Retroviral Integration Process in the Human Genome: Is It Really Non-Random? A New Statistical Approach

Retroviral vectors are widely used in gene therapy to introduce therapeutic genes into patients' cells, since, once delivered to the nucleus, the genes of interest are stably inserted (integrated) into the target cell genome. There is now compelling evidence that integration of retroviral vectors follows non-random patterns in mammalian genome, with a preference for active genes and regulatory regions. In particular, Moloney Leukemia Virus (MLV)–derived vectors show a tendency to integrate in the proximity of the transcription start site (TSS) of genes, occasionally resulting in the deregulation of gene expression and, where proto-oncogenes are targeted, in tumor initiation. This has drawn the attention of the scientific community to the molecular determinants of the retroviral integration process as well as to statistical methods to evaluate the genome-wide distribution of integration sites. In recent approaches, the observed distribution of MLV integration distances (IDs) from the TSS of the nearest gene is assumed to be non-random by empirical comparison with a random distribution generated by computational simulation procedures. To provide a statistical procedure to test the randomness of the retroviral insertion pattern, we propose a probability model (Beta distribution) based on IDs between two consecutive genes. We apply the procedure to a set of 595 unique MLV insertion sites retrieved from human hematopoietic stem/progenitor cells. The statistical goodness of fit test shows the suitability of this distribution to the observed data. Our statistical analysis confirms the preference of MLV-based vectors to integrate in promoter-proximal regions

Using Tocher's curve to convert subjective quantile-estimates into a probability distribution function

One standard approach for estimating a subjective distribution is to elicit subjective quantiles from a human expert. However, most decision-making models require a random variable's moments and/or distribution function instead of its quantiles. In the literature little attention has been given to the problem of converting a given set of subjective quantiles into moments and/or a distribution function. We show that this conversion problem is far from trivial, and that the most commonly used conversion procedure often produces large errors. An alternative procedure using `Tocher's curve' is proposed, and its performance is evaluated with a wide variety of test distributions. The method is shown to be more accurate than a commonly used procedure.link_to_subscribed_fulltex

Comparison of procedures for estimating the parent probability distribution from a given set of fractiles

On one hand, eliciting subjective probabilities (fractiles) is a well-established procedure. On the other hand, knowledge of a subjective variable's central moments or distribution function is often assumed. However, the problem of converting elicited fractiles into the required moments or distribution function has been largely ignored. We show that this conversion problem is far from trivial, and that the most commonly used conversion procedures often produce huge errors. Alternative procedures are proposed; the `Tocher's curve' and `linear function of fractiles' methods are shown to be much more accurate than the commonly used procedures.link_to_subscribed_fulltex

Pricing/inventory decisions and profit shares in a non-integrated marketing channel for a single-period product

We consider the situation in which the manufacturer of a single-period product first sets the unit wholesale price and then the retailer responds with an order size. We present mostly analytical results on the effects of the problem's environmental parameters (such as shortage cost and demand uncertainty) on the optimal decisions (ie, the unit wholesale price and retailer's order size) and on the expected profits of the manufacturer and of the retailer. Some of these effects are counter-intuitive and/or contradict related results published recently for similar models. The most important finding is that demand uncertainty is always harmful to the manufacturer but is very often beneficial to the retailer. This means that when the manufacturer can set the wholesale price, the manufacturer should be much more supportive (or even aggressive) than previously advised towards activities such as market surveys and 'Quick Response' that reduce the retailer's market uncertainty; in contrast, the retailer need not be as enthusiastic about these activities.link_to_subscribed_fulltex

Unidirectional rotary motion in achiral molecular motors

Control of the direction of motion is an essential feature of biological rotary motors and results from the intrinsic chirality of the amino acids from which the motors are made. In synthetic autonomous light-driven rotary motors, point chirality is transferred to helical chirality, and this governs their unidirectional rotation. However, achieving directional rotary motion in an achiral molecular system in an autonomous fashion remains a fundamental challenge. Here, we report an achiral molecular motor in which the presence of a pseudo-asymmetric carbon atom proved to be sufficient for exclusive autonomous disrotary motion of two appended rotor moieties. Isomerization around the two double bonds enables both rotors to move in the same direction with respect to their surroundings-like wheels on an axle-demonstrating that autonomous unidirectional rotary motion can be achieved in a symmetric system

Single rotating molecule-machines: Nanovehicles and molecular motors

cited By 3International audienceIn the last decade many molecular machines with controlled molecular motions have been synthesized. In the present review chapter we will present and discuss our contribution to the field, in particular through some examples of rotating molecular machines that have been designed, synthesized, and studied in our group. After starting by explaining why it is so important to study such machines as single molecules, we will focus on two families of molecular machines, nanovehicles and molecular motors. The first members of the nanovehicle family are molecules with two triptycenes as wheels: the axle and the wheelbarrow. Then come the four-wheel nanocars. Since triptycene wheels are not very mobile on metallic surfaces, alternative wheels with a bowl-shape structure have also been synthesized and studied on surfaces. The molecular motors are built around ruthenium organometallic centers and have a piano-stool geometry with peripheric ferrocenyl groups