History-Adjusted Marginal Structural Models to Estimate Time-Varying Effect Modification

Much of epidemiology and clinical medicine is focused on the estimation of treatments or interventions administered over time. In such settings of longitudinal treatment, time-dependent confounding is often an important source of bias. Marginal structural models are a powerful tool for estimating the causal effect of a treatment using observational data, particularly when time-dependent confounding is present. Recent statistical work presented a generalization of marginal structural models, called history-adjusted marginal structural models. Unlike standard marginal structural models, history-adjusted marginal structural models can be used to estimate modification of treatment effects by time-varying covariates. Estimation of time-dependent causal effect modification is frequently of great practical relevance. For example, clinical researchers are often interested in how the prognostic significance of a biomarker for treatment response can change over time. This article provides a practical introduction to the implementation and interpretation of history-adjusted marginal structural models. The method is illustrated using a clinical question drawn from the treatment of HIV infection. Observational cohort data from San Francisco, California, collected between 2000 and 2004, are used to estimate the effect of time until switching antiretroviral therapy regimen among patients receiving a non-suppressive regimen, and how this effect differs depending on CD4 T cell count

Sorting switch of mitochondrial presequence translocase involves coupling of motor module to respiratory chain

The mitochondrial presequence translocase transports preproteins to either matrix or inner membrane. Two different translocase forms have been identified: the matrix transport form, which binds the heat-shock protein 70 (Hsp70) motor, and the inner membrane–sorting form, which lacks the motor but contains translocase of inner mitochondrial membrane 21 (Tim21). The sorting form interacts with the respiratory chain in a Tim21-dependent manner. It is unknown whether the respiratory chain–bound translocase transports preproteins and how the switch between sorting form and motor form occurs. We report that the respiratory chain–bound translocase contains preproteins in transit and, surprisingly, not only sorted but also matrix-targeted preproteins. Presequence translocase-associated motor (Pam) 16 and 18, two regulatory components of the six-subunit motor, interact with the respiratory chain independently of Tim21. Thus, the respiratory chain–bound presequence translocase is not only active in preprotein sorting to the inner membrane but also in an early stage of matrix translocation. The motor does not assemble en bloc with the translocase but apparently in a step-wise manner with the Pam16/18 module before the Hsp70 core

Properties of the giant HII regions and bar in the nearby spiral galaxy NGC5430

In order to better understand the impact of the bar on the evolution of spiral galaxies, we measure the properties of giant HII regions and the bar in the SB(s)b galaxy NGC5430. We use two complementary data sets, both obtained at the Observatoire du Mont-M\'egantic: a hyperspectral data cube from the imaging Fourier transform spectrograph SpIOMM, and high-resolution spectra across the bar from a long-slit spectrograph. We flux-calibrate SpIOMM spectra for the first time, and produce H{\alpha} and [NII]{\lambda}6584\r{A} intensity maps from which we identify 51 giant HII regions in the spiral arms and bar. We evaluate the type of activity, the oxygen abundance and the age of the young populations contained in these giant HII regions and in the bar. Thus, we confirm that NGC5430 does not harbour a strong AGN, and that its Wolf-Rayet knot shows a pure HII region nature. We find no variation in abundance or age between the bar and spiral arms, nor as a function of galactocentric radius. These results are consistent with the hypothesis that a chemical mixing mechanism is at work in the galaxy's disc to flatten the oxygen abundance gradient. Using the starburst99 model, we estimate the ages of the young populations, and again find no variations in age between the bar and the arms or as a function of radius. Instead, we find evidence for two galaxy-wide waves of star formation, about 7.1 Myr and 10.5 Myr ago. While the bar in NGC5430 is an obvious candidate to trigger these two episodes, it is not clear how the bar could induce widespread star formation on such a short time-scale.Comment: 14 pages, 9 figures, 3 tables, accepted for publication in MNRA

Cellular metabolism regulates contact sites between vacuoles and mitochondria

Emerging evidence suggests that contact sites between different organelles form central hubs in the coordination of cellular physiology. Although recent work has emphasized the crucial role of the endoplasmic reticulum in interorganellar crosstalk, the cooperative behavior of other organelles is largely unexplored. Here, we identify a contact site named vCLAMP (vacuole and mitochondria patch) that integrates mitochondria with the lysosome-like vacuole and thus the endocytic pathway. vCLAMPs depend on the vacuolar HOPS tethering complex subunit Vps39/Vam6 and the Rab GTPase Ypt7, which also participate in membrane fusion at the vacuole. Intriguingly, vCLAMPs are located proximal to the ER-mitochondria encounter structure (ERMES) complexes, and an increase in vCLAMPs can rescue the growth defect of ERMES mutants. Importantly, the persistence of vCLAMPs is regulated by phosphorylation of Vps39 and is strongly reduced during respiratory growth. The identification of this organelle contact site reveals a physical and metabolic interconnection between the endocytic pathway and mitochondria