Novel POLE pathogenic germline variant in a family with multiple primary tumors results in distinct mutational signatures.

We describe a family in which four siblings exhibited multiple or classic colonic polyposis with or without colorectal carcinoma (CRC). One female developed three primary tumors, including CRC and carcinomas of the ovary and breast. Whole-exome sequencing of germline DNA from affected and unaffected individuals revealed a novel missense mutation in the exonuclease domain of POLE (c.833C>A; p.Thr278Lys) associated with a highly penetrant, autosomal-dominant inheritance pattern. Functional studies in yeast and demonstration of a high mutational burden in the available tumors confirmed the pathogenicity of the novel variant. Prominent POLE-deficient somatic mutational signatures were seen in the CRCs, but in contrast, a mutational signature typical of concomitant tumoral loss of POLE and mismatch-repair function (POLE-exo* /MSI) was noted in the breast cancer. The breast cancer also showed distinctive pathological characteristics that reflect the presence of both the germline POLE variant and the secondary somatic MMR alterations.

Adipocyte MTERF4 regulates non-shivering adaptive thermogenesis and sympathetic-dependent glucose homeostasis.

In humans, low brown adipose tissue (BAT) mass and activity have been associated with increased adiposity and fasting glucose levels, suggesting that defective BAT-dependent thermogenesis could contribute to the development of obesity and/or type 2 diabetes. The thermogenic function of BAT relies on a vast network of mitochondria exclusively equipped with UCP1. Mitochondrial biogenesis is exquisitely regulated by a well-defined network of transcription factors that coordinate the expression of nuclear genes required for the formation of functional mitochondria. However, less is known about the mitochondrial factors that control the expression of the genes encoded by the mitochondrial genome. Here, we have studied the role of mitochondrial transcription termination factor-4 (MTERF4) in BAT by using a new mouse model devoid of MTERF4 specifically in adipocytes (MTERF4-FAT-KO mice). Lack of MTERF4 in BAT leads to reduced OxPhos mitochondrial protein levels and impaired assembly of OxPhos complexes I, III and IV due to deficient translation of mtDNA-encoded proteins. As a result, brown adipocytes lacking MTERF4 exhibit impaired respiratory capacity. MTERF4-FAT-KO mice show a blunted thermogenic response and are unable to maintain body temperature when exposed to cold. Despite impaired BAT function, MTERF4-FAT-KO mice do not develop obesity or insulin resistance. Still, MTERF4-FAT-KO mice became resistant to the insulin-sensitizing effects of ß3-specific adrenergic receptor agonists. Our results demonstrate that MTERF4 regulates mitochondrial protein translation and is essential for proper BAT thermogenic activity. Our study also supports the notion that pharmacological activation of BAT is a plausible therapeutic target for the treatment of insulin resistance.

Ehrenfest urn revisited: playing the game on a realistic fluid model.

The Ehrenfest urn process, also known as the dogs and fleas model, is realistically simulated by molecular dynamics of the Lennard-Jones fluid. The key variable is Delta(z) -i.e., the absolute value of the difference between the number of particles in one half of the simulation box and in the other half. This is a pure-jump stochastic process induced, under coarse graining, by the deterministic time evolution of the atomic coordinates. We discuss the Markov hypothesis by analyzing the statistical properties of the jumps and the waiting times between the jumps. In the limit of a vanishing integration time step, the distribution of waiting times becomes closer to an exponential and, therefore, the continuous-time jump stochastic process is Markovian. The random variable Delta(z) behaves as a Markov chain and, in the gas phase, the observed transition probabilities follow the predictions of the Ehrenfest theory.

Velocity and energy distributions in microcanonical ensembles of hard spheres.

In a microcanonical ensemble (constant NVE, hard reflecting walls) and in a molecular dynamics ensemble (constant NVEPG, periodic boundary conditions) with a number N of smooth elastic hard spheres in a d-dimensional volume V having a total energy E, a total momentum P, and an overall center of mass position G, the individual velocity components, velocity moduli, and energies have transformed beta distributions with different arguments and shape parameters depending on d, N, E, the boundary conditions, and possible symmetries in the initial conditions. This can be shown marginalizing the joint distribution of individual energies, which is a symmetric Dirichlet distribution. In the thermodynamic limit the beta distributions converge to gamma distributions with different arguments and shape or scale parameters, corresponding respectively to the Gaussian, i.e., Maxwell-Boltzmann, Maxwell, and Boltzmann or Boltzmann-Gibbs distribution. These analytical results agree with molecular dynamics and Monte Carlo simulations with different numbers of hard disks or spheres and hard reflecting walls or periodic boundary conditions. The agreement is perfect with our Monte Carlo algorithm, which acts only on velocities independently of positions with the collision versor sampled uniformly on a unit half sphere in d dimensions, while slight deviations appear with our molecular dynamics simulations for the smallest values of N.

First-passage and first-exit times of a Bessel-like stochastic process.

We study a stochastic process X(t) which is a particular case of the Rayleigh process and whose square is the Bessel process, with various applications in physics, chemistry, biology, economics, finance, and other fields. The stochastic differential equation is dX(t)=(nD/X(t))dt+√(2D)dW(t), where W(t) is the Wiener process. The drift term can arise from a logarithmic potential or from taking X(t) as the norm of a multidimensional random walk. Due to the singularity of the drift term for X(t)=0, different natures of boundary at the origin arise depending on the real parameter n: entrance, exit, and regular. For each of them we calculate analytically and numerically the probability density functions of first-passage times or first-exit times. Nontrivial behavior is observed in the case of a regular boundary.