Asymptotic analysis of noisy fitness maximization, applied to metabolism and growth

We consider a population dynamics model coupling cell growth to a diffusion in the space of metabolic phenotypes as it can be obtained from realistic constraints-based modelling. In the asymptotic regime of slow diffusion, that coincides with the relevant experimental range, the resulting non-linear Fokker-Planck equation is solved for the steady state in the WKB approximation that maps it into the ground state of a quantum particle in an Airy potential plus a centrifugal term. We retrieve scaling laws for growth rate fluctuations and time response with respect to the distance from the maximum growth rate suggesting that suboptimal populations can have a faster response to perturbations.Comment: 24 pages, 6 figure

NODAL/Activin signalling to chromatin: mechanisms of SMAD2-regulated transcription

NODAL/Activin signalling regulates key processes during embryonic development via SMAD2. How SMAD2 activates programmes of gene expression that are modulated over time, however, is not known. In this thesis, using the P19 embryonic teratoma cell line as a model system, I delineate the sequence of events that occur from SMAD2 binding to transcriptional activation, and the underlying mechanisms. I show that NODAL/Activin signalling induces dramatic changes in the chromatin landscape, and orchestrates a dynamic transcriptional network regulated by SMAD2, which acts via multiple mechanisms. By combining different genome-wide approaches, I have discovered two modes of SMAD2 binding. SMAD2 can bind pre-acetylated nucleosome-depleted sites, where it promotes a further increase in H3K9ac/H3K27ac. However, SMAD2 also binds to unacetylated, closed chromatin, independently of pioneer factors, where it induces nucleosome displacement and H3 acetylation. For a subset of genes, this requires cooperation with the remodeller SMARCA4 and the transcription factor FOXH1. I demonstrate that SMAD2 regulates RNA Polymerase II via de novo recruitment to target promoters, and that long term modulation of the transcriptional responses requires continued NODAL/Activin signalling. Moreover, SMAD2 binding does not necessarily equate with transcriptional kinetics, and my data suggest that SMAD2 recruits multiple co-factors during sustained signaling to shape the downstream transcriptional programme. I have used ATAC-seq to identify specific transcription factor footprints at SMAD2 binding sites, and future work will aim to unveil and characterise the network of transcription factors that collaborate with SMAD2 and enable cells to correctly interpret NODAL/Activin signaling over time

Options for road user charges - two Italian case studies

This paper discusses the impact that tolling schemes with a higher degree of differentiation of tariffs among demand categories can have on road demand. The question addressed in the paper is whether the differentiation of inter-urban road tolls can help to manage demand and meet targets like alleviating congestion, reducing emissions or making feasible project financing schemes, where toll revenues are used to cover construction and operating costs. The paper is mainly based on the results of the DIFFERENT research project, co-funded by the European Commission DG TREN, where a number of modelling tests have been carried out using two different transport network models. Based on modelling results we conclude that a trade-off between alternative targets of toll differentiation exists and that results vary according to the specific context of the application. In non-congested corridors charge differentiation can raise money, but there is little room for social benefits, whereas in congested areas travel speed on the road network can be improved by introducing charges on congested non-motorway links. Additionally, achievement of benefits from differentiated charges may require the co-ordinated introduction of charges on ordinary roads as well as on motorways

Are We Using Autoencoders in a Wrong Way?

Autoencoders are certainly among the most studied and used Deep Learning models: the idea behind them is to train a model in order to reconstruct the same input data. The peculiarity of these models is to compress the information through a bottleneck, creating what is called Latent Space. Autoencoders are generally used for dimensionality reduction, anomaly detection and feature extraction. These models have been extensively studied and updated, given their high simplicity and power. Examples are (i) the Denoising Autoencoder, where the model is trained to reconstruct an image from a noisy one; (ii) Sparse Autoencoder, where the bottleneck is created by a regularization term in the loss function; (iii) Variational Autoencoder, where the latent space is used to generate new consistent data. In this article, we revisited the standard training for the undercomplete Autoencoder modifying the shape of the latent space without using any explicit regularization term in the loss function. We forced the model to reconstruct not the same observation in input, but another one sampled from the same class distribution. We also explored the behaviour of the latent space in the case of reconstruction of a random sample from the whole dataset

Clinical Features That Evoke the Concept of Disinhibition in Tourette Syndrome

The capacity to efficiently control motor output, by either refraining from prepotent actions or disengaging from ongoing motor behaviors, is necessary for our ability to thrive in a stimulus-rich and socially complex environment. Failure to engage in successful inhibitory motor control could lead to aberrant behaviors typified by an excess of motor performance. In tic disorders and Tourette syndrome (TS) - the most common tic disorder encountered in clinics - surplus motor output is rarely the only relevant clinical sign. A range of abnormal behaviors is often encountered which are historically viewed as "disinhibition phenomena". Here, we present the different clinical features of TS from distinct categorical domains (motor, sensory, complex behavioral) that evoke the concept of disinhibition and discuss their associations. We also present evidence for their consideration as phenomena of inhibitory dysfunction and provide an overview of studies on TS pathophysiology which support this view. We then critically dissect the concept of disinhibition in TS and illuminate other salient aspects, which should be considered in a unitary pathophysiological approach. We briefly touch upon the dangers of oversimplification and emphasize the necessity of conceptual diversity in the scientific exploration of TS, from disinhibition and beyond

Biochemical data from the characterization of a new pathogenic mutation of human pyridoxine-5'-phosphate oxidase (PNPO)

PNPO deficiency is responsible of severe neonatal encephalopathy, responsive to pyridoxal-5’-phosphate (PLP) or pyridoxine. Recent studies widened the phenotype of this condition and detected new genetic variants on PNPO gene, whose pathogenetic role and clinical expression remain to be established. One of these mutations, Arg116Gln, is of particular interest because of its later onset of symptoms (beyond the first months of life) and its peculiar epileptic manifestations in patients. This protein variant was expressed as recombinant protein in E coli, purified to homogeneity, and characterized with respect to structural and kinetic properties, stability, binding constants of cofactor flavin mononucleotide (FMN) and product (PLP) in order to define the molecular and structural bases of its pathogenicity. For interpretation and discussion of reported data, together with the description of clinical studies, refer to the article [7][1] (doi: 10.1016/j.ymgme.2017.08.003)

Robust Model Predictive Control With Integral Sliding Mode in Continuous-Time Sampled-Data Nonlinear Systems

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Coupling of Photonic Waveguides to Integrated Detectors Using 3D Inverse Tapering

We report on the design, fabrication, and characterization of a Silicon Nitride (SiN)-based integrated photonic chip in which the dielectric waveguides are coupled to photodetectors integrated homogeneously into the Silicon substrate. The photonic-electronic coupling was realized by a 3D inverse tapering of SiN waveguides. The novelty of our approach consists in tapering the waveguide in the vertical direction by means of an engineered wet chemical etching. This allows for a smooth transition from a full-height to an arbitrarily thin waveguide thickness at the detector location, expanding adiabatically the optical mode towards the latter. The measured chips showed a responsivity $R\approx 109~\mu$A/mW and a corresponding quantum efficiency of $16\%$ at an excitation wavelength of $850$~nm. Our technological solution offers a versatile method for a top-down monolithic integration of lightwave circuitries with substrate-located photon sensing devices