework for high performance and dependable machine learning in critical applications

Model selection in High-Dimensions: A Quadratic-risk based approach

In this article we propose a general class of risk measures which can be used for data based evaluation of parametric models. The loss function is defined as generalized quadratic distance between the true density and the proposed model. These distances are characterized by a simple quadratic form structure that is adaptable through the choice of a nonnegative definite kernel and a bandwidth parameter. Using asymptotic results for the quadratic distances we build a quick-to-compute approximation for the risk function. Its derivation is analogous to the Akaike Information Criterion (AIC), but unlike AIC, the quadratic risk is a global comparison tool. The method does not require resampling, a great advantage when point estimators are expensive to compute. The method is illustrated using the problem of selecting the number of components in a mixture model, where it is shown that, by using an appropriate kernel, the method is computationally straightforward in arbitrarily high data dimensions. In this same context it is shown that the method has some clear advantages over AIC and BIC.Comment: Updated with reviewer suggestion

In Vitro Susceptibility of Mycobacterium tuberculosis to Amikacin, Kanamycin, and Capreomycin

Amikacin, kanamycin and capreomycin are listed among the most important 2nd line drugs for multidrug resistant tuberculosis. Although amikacin and kanamycin are administered in the same dose and show the same pharmacokinetics, they have different WHO breakpoints suggesting that the two drugs have a different minimal inhibitory concentrations (MIC). The aim of this paper was to investigate possible differences in MIC between the aminoglycosides and capreomycin.Using the direct concentration method, a concentration range of amikacin, kanamycin and capreomycin (0.25, 0.50, 1.0, 2.0, 4.0, 8.0, 16.0, 32.0 and 64.0 mg/L) was tested against 57 clinical Mycobacterium tuberculosis strains. The 7H10 agar plates were examined for mycobacterial growth after 14 days.At 2 mg/L, 48 strains (84%) were inhibited by amikacin and only five strains (9%) were inhibited by kanamycin (p < 0.05, Wilcoxon Signed Rank Test). The median MICs of amikacin, kanamycin and capreomycin were 2, 4 and 8 mg/L, respectively. No difference was observed between multidrug resistant and fully susceptible strains in the MIC-distribution of amikacin, kanamycin and capreomycin.The results indicate that amikacin is more active against M. tuberculosis than kanamycin and capreomycin in the absolute concentration method. The impact of this difference on clinical outcome in daily practice requires a prospective study including pharmacokinetic and pharmacodynamics evaluations