Structural basis of BAK activation in mitochondrial apoptosis initiation

BCL-2 proteins regulate mitochondrial poration in apoptosis initiation. How the pore-forming BCL-2 Effector BAK is activated remains incompletely understood mechanistically. Here we investigate autoactivation and direct activation by BH3-only proteins, which cooperate to lower BAK threshold in membrane poration and apoptosis initiation. We define in trans BAK autoactivation as the asymmetric “BH3-in-groove” triggering of dormant BAK by active BAK. BAK autoactivation is mechanistically similar to direct activation. The structure of autoactivated BAK BH3-BAK complex reveals the conformational changes leading to helix α1 destabilization, which is a hallmark of BAK activation. Helix α1 is destabilized and restabilized in structures of BAK engaged by rationally designed, high-affinity activating and inactivating BID-like BH3 ligands, respectively. Altogether our data support the long-standing hit-and-run mechanism of BAK activation by transient binding of BH3-only proteins, demonstrating that BH3-induced structural changes are more important in BAK activation than BH3 ligand affinity.

Complexity Analysis of a Sampling-Based Interior Point Method for Convex Optimization

We develop a short-step interior point method to optimize a linear function over a convex body assuming that one only knows a membership oracle for this body. The approach is based a sketch of a universal interior point method using the so-called entropic barrier. It is well known that the gradient and Hessian of the entropic barrier can be approximated by sampling from Boltzmann-Gibbs distributions and the entropic barrier was shown to be self-concordant. The analysis of our algorithm uses properties of the entropic barrier, mixing times for hit-and-run random walks, approximation quality guarantees for the mean and covariance of a log-concave distribution, and results on inexact Newton-type methods.

HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications

PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This “hit and run” mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.

Factors Influencing Fatalities or Severe Injuries to Pedestrians Lying on the Road in Japan: Nationwide Police Database Study

To help reduce the number of pedestrians lying on the road suffering fatal or severe injuries as a result of vehicle collisions, we investigated the influencing factors. We conducted an analysis of the records of the Institute for Traffic Accident Research and Data Analysis Japan between 2012 and 2018; we found that 2452 pedestrians lying on the road were involved in collisions (797 fatalities, 784 severely injured, 871 mildly injured). Multivariate logistic regression analysis identified the following as major factors that positively influenced the fatalities: head or neck injuries (odds ratio [OR], 90.221); trunk injuries (OR, 71.040); trucks as offending vehicle (OR, 2.741); collision velocity of 10–20 km/h (OR, 31.794), 20–30 km/h (OR, 2.982), 30–40 km/h (OR, 8.394), 40–50 km/h (OR, 16.831), and >50 km/h (OR, 18.639); and hit-and-run cases (OR, 1.967). The following had a positive influence on severe injuries: trunk injuries (OR, 4.060); collision velocity of 10–20 km/h (OR, 2.540), 20–30 km/h (OR, 3.700), 30–40 km/h (OR, 5.297), 40–50 km/h (OR, 5.719), and ≥50 km/h (OR, 5.244); and hit-and-run cases (OR, 2.628). Decreasing the collision velocity, avoiding collisions to the head and neck or trunk, and preventing hit-and-run cases would be effective in reducing fatal or severe injuries to pedestrians lying on the road.

On the mixing time of coordinate Hit-and-Run

We obtain a polynomial upper bound on the mixing time $T_{CHR}(\epsilon)$ of the coordinate Hit-and-Run (CHR) random walk on an $n-$ dimensional convex body, where $T_{CHR}(\epsilon)$ is the number of steps needed to reach within $\epsilon$ of the uniform distribution with respect to the total variation distance, starting from a warm start (i.e., a distribution which has a density with respect to the uniform distribution on the convex body that is bounded above by a constant). Our upper bound is polynomial in n, R and $\frac{1}{\epsilon}$ , where we assume that the convex body contains the unit $\Vert\cdot\Vert_\infty$ -unit ball $B_\infty$ and is contained in its R-dilation $R\cdot B_\infty$ . Whether CHR has a polynomial mixing time has been an open question.

Jihadist expansion into West Africa will take time

Significance While the overall number of incidents is fewer than a dozen since the rise of the region's jihadist insurgencies in the early 2010s, the trend lends credence to growing warnings about the jihadist threat to coastal West African countries. Concern has focused on Ivory Coast and Benin, but there is also nervousness about Ghana, Togo and even Senegal. Impacts Western governments will boost security assistance to coastal states. Intelligence sharing and joint operations will not forestall cross-border hit-and-run attacks. Most regional states will resort to security-focused responses whose abuses drive jihadist recruitment.

Learning constraints from demonstrations with grid and parametric representations

We extend the learning from demonstration paradigm by providing a method for learning unknown constraints shared across tasks, using demonstrations of the tasks, their cost functions, and knowledge of the system dynamics and control constraints. Given safe demonstrations, our method uses hit-and-run sampling to obtain lower cost, and thus unsafe, trajectories. Both safe and unsafe trajectories are used to obtain a consistent representation of the unsafe set via solving an integer program. Our method generalizes across system dynamics and learns a guaranteed subset of the constraint. In addition, by leveraging a known parameterization of the constraint, we modify our method to learn parametric constraints in high dimensions. We also provide theoretical analysis on what subset of the constraint and safe set can be learnable from safe demonstrations. We demonstrate our method on linear and nonlinear system dynamics, show that it can be modified to work with suboptimal demonstrations, and that it can also be used to learn constraints in a feature space.