Identification of X-chromosomal genes that drive global X-dosage effects in mammals

X-chromosomal genes contribute to sex differences, in particular during early development, whenboth X chromosomes are active in females. Here, double X-dosage shifts female pluripotent cells towards the naive stem cell state by increasing pluripotency factor expression, inhibiting thedifferentiation-promoting MAP kinase (MAPK) signalling pathway and delaying differentiation. Toidentify the genetic basis of these sex differences, we have performed a series of CRISPR knockoutscreens in murine embryonic stem cells to comprehensively identify X-linked genes that cause thefemale pluripotency phenotype. We found multiple genes that act in concert, among which Klhl13plays a central role. We show that this E3 ubiquitin ligase substrate adaptor protein promotes pluripotency factor expression, delays differentiation and represses MAPK target genes, and weidentify putative substrates. We thus elucidate the mechanisms that drive sex-induced differences inpluripotent cells with implications for gender medicine in the context of induced pluripotent stem cellbased therapies

Two coupled feedback loops explain random mono-allelic Xist upregulation at the onset of X-chromosome inactivation

In female mammal s, dosage compensation for X-linked genes is ensured through random X-chromosome inactivation, which is initiated by mono-allelic up-regulation of Xist . We use mathematical modeling to identify the regulatory principles required to establish the mono-allelic and female-specific Xist expression pattern and test model predictions experimentally. A cis -acting positive feedback, which in mice is mediated by mutual repression of Xist and its antisense transcript Tsix , together with a trans -acting negative feedba ck are sufficient to explain mono-allelic Xist up-regulation. The model can reproduce data from several mutant, aneuploid and polyploid murine cell lines and explain s Xist expression patterns in other mammalian species. Furthermore, it predicts that transient , reversible bi-allelic Xist expression is not restricted to rabbits and humans but can also occur in mice, which we indeed confirm to occur in mouse embryos. Overall, our study provides a conceptual framework of the molecular mechanisms required to initiate random X-chromosome inactivation

Derivatives of spin dynamics simulations

We report analytical equations for the derivatives of spin dynamics simulations with respect to pulse sequence and spin system parameters. The methods described are significantly faster, more accurate and more reliable than the finite difference approximations typically employed. The resulting derivatives may be used in fitting, optimization, performance evaluation and stability analysis of spin dynamics simulations and experiments. Keywords: NMR, EPR, simulation, analytical derivatives, optimal control, spin chemistry, radical pair.Comment: Accepted by The Journal of Chemical Physic

Integrated analysis of Xist upregulation and gene silencing at the onset of random X-chromosome inactivation at high temporal and allelic resolution

To ensure dosage compensation between the sexes, one randomly chosen X chromosome is silenced in each female cell in the process of X-chromosome inactivation (XCI). XCI is initiated during early development through upregulation of the long non-coding RNA Xist, which mediateschromosome-wide gene silencing. Cell differentiation, Xist upregulation and silencing are thought tobe coupled at multiple levels to ensure inactivation of exactly one out of two X chromosomes. Here we perform an integrated analysis of all three processes through allele-specific single-cellRNA-sequencing. Specifically, we assess the onset of random XCI with high temporal resolution indifferentiating mouse embryonic stem cells, and develop dedicated analysis approaches. By exploitingthe inter-cellular heterogeneity of XCI onset, we identify Nanog downregulation as its main trigger and discover additional putative Xist regulators. Moreover, we confirm several predictions of thestochastic model of XCI where monoallelic silencing is thought to be ensured through negativefeedback regulation. Finally, we show that genetic variation modulates the XCI process at multiplelevels, providing a potential explanation for the long-known Xce effect, which leads to preferentialinactivation of a specific X chromosome in inter-strain crosses. We thus draw a detailed picture of thedifferent levels of regulation that govern the initiation of XCI. The experimental and computationalstrategies we have developed here will allow us to profile random XCI in more physiological contexts,including primary human cells in vivo

Single to Double Hump Transition in the Equilibrium Distribution Function of Relativistic Particles

We unveil a transition from single peaked to bimodal velocity distribution in a relativistic fluid under increasing temperature, in contrast with a non-relativistic gas, where only a monotonic broadening of the bell-shaped distribution is observed. Such transition results from the interplay between the raise in thermal energy and the constraint of maximum velocity imposed by the speed of light. We study the Bose-Einstein, the Fermi-Dirac, and the Maxwell-J\"uttner distributions, all exhibiting the same qualitative behavior. We characterize the nature of the transition in the framework of critical phenomena and show that it is either continuous or discontinuous, depending on the group velocity. We analyze the transition in one, two, and three dimensions, with special emphasis on two-dimensions, for which a possible experiment in graphene, based on the measurement of the Johnson-Nyquist noise, is proposed.Comment: 5 pages, 5 figure

On Existence and Properties of Approximate Pure Nash Equilibria in Bandwidth Allocation Games

In \emph{bandwidth allocation games} (BAGs), the strategy of a player consists of various demands on different resources. The player's utility is at most the sum of these demands, provided they are fully satisfied. Every resource has a limited capacity and if it is exceeded by the total demand, it has to be split between the players. Since these games generally do not have pure Nash equilibria, we consider approximate pure Nash equilibria, in which no player can improve her utility by more than some fixed factor $\alpha$ through unilateral strategy changes. There is a threshold $\alpha_\delta$ (where $\delta$ is a parameter that limits the demand of each player on a specific resource) such that $\alpha$-approximate pure Nash equilibria always exist for $\alpha \geq \alpha_\delta$, but not for $\alpha < \alpha_\delta$. We give both upper and lower bounds on this threshold $\alpha_\delta$ and show that the corresponding decision problem is ${\sf NP}$-hard. We also show that the $\alpha$-approximate price of anarchy for BAGs is $\alpha+1$. For a restricted version of the game, where demands of players only differ slightly from each other (e.g. symmetric games), we show that approximate Nash equilibria can be reached (and thus also be computed) in polynomial time using the best-response dynamic. Finally, we show that a broader class of utility-maximization games (which includes BAGs) converges quickly towards states whose social welfare is close to the optimum