Vertex results for the robust analysis of uncertain biochemical systems

We consider the problem of assessing the sensitivity of uncertain biochemical systems in the presence of input perturbations (either constant or periodic) around a stable steady state. In particular, we propose approaches for the robust sensitivity analysis of systems with uncertain parameters assumed to take values in a hyper-rectangle. We highlight vertex results, which allow us to check whether a property is satisfied for all parameter choices in the hyper-rectangle by simply checking whether it is satisfied for all parameter choices at the vertices of the hyper-rectangle. We show that, for a vast class of systems, including (bio)chemical reaction networks with mass-action kinetics, the system Jacobian has a totally multiaffine structure (namely, all minors of the Jacobian matrix are multiaffine functions of the uncertain parameters), which can be exploited to obtain several vertex results. We consider different problems: robust non-singularity; robust stability of the steady-state; robust steady-state sensitivity analysis, in the case of constant perturbations; robust frequency-response sensitivity analysis, in the presence of periodic perturbations; and robust adaptation analysis. The developed theory is then applied to gain insight into some examples of uncertain biochemical systems, including the incoherent feed-forward loop, the coherent feed-forward loop, the Brusselator oscillator and the Goldbeter oscillator

Biological effects of EF24, a curcumin derivative, alone or combined with mitotane in adrenocortical tumor cell lines

Background: Curcumin has numerous properties and is used in many preclinical conditions, including cancer. It has low bioavailability, while its derivative EF24 shows enhanced solubility. However, its effects have never been explored in adrenocortical tumor cell models. The efficacy of EF24 alone or combined with mitotane (reference drug for adrenocortical cancer) was evaluated in two adrenocortical tumor cell lines, SW13 and H295R. Method and Results: EF24 reduced cell viability with an IC50 (half maximal inhibitory concentration) of 6.5 \ub1 2.4 \ub5M and 4.9 \ub1 2.8 \ub5M for SW13 and H295R cells, respectively. Combination index (EF24 associated with mitotane) suggested an additivity effect in both cell lines. Cell cycle analysis revealed an increase in subG0/G1 phase, while motility assay showed a decrease in migratory cell capacity, and similarly, clonogenic assay indicated that EF24 could reduce colony numbers. Furthermore, Wnt/\u3b2-catenin, NF-\u3baB, MAPK, and PI3k/Akt pathways were modulated by Western blot analysis when treating cells with EF24 alone or combined with mitotane. In addition, intracellular reactive oxygen species levels increased in both cell lines. Conclusion: This work analyzed EF24 in adrenocortical tumor cell lines for the first time. These results suggest that EF24 could potentially impact on adrenocortical tumors, laying the foundation for further research in animal models

The transcriptional regulator ZNF398 mediates pluripotency and epithelial character downstream of TGF-beta in human PSCs

Human pluripotent stem cells (hPSCs) have the capacity to give rise to all differentiated cells of the adult. TGF-beta is used routinely for expansion of conventional hPSCs as flat epithelial colonies expressing the transcription factors POU5F1/OCT4, NANOG, SOX2. Here we report a global analysis of the transcriptional programme controlled by TGF-beta followed by an unbiased gain-of-function screening in multiple hPSC lines to identify factors mediating TGF-beta activity. We identify a quartet of transcriptional regulators promoting hPSC self-renewal including ZNF398, a human-specific mediator of pluripotency and epithelial character in hPSCs. Mechanistically, ZNF398 binds active promoters and enhancers together with SMAD3 and the histone acetyltransferase EP300, enabling transcription of TGF-beta targets. In the context of somatic cell reprogramming, inhibition of ZNF398 abolishes activation of pluripotency and epithelial genes and colony formation. Our findings have clear implications for the generation of bona fide hPSCs for regenerative medicine

Black strings in AdS_5

We present non-extremal magnetic black string solutions in five-dimensional gauged supergravity. The conformal infinity is the product of time and S^1xS_h, where S_h denotes a compact Riemann surface of genus h. The construction is based on both analytical and numerical techniques. We compute the holographic stress tensor, the Euclidean action and the conserved charges of the solutions and show that the latter satisfy a Smarr-type formula. The phase structure is determined in the canonical ensemble, and it is shown that there is a first order phase transition from small to large black strings, which disappears above a certain critical magnetic charge that is obtained numerically. For another particular value of the magnetic charge, that corresponds to a twisting of the dual super Yang-Mills theory, the conformal anomalies coming from the background curvature and those arising from the coupling to external gauge fields exactly cancel. We also obtain supersymmetric solutions describing waves propagating on extremal BPS magnetic black strings, and show that they possess a Siklos-Virasoro reparametrization invariance.Comment: 40 pages, 7 figures, JHEP3. v2: minor corrections, 2 references added. v3: typos in holographic stress tensor corrected, 3 references adde

Do a Few Weeks Matter? Late Preterm Infants and Breastfeeding Issues

The late preterm infant population is increasing globally. Many studies show that late preterm infants are at risk of experiencing challenges common to premature babies, with breastfeeding issues being one of the most common. In this study, we investigated factors and variables that could interfere with breastfeeding initiation and duration in this population. We conducted a prospective observational study, in which we administered questionnaires on breastfeeding variables and habits to mothers of late preterm infants who were delivered in the well-baby nursery of our hospital and followed up for three months after delivery. We enrolled 149 mothers and 189 neonates, including 40 pairs of twins. Our findings showed that late preterm infants had a low rate of breastfeeding initiation and early breastfeeding discontinuation at 15, 40 and 90 days of life. The mothers with higher educational levels and previous positive breastfeeding experience had a longer breastfeeding duration. The negative factors for breastfeeding were the following: Advanced maternal age, Italian ethnicity, the feeling of reduced milk supply and having twins. This study underlines the importance of considering these variables in the promotion and protection of breastfeeding in this vulnerable population, thus offering mothers tailored support

Predicting adaptation for uncertain systems with robust real plots

In systems biology, perfect adaptation (adaptation) denotes the property of a system reacting to a step input stimulus by completely (partially) restoring the pre-stimulus output value at steady state. We address the problem of predicting adaptation for uncertain dynamical systems. To this aim, we introduce a formal definition of adaptation tailored to the robust analysis of dynamical systems. Whilst the definition is more general and valid also for the step response analysis of nonlinear systems, in the linear case such a definition of adaptation reduces to the presence of a single real zero that dominates all poles. Based on this definition, we can assess robust adaptation by means of the robust real plot, which characterises the position of real zeros and poles for linear systems with parametric uncertainties

Mathematical modelling of SigE regulatory network reveals new insights into bistability of mycobacterial stress response

Background: The ability to rapidly adapt to adverse environmental conditions represents the key of success of many pathogens and, in particular, of Mycobacterium tuberculosis. Upon exposition to heat shock, antibiotics or other sources of stress, appropriate responses in terms of genes transcription and proteins activity are activated leading part of a genetically identical bacterial population to express a different phenotype, namely to develop persistence. When the stress response network is mathematically described by an ordinary differential equations model, development of persistence in the bacterial population is associated with bistability of the model, since different emerging phenotypes are represented by different stable steady states. Results: In this work, we develop a mathematical model of SigE stress response network that incorporates interactions not considered in mathematical models currently available in the literature. We provide, through involved analytical computations, accurate approximations of the system’s nullclines, and exploit the obtained expressions to determine, in a reliable though computationally efficient way, the number of equilibrium points of the system. Conclusions: Theoretical analysis and perturbation experiments point out the crucial role played by the degradation pathway involving RseA, the anti-sigma factor of SigE, for coexistence of two stable equilibria and the emergence of bistability. Our results also indicate that a fine control on RseA concentration is a necessary requirement in order for the system to exhibit bistability

Plasmatic and chamber-specific modulation of cardiac microRNAs in an acute model of DOX-induced cardiotoxicity.

Doxorubicin (DOX) is a chemotherapeutic drug limited in its usefulness by an adverse side effect, cardiotoxicity. The mechanisms leading to this detrimental occurrence are not completely clear, and lately many authors focused their attention on the possible role of microRNAs (miRNAs), small regulators of cardiovascular functions, in this phenomenon. Notably, these molecules recently emerged also as potential circulating biomarkers of several cardiac diseases. Thus, the aim of this study was the simultaneous investigation of circulating and cardiac tissue miRNAs expression upon DOX treatment in vivo. Twenty C57BL/6 female mice were administered with 24 mg/Kg cumulative dose of DOX or saline (CTRL) for 2 weeks. Echocardiography was performed at baseline and at the end of treatment (T1). Plasma and heart samples were collected at T1, separating atria from left (LV) and right (RV) ventricles, and miRNAs expression was tested by RT-qPCR-based arrays. All putatively DOX-regulated candidates were then validated by single assays in vivo and then evaluated also in murine immortalized cardiomyocytes (HL-1) treated with 1 μM DOX for 24 h. In the end, bioinformatics target prediction was performed for all DOX-miRNAs. Cardiotoxicity onset was diagnosed upon impairment of six cardiac functional parameters in DOX-treated mice at T1. Samples collection, followed by screening and validation steps, identified eleven miRNAs dysregulated by the drug in plasma, while seven resulted as altered in separate heart chambers. Interestingly, miR-34a-5p and miR-451a showed a dysregulation in both plasma and tissue samples of DOX-administered animals, whereas five additional miRNAs presented chamber specific modulation. Of note, in vitro experiments showed a very modest overlap with in vivo results. Bioinformatics prediction analysis performed on miR-34a-5p and miR-451a identified several putative targets presenting no significant association with cardiotoxicity. Anyhow, the same analyses, conducted by combining all miRNAs regulated by DOX in each heart chamber, evidenced a possible dysregulation of the adherens junctions gene network, known to be involved in the onset and progression of dilated cardiomyopathy, an established detrimental side effect of the drug. This is the first work investigating miRNAs regulation by DOX both in plasma and heart districts of treated animals. Our results indicate a strong association of miR-34a-5p and miR-451a to DOX-induced cardiotoxicity. In addition, the observed altered expression of diverse miRNAs in separated cardiac chambers hints at a specific response to the drug, implying the existence of different players and pathways leading to dysfunction onset