First passage times as a measure of hysteresis in stochastic gene regulatory circuits

GAIN Oportunius Grant from Xunta de Galicia.[Abstract]: In the context of phenotype switching and cell fate determination, numerousexperimental studies report hysteresis, despite the fact that the (forward) Chemical Master Equation governing the inherently stochastic underlying gene regulatory networks has a unique steady state (precluding memory effects and hysteresis). In previous works, we demonstrate thathysteresis is a transient phenomenon in systems far from the thermodynamic limit, using the convergence rates of the partial integro-differential equation associated to the forward master equation governing the stochastic process. Here, we make use of the backward master equationto quantify hysteresis and irreversibility based on First Passage Times. First, we derive the backward master equation for a gene regulatory network with protein production in bursts. Solving this equation, we obtain the probability distributions of the first times to reach some fixed final state from one starting state. The mean first passage time provides a measure to quantify how hysteresis and irreversibility in gene regulation at the singlecell level are transient effects that vanish at steady state. In addition, we provide a theoretical basis that reconciles phenotype coexistence and prevalence far from the thermodynamic limit. In fact, we substitute the notion of pseudo-potential (the so-called Waddington landscape) by a time evolving landscape built upon the Chemical Master Equation (CME) in which phenotypes,rather than prevail, persist with different intensities.Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación; FJC2019-041397-

Anti-biofilm multi drug-loaded 3D printed hearing aids

Over 5% of the world's population has disabling hearing loss, which affects approximately one third of individuals over 65 years. Hearing aids are commonly used in this population group, but prolonged use of these devices may cause ear infections. We describe for the first time, the use of 3D printing to fabricate hearing aids loaded with two antibiotics, ciprofloxacin and fluocinolone acetonide. Digital light processing 3D printing was employed to manufacture hearing aids from two polymer resins, ENG hard and Flexible. The inclusion of the antibiotics did not affect the mechanical properties of the hearing aids. All multi-drug-loaded devices exhibited a hydrophilic surface, excellent blood compatibility and anti-biofilm activity against P. aeruginosa and S. aureus. Hearing aids loaded with ciprofloxacin (6% w/w) and fluocinolone acetonide (0.5% w/w) sustained drug release for more than two weeks and inhibited biofilm formation on the surface of the devices and bacteria growth in the surrounding medium. In summary, this work highlights the potential of vat photopolymerization 3D printing as a versatile manufacturing approach to fabricate high-fidelity patient-specific medical devices with anti-bacterial properties

A systematic approach to plant-wide control based on thermodynamics

Abstract In this work, a systematic approach to plant-wide control design is proposed. The method combines ingredients from process networks, thermodynamics and systems theory to derive robust decentralized controllers that will ensure complete plant stability. As a first step, the considered process system is decomposed into abstract mass and energy inventory networks. In this framework, conceptual inventory control loops are then designed for the mass and energy layers to guarantee that the states of the plant, both in terms of extensive and intensive properties, will converge to a compact convex region defined by constant inventories. This result by itself does not ensure the convergence of intensive variables to a desired operation point as complex dynamic phenomena such as multiplicities may appear in the invariant set. In order to avoid these phenomena, thermodynamics naturally provides the designer, in these convex regions, with a legitimate storage or Lyapunov function candidate, the entropy, that can be employed to ensure global stability. Based on this, the control structure design procedure is completed with the realization of the conceptual inventory and intensive variable control loops over the available degrees of freedom in the system. To that purpose, both PI and feedback linearization control are employed. The different aspects of the proposed methodology will be illustrated on a non-isothermal chemical reaction network

EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369