Cram\'er-Rao bounds for synchronization of rotations

Synchronization of rotations is the problem of estimating a set of rotations R_i in SO(n), i = 1, ..., N, based on noisy measurements of relative rotations R_i R_j^T. This fundamental problem has found many recent applications, most importantly in structural biology. We provide a framework to study synchronization as estimation on Riemannian manifolds for arbitrary n under a large family of noise models. The noise models we address encompass zero-mean isotropic noise, and we develop tools for Gaussian-like as well as heavy-tail types of noise in particular. As a main contribution, we derive the Cram\'er-Rao bounds of synchronization, that is, lower-bounds on the variance of unbiased estimators. We find that these bounds are structured by the pseudoinverse of the measurement graph Laplacian, where edge weights are proportional to measurement quality. We leverage this to provide interpretation in terms of random walks and visualization tools for these bounds in both the anchored and anchor-free scenarios. Similar bounds previously established were limited to rotations in the plane and Gaussian-like noise

Out-of-hospital births and the supply of maternity units in France.

International audienceMaternity unit closures in France have increased distances that women travel to deliver in hospital. We studied how the supply of maternity units influences the rate of out-of-hospital births using birth certificate data. In 2005-6, 4.3 per 1000 births were out-of-hospital. Rates were more than double for women living 30km or more from their nearest unit and were even higher for women of high parity. These associations persisted in multilevel analyses adjusting for other maternal characteristics. Long distances to maternity units should be a concern to health planners because of the maternal and infant health risks

Nucleocytoplasmic shuttling of the rabies virus P protein requires a nuclear localization signal and a CRM1-dependent nuclear export signal

AbstractRabies virus P protein is a co-factor of the viral RNA polymerase. It has been shown previously that P mRNA directs the synthesis of four N-terminally truncated P products P2, P3, P4, and P5 due to translational initiation by a leaky scanning mechanism at internal Met codons. Whereas P and P2 are located in the cytoplasm, P3, P4, and P5 are found in the nucleus. Here, we have analyzed the molecular basis of the subcellular localization of these proteins. Using deletion mutants fused to GFP protein, we show the presence of a nuclear localization signal (NLS) in the C-terminal part of P (172–297). This domain contains a short lysine-rich stretch (211KKYK214) located in close proximity with arginine 260 as revealed by the crystal structure of P. We demonstrate the critical role of lysine 214 and arginine 260 in NLS activity. In the presence of Leptomycin B, P is retained in the nucleus indicating that it contains a CRM1-dependent nuclear export signal (NES). The subcellular distribution of P deletion mutants indicates that the domain responsible for export is the amino-terminal part of the protein. The use of fusion proteins that have amino terminal fragments of P fused to β-galactosidase containing the NLS of SV40 T antigen allows us to identify a NES between residues 49 and 58. The localization of NLS and NES determines the cellular distribution of the P gene products

Antiprion drugs 6-aminophenanthridine and guanabenz reduce PABPN1 toxicity and aggregation in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset syndrome characterized by progressive degeneration of specific muscles. OPMD is caused by extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Insoluble nuclear inclusions form in diseased muscles. We have generated a Drosophila model of OPMD that recapitulates the features of the disorder. Here, we show that the antiprion drugs 6-aminophenanthridine (6AP) and guanabenz acetate (GA), which prevent formation of amyloid fibers by prion proteins in cell models, alleviate OPMD phenotypes in Drosophila, including muscle degeneration and nuclear inclusion formation. The large ribosomal RNA and its activity in protein folding were recently identified as a specific cellular target of 6AP and GA. We show that deletions of the ribosomal DNA locus reduce OPMD phenotypes and act synergistically with sub-effective doses of 6AP. In a complementary approach, we demonstrate that ribosomal RNA accelerates in vitro fibril formation of PABPN1 N-terminal domain. These results reveal the conserved role of ribosomal RNA in different protein aggregation disorders and identify 6AP and GA as general anti-aggregation molecules

Protein folding activity of ribosomal rna is a selective target of two unrelated antiprion drugs

Background: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases.Methodology/Principal Findings: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome.Conclusion/Significance: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity

Model generation of coronary artery bifurcations from CTA and single plane angiography

International audiencePurpose: To generate accurate and realistic models of coronary artery bifurcations before and after percutaneous coronary intervention (PCI), using information from two image modalities. Because bifurcations are regions where atherosclerotic plaque appears frequently and intervention is more challenging, generation of such realistic models could be of high value to predict the risk of restenosis or thrombosis after stent implantation, and to study geometrical and hemodynamical changes. Methods: Two image modalities have been employed to generate the bifurcation models: computer tomography angiography (CTA) to obtain the 3D trajectory of vessels, and 2D conventional coronary angiography (CCA) to obtain radius information of the vessel lumen, due to its better contrast and image resolution. In addition, CCA can be acquired right before and after the intervention in the operation room; therefore, the combination of CTA and CCA allows the generation of realistic prepro-cedure and postprocedure models of coronary bifurcations. The method proposed is semiautomatic, based on landmarks manually placed on both image modalities. Results: A comparative study of the models obtained with the proposed method with models manually obtained using only CTA, shows more reliable results when both modalities are used together. The authors show that using preprocedure CTA and postprocedure CCA, realistic postprocedure models can be obtained. Analysis carried out of the Murray's law in all patient bifurcations shows the geometric improvement of PCI in our models, better than using manual models from CTA alone. An experiment using a cardiac phantom also shows the feasibility of the proposed method. Conclusions: The authors have shown that fusion of CTA and CCA is feasible for realistic generation of coronary bifurcation models before and after PCI. The method proposed is efficient, and relies on minimal user interaction, and therefore is of high value to study geometric and hemo-dynamic changes of treated patients

Protein Folding Activity of Ribosomal RNA Is a Selective Target of Two Unrelated Antiprion Drugs

International audienceBACKGROUND: 6-Aminophenanthridine (6AP) and Guanabenz (GA, a drug currently in use for the treatment of hypertension) were isolated as antiprion drugs using a yeast-based assay. These structurally unrelated molecules are also active against mammalian prion in several cell-based assays and in vivo in a mouse model for prion-based diseases. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the identification of cellular targets of these drugs. Using affinity chromatography matrices for both drugs, we demonstrate an RNA-dependent interaction of 6AP and GA with the ribosome. These specific interactions have no effect on the peptidyl transferase activity of the ribosome or on global translation. In contrast, 6AP and GA specifically inhibit the ribosomal RNA-mediated protein folding activity of the ribosome. CONCLUSION/SIGNIFICANCE: 6AP and GA are therefore the first compounds to selectively inhibit the protein folding activity of the ribosome. They thus constitute precious tools to study the yet largely unexplored biological role of this protein folding activity

Early T Cell Signalling Is Reversibly Altered in PD-1+ T Lymphocytes Infiltrating Human Tumors

To improve cancer immunotherapy, a better understanding of the weak efficiency of tumor-infiltrating T lymphocytes (TIL) is necessary. We have analyzed the functional state of human TIL immediately after resection of three types of tumors (NSCLC, melanoma and RCC). Several signalling pathways (calcium, phosphorylation of ERK and Akt) and cytokine secretion are affected to different extents in TIL, and show a partial spontaneous recovery within a few hours in culture. The global result is an anergy that is quite distinct from clonal anergy induced in vitro, and closer to adaptive tolerance in mice. PD-1 (programmed death -1) is systematically expressed by TIL and may contribute to their anergy by its mere expression, and not only when it interacts with its ligands PD-L1 or PD-L2, which are not expressed by every tumor. Indeed, the TCR-induced calcium and ERK responses were reduced in peripheral blood T cells transfected with PD-1. Inhibition by sodium stibogluconate of the SHP-1 and SHP-2 phosphatases that associate with several inhibitory receptors including PD-1, relieves part of the anergy apparent in TIL or in PD-1-transfected T cells. This work highlights some of the molecular modifications contributing to functional defects of human TIL

PerDiS: design, implementation, and use of a PERsistent DIstributed Store

International audienceThe PerDiS (Persistent Distributed Store) project addresses the issue of providing support for distributed collaborative engineering applications. We describe the design and implementation of the PerDiS platform, and its support for such applications. Collaborative engineering raises system issues related to the sharing of large volumes of fine-grain, complex objects across wide-area networks and administrative boundaries. PerDiS manages all these aspects in a well defined, integrated, and automatic way. Distributed application programming is simplified because it uses the same memory abstraction as in the centralized case. Porting an existing centralized program written in C or C++ is usually a matter of a few, well-isolated changes. We present some performance results from a proof-of-concept platform that runs a number of small, but real, distributed applications on Unix and Windows NT. These confirm that the PerDiS abstraction is well adapted to the targeted application area and that the overall performance is promising compared to alternative approache

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal