Resource Usage Protocols for Iterators

We discuss usage protocols for iterator objects that prevent concurrent modifications of the underlying collection while iterators are in progress. We formalize these protocols in Java-like object interfaces, enriched with separation logic contracts. We present examples of iterator clients and proofs that they adhere to the iterator protocol, as well as examples of iterator implementations and proofs that they implement the iterator interface

Multivariate Dynamic Probit Models: An Application to Financial Crises Mutation

In this paper we propose a multivariate dynamic probit model. Our model can be considered as a non-linear VAR model for the latent variables associated with correlated binary time-series data. To estimate it, we implement an exact maximum-likelihood approach, hence providing a solution to the problem generally encountered in the formulation of multivariate probit models. Our framework allows us to apprehend dynamics and causality in several ways. Furthermore, we propose an impulse-response analysis for such models. An empirical application on three nancial crises is nally proposed.Non-linear VAR, Multivariate dynamic probit models, Exact maximum likelihood, Impulse-response function, Financial crises

Backtesting value-at-risk : a GMM duration-based test

This paper proposes a new duration-based backtesting procedure for VaR forecasts. The GMM test framework proposed by Bontemps (2006) to test for the distributional assumption (i.e. the geometric distribution) is applied to the case of the VaR forecasts validity. Using simple J-statistic based on the moments defined by the orthonormal polynomials associated with the geometric distribution, this new approach tackles most of the drawbacks usually associated to duration based backtesting procedures. First, its implementation is extremely easy. Second, it allows for a separate test for unconditional coverage, independence and conditional coverage hypothesis (Christoffersen, 1998). Third, feasibility of the tests is improved. Fourth, Monte-Carlo simulations show that for realistic sample sizes, our GMM test outperforms traditional duration based test. An empirical application for Nasdaq returns confirms that using GMM test leads to major consequences for the ex-post evaluation of the risk by regulation authorities. Without any doubt, this paper provides a strong support for the empirical application of duration-based tests for VaR forecasts

Risk measure inference

Fichier WP en ligne International audienceWe propose a bootstrap-based test of the null hypothesis of equality of two firms? conditional Risk Measures (RMs) at a single point in time. The test can be applied to a wide class of conditional risk measures issued from parametric or semi-parametric models. Our iterative testing procedure produces a grouped ranking of the RMs, which has direct application for systemic risk analysis. Firms within a group are statistically indistinguishable form each other, but significantly more risky than the firms belonging to lower ranked groups. A Monte Carlo simulation demonstrates that our test has good size and power properties. We apply the procedure to a sample of 94 U.S. financial institutions using ?CoVaR, MES, and %SRISK. We find that for some periods and RMs, we cannot statistically distinguish the 40 most risky firms due to estimation uncertainty

MAD3 AND MAD4 - NOVEL MAX-INTERACTING TRANSCRIPTIONAL REPRESSORS THAT SUPPRESS C-MYC DEPENDENT TRANSFORMATION AND ARE EXPRESSED DURING NEURAL AND EPIDERMAL DIFFERENTIATION

The basic helix-loop-helix-leucine zipper (bHLHZip) protein Max associates with members of the Myc family, as well as with the related proteins Mad (Mad1) and Mxi1, Whereas both Myc:Max and Mad:Max heterodimers bind related E-box sequences, Myc:Max activates transcription and promotes proliferation while Mad:Max represses transcription and suppresses Myc dependent transformation, Here we report the identification and characterization of two novel Mad1-and Mxi1-related proteins, Mad3 and Mad4. Mad3 and Mad4 interact with both Max and mSin3 and repress transcription from a promoter containing CACGTG binding sites, Using a rat embryo fibroblast transformation assay, we show that both Mad3 and Mad4 inhibit c-Myc dependent cell transformation, An examination of the expression patterns of all mad genes during murine embryogenesis reveals that mad1, mad3 and mad4 are expressed primarily in growth-arrested differentiating cells. mxi1 is also expressed in differentiating cells, but is co-expressed with either c-myc, N-myc, or both in proliferating cells of the developing central nervous system and the epidermis, In the developing central nervous system and epidermis, downregulation of myc genes occurs concomitant with upregulation of mad family genes, These expression patterns, together with the demonstrated ability of Mad family proteins to interfere with the proliferation promoting activities of Myc, suggest that the regulated expression of Myc and Mad family proteins function in a concerted fashion to regulate cell growth in differentiating tissues

Safety, feasibility, and effectiveness of virtual pulmonary rehabilitation in the real world

Purpose: To assess the feasibility, safety, and effectiveness of a VIrtual PulmonAry Rehabilitation (VIPAR) program in a real-world setting. Patients and methods: Twenty-one patients with stable chronic lung disease at a spoke site received (VIPAR) through live video conferencing with a hub where 24 patients were receiving 14 sessions of standard, outpatient, multi-disciplinary pulmonary rehabilitation (PR) in a hospital. We studied three such consecutive PR programs with 6–10 patients at each site. The hub had a senior physiotherapist, occupational therapist, exercise assistant, and guest lecturer, and the spoke usually had only an exercise instructor and nurse present. Uptake, adverse events (AEs), and early clinical changes were compared within and between groups. Travel distances were estimated using zip codes. Results: Mean attendance was 11.0 sessions in the hub and 10.5 sessions in the spoke (P=0.65). There was a single (mild) AE (hypoglycemia) in all three hub programs and no AEs in the three spoke programs. Mean COPD Assessment Test scores improved from 25.3 to 21.5 in the hub (P<0.001, 95% CI 2.43–5.17) and from 23.4 to 18.8 (P<0.001, 2.23–7.02) in the spoke group, with no difference between the groups (P=0.51, -3.35–1.70). Mean incremental shuttle walk test scores improved from 142 to 208 m (P<0.001, 75–199) in the hub and from 179 to 316 minutes in the spoke (P<0.001, 39.3–92.4), with a greater improvement in the spoke (P=0.025, 9.31–133). Twenty-one patients saved a total of 8,609.8 miles over the three programs by having the PR in their local spoke, rather than traveling to the usual nearest (hospital) hub. Conclusion: Video-conferencing, which links a local site to a standard PR program is feasible, safe, and demonstrates at least equivalent short-term clinical gains. Throughput can be increased, with less staffing ratios and significantly less traveling

The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress

The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81

Oesophageal adenocarcinoma is associated with a deregulation in the MYC/MAX/MAD network

Oesophageal adenocarcinoma, which arises from an acquired columnar lesion, Barrett's metaplasia, is rising in incidence more rapidly than any other cancer in the Western world. Elevated expression of c-MYC has been demonstrated in oesophageal adenocarcinoma; however, the expression of other members of the MYC/MAX/MAD network has not been addressed. The aims of this work were to characterise the expression of c-MYC, MAX and the MAD family in adenocarcinoma development and assess the effects of overexpression on cellular behaviour. mRNA expression in samples of Barrett's metaplasia and oesophageal adenocarcinoma were examined by qRT–PCR. Semi-quantitative immunohistochemistry and western blotting were used to examine cellular localisation and protein levels. Cellular proliferation and mRNA expression were determined in SEG1 cells overexpressing c-MYCER or MAD1 using a bromodeoxyuridine assay and qRT–PCR, respectively. Consistent with previous work expression of c-MYC was deregulated in oesophageal adenocarcinoma. Paradoxically, increased expression of putative c-MYC antagonists MAD1 and MXI1 was observed in tumour specimens. Overexpression of c-MYC and MAD proteins in SEG1 cells resulted in differential expression of MYC/MAX/MAD network members and reciprocal changes in proliferation. In conclusion, the expression patterns of c-MYC, MAX and the MAD family were shown to be deregulated in the oesophageal cancer model