Intertwinings for Continuum Particle Systems: An Algebraic Approach

We develop the algebraic approach to duality, more precisely to intertwinings, within the context of particle systems in general spaces, focusing on the $su(1,1)$ current algebra. We introduce raising, lowering, and neutral operators indexed by test functions and we use them to construct unitary operators, which act as self-intertwiners for some Markov processes having the Pascal process's law as a reversible measure. We show that such unitaries relate to generalized Meixner polynomials. Our primary results are continuum counterparts of results in the discrete setting obtained by Carinci, Franceschini, Giardin\`a, Groenevelt, and Redig (2019).Comment: 19 page

Hydrodynamics for the partial exclusion process in random environment

In this paper, we introduce a random environment for the exclusion process in $\Z^d$ obtained by assigning a maximal occupancy to each site. This maximal occupancy is allowed to randomly vary among sites, and partial exclusion occurs. Under the assumption of ergodicity under translation and uniform ellipticity of the environment, we derive a quenched hydrodynamic limit in path space by strengthening the mild solution approach initiated in \cite{nagy_symmetric_2002} and \cite{faggionato_bulk_2007}. To this purpose, we prove, employing the technology developed for the random conductance model, a homogenization result in the form of an arbitrary starting point quenched invariance principle for a single particle in the same environment, which is a result of independent interest. The self-duality property of the partial exclusion process allows us to transfer this homogenization result to the particle system and, then, apply the tightness criterion in \cite{redig_symmetric_2018}

Switching Interacting Particle Systems: Scaling Limits, Uphill Diffusion and Boundary Layer

This paper considers three classes of interacting particle systems on Z: independent random walks, the exclusion process, and the inclusion process. Particles are allowed to switch their jump rate (the rate identifies the type of particle) between 1 (fast particles) and ϵ∈ [0 , 1] (slow particles). The switch between the two jump rates happens at rate γ∈ (0 , ∞). In the exclusion process, the interaction is such that each site can be occupied by at most one particle of each type. In the inclusion process, the interaction takes places between particles of the same type at different sites and between particles of different type at the same site. We derive the macroscopic limit equations for the three systems, obtained after scaling space by N- 1, time by N2, the switching rate by N- 2, and letting N→ ∞. The limit equations for the macroscopic densities associated to the fast and slow particles is the well-studied double diffusivity model. This system of reaction-diffusion equations was introduced to model polycrystal diffusion and dislocation pipe diffusion, with the goal to overcome the limitations imposed by Fick’s law. In order to investigate the microscopic out-of-equilibrium properties, we analyse the system on [N] = { 1 , … , N} , adding boundary reservoirs at sites 1 and N of fast and slow particles, respectively. Inside [N] particles move as before, but now particles are injected and absorbed at sites 1 and N with prescribed rates that depend on the particle type. We compute the steady-state density profile and the steady-state current. It turns out that uphill diffusion is possible, i.e., the total flow can be in the direction of increasing total density. This phenomenon, which cannot occur in a single-type particle system, is a violation of Fick’s law made possible by the switching between types. We rescale the microscopic steady-state density profile and steady-state current and obtain the steady-state solution of a boundary-value problem for the double diffusivity model

Leukemia inhibitory factor protects cholangiocarcinoma cells from drug-induced apoptosis via a PI3K/AKT-dependent Mcl-1 activation

Cholangiocarcinoma is an aggressive, strongly chemoresistant liver malignancy. Leukemia inhibitory factor (LIF), an IL-6 family cytokine, promotes progression of various carcinomas. To investigate the role of LIF in cholangiocarcinoma, we evaluated the expression of LIF and its receptor (LIFR) in human samples. LIF secretion and LIFR expression were assessed in established and primary human cholangiocarcinoma cell lines. In cholangiocarcinoma cells, we tested LIF effects on proliferation, invasion, stem cell-like phenotype, chemotherapy-induced apoptosis (gemcitabine+cisplatin), expression levels of pro-apoptotic (Bax) and anti-apoptotic (Mcl-1) proteins, with/without PI3K inhibition, and of pSTAT3, pERK1/2, pAKT. LIF effect on chemotherapy-induced apoptosis was evaluated after LIFR silencing and Mcl-1 inactivation. Results show that LIF and LIFR expression were higher in neoplastic than in control cholangiocytes; LIF was also expressed by tumor stromal cells. LIF had no effects on cholangiocarcinoma cell proliferation, invasion, and stemness signatures, whilst it counteracted drug-induced apoptosis. Upon LIF stimulation, decreased apoptosis was associated with Mcl-1 and pAKT up-regulation and abolished by PI3K inhibition. LIFR silencing and Mcl-1 blockade restored drug-induced apoptosis. In conclusion, autocrine and paracrine LIF signaling promote chemoresistance in cholangiocarcinoma by up-regulating Mcl-1 via a novel STAT3- and MAPK-independent, PI3K/AKT-dependent pathway. Targeting LIF signaling may increase CCA responsiveness to chemotherapy

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes

Orthogonal polynomial duality of boundary driven particle systems and non-equilibrium correlations

We consider symmetric partial exclusion and inclusion processes in a general graph in contact with reservoirs, where we allow both for edge disorder and well-chosen site disorder. We extend the classical dualities to this context and then we derive new orthogonal polynomial dualities. From the classical dualities, we derive the uniqueness of the non-equilibrium steady state and obtain correlation inequalities. Starting from the orthogonal polynomial dualities, we show universal properties of n-point correlation functions in the non-equilibrium steady state for systems with at most two different reservoir parameters, such as a chain with reservoirs at left and right ends.Nous considérons des processus d’exclusion partielle, et des processus d’inclusion sur un graphe général en contact avec des réservoirs. Nous autorisons la présence de inhomogenéités sur les arrêts ainsi que sur les sommets du graph. Nous généralisons les “dualités classiques” dans ce contexte et nous démontrons des nouvelles dualités orthogonales. À partir des dualités classiques, nous démontrons l’unicité de l’état stationnaire non-équilibre, ainsi que des inégalités de corrélation. À partir des dualités orthogonales nous démontrons des propriétés universelles des fonctions de corrélation à n points dans l’état stationnaire non-équilibre pour des systèmes avec deux paramètres de réservoirs inégaux, comme par exemple une chaîne avec des réservoirs à droite et à gauche

Effects of NMES pulse width and intensity on muscle mechanical output and oxygen extraction in able-bodied and paraplegic individuals

PURPOSE: Neuromuscular Electrical Stimulation (NMES) is commonly used in neuromuscular rehabilitation protocols, and its parameters selection substantially affects the characteristics of muscle activation. Here, we investigated the effects of short pulse width (200s) and higher intensity (short-high) NMES or long pulse width (1000s) and lower intensity (long-low) NMES on muscle mechanical output and fractional oxygen extraction. Muscle contractions were elicited with 100Hz stimulation frequency, and the initial torque output was matched by adjusting stimulation intensity.METHODS: Fourteen able-bodied and six spinal cord-injured (SCI) individuals participated in the study. The NMES protocol (75 isometric contractions, 1-s on-3-s off) targeting the knee extensors was performed with long-low or short-high NMES applied over the midline between anterior superior iliac spine and patella protrusion in two different days. Muscle work was estimated by torque-time integral, contractile properties by rate of torque development and half-relaxation time, and vastus lateralis fractional oxygen extraction was assessed by Near-Infrared Spectroscopy (NIRS).RESULTS: Torque-time integral elicited by the two NMES paradigms was similar throughout the stimulation protocol, with differences ranging between 1.4% (p=0.877; able-bodied, mid-part of the protocol) and 9.9% (p=0.147; SCI, mid-part of the protocol). Contractile properties were also comparable in the two NMES paradigms. However, long-low NMES resulted in higher fractional oxygen extraction in able-bodied (+36%; p=0.006).CONCLUSION: Long-low and short-high NMES recruited quadriceps femoris motor units that demonstrated similar contractile and fatigability properties. However, long-low NMES conceivably resulted in the preferential recruitment of vastus lateralis muscle fibers as detected by NIRS

Development and validation of a scoring system to predict response to obeticholic acid in primary biliary cholangitis

Background & aims: Obeticholic acid (OCA) is the only licensed second-line therapy for primary biliary cholangitis (PBC). With novel therapeutics in advanced development, clinical tools are needed to tailor the treatment algorithm. We aimed to derive and externally validate the OCA response score (ORS) for predicting the response probability of individuals with PBC to OCA. Methods: We used data from the Italian RECAPITULATE (N 441) and the IBER-PBC (N 244) OCA real-world prospective cohorts to derive/validate a score including widely available variables obtained either pre-treatment (ORS), or also after 6 months of treatment (ORS+). Multivariable Cox's regressions with backward selection were applied to obtain parsimonious predictive models. The predicted outcomes were biochemical response according to POISE (ALP/ULN<1.67 with a reduction of at least 15%, and normal bilirubin), or ALP/ULN<1.67, or NORMAL RANGE criteria (NR: normal ALP, ALT and bilirubin) up to 24 months. Results: Depending on the response criteria, ORS included age, pruritus, cirrhosis, ALP/ULN, ALT/ULN, GGT/ULN and bilirubin. ORS+ also included ALP/ULN and bilirubin after 6 months of OCA therapy. Internally validated c-statistics for ORS were of 0.75, 0.78 and 0.72 for POISE, ALP/ULN<1.67 and NR response, which raised to 0.83, 0.88, 0.81 with ORS+, respectively. The respective performances in validation were of 0.70, 0.72 and 0.71 for ORS, and 0.80, 0.84, 0.78 for ORS+. Results were consistent across groups with mild/severe disease. Conclusions: We developed and externally validated a scoring system capable to predict OCA response according to different criteria. This tool will enhance a stratified second-line therapy model to streamline standard care and trial delivery in PBC