59 research outputs found
Exploring families of energy-dissipation landscapes via tilting -- Three types of EDP convergence
This paper revolves around a subtle distinction between two concepts: passing to the limit in a family of gradient systems, on one hand, and deriving effective kinetic relations on the other. The two concepts are strongly related, and in many examples they even appear to be the same. Our main contributions are to show that they are different, to show that well-known techniques developed for the former may give incorrect results for the latter, and to introduce new tools to remedy this. The approach is based on the Energy-Dissipation Principle that provides a variational formulation to gradient-flow equations that allows one to apply techniques from Γ-convergence of functional on states and functionals on trajectories
A framework of nonequilibrium statistical mechanics. II. Coarse-graining
For a given thermodynamic system, and a given choice of coarse-grained state
variables, the knowledge of a force-flux constitutive law is the basis for any
nonequilibrium modeling. In the first paper of this series we established how,
by a generalization of the classical fluctuation-dissipation theorem (FDT), the
structure of a constitutive law is directly related to the distribution of the
fluctuations of the state variables. When these fluctuations can be expressed
in terms of diffusion processes, one may use Green-Kubo-type coarse-graining
schemes to find the constitutive laws. In this paper we propose a
coarse-graining method that is valid when the fluctuations are described by
means of general Markov processes, which include diffusions as a special case.
We prove the success of the method by numerically computing the constitutive
law for a simple chemical reaction . Furthermore, we show
that one cannot find a consistent constitutive law by any Green-Kubo-like
scheme.Comment: This paper and its precursor (I) replace the previous paper
arXiv:1809.07253. Now the content and the presentation style are more
targeted to physicists, with particular emphasis on the applications to
specific physical systems. The theoretical and the practical aspects have
been separated from each other in the two paper
A framework of nonequilibrium statistical mechanics. I. Role and type of fluctuations
Understanding the fluctuations by which phenomenological evolution equations
with thermodynamic structure can be enhanced is the key to a general framework
of nonequilibrium statistical mechanics. These fluctuations provide an
idealized representation of microscopic details. We consider
fluctuation-enhanced equations associated with Markov processes and elaborate
the general recipes for evaluating dynamic material properties, which
characterize force-flux constitutive laws, by statistical mechanics. Markov
processes with continuous trajectories are conveniently characterized by
stochastic differential equations and lead to Green-Kubo-type formulas for
dynamic material properties. Markov processes with discontinuous jumps include
transitions over energy barriers with the rates calculated by Kramers. We
describe a unified approach to Markovian fluctuations and demonstrate how the
appropriate type of fluctuations (continuous versus discontinuous) is reflected
in the mathematical structure of the phenomenological equations.Comment: This paper and its continuation (II) replace the previous paper
arXiv:1809.07253. Now the content and the presentation style are more
targeted to physicists, with particular emphasis on the applications to
specific physical systems. The theoretical and the practical aspects have
been separated from each other in the two paper
Partial mean-field model for neurotransmission dynamics
This article addresses reaction networks in which spatial and stochastic
effects are of crucial importance. For such systems, particle-based models
allow us to describe all microscopic details with high accuracy. However, they
suffer from computational inefficiency if particle numbers and density get too
large. Alternative coarse-grained-resolution models reduce computational effort
tremendously, e.g., by replacing the particle distribution by a continuous
concentration field governed by reaction-diffusion PDEs. We demonstrate how
models on the different resolution levels can be combined into hybrid models
that seamlessly combine the best of both worlds, describing molecular species
with large copy numbers by macroscopic equations with spatial resolution while
keeping the stochastic-spatial particle-based resolution level for the species
with low copy numbers. To this end, we introduce a simple particle-based model
for the binding dynamics of ions and vesicles at the heart of the
neurotransmission process. Within this framework, we derive a novel hybrid
model and present results from numerical experiments which demonstrate that the
hybrid model allows for an accurate approximation of the full particle-based
model in realistic scenarios.Comment: 16 pages + 2 pages appendix, 5 figures. Submitted to Mathematical
Bioscience
Acute Relaxation Response Induced by Tibetan Singing Bowl Sounds : A Randomized Controlled Trial
UDBELLATERRAThe prevalence of anxiety has increased dramatically due to COVID-19, so effective preventive interventions are welcome. The main objective of our study was to compare the acute relaxation response (RR) induced by Tibetan singing bowl (TSB) sound-based treatment against progressive muscle relaxation (PMR) and a control waiting list group (CWL) in a single treatment session in an adult nonclinical anxious population. In this cross-sectional randomized control trial, 50 participants selected based on high state anxiety were randomly assigned to one of the experimental groups. Pre/post self-reported anxiety, electroencephalographic activity (EEG), and heart rate variability (HRV) were recorded at baseline (T1), minute 15 (T2), minute 30 (T3), and minute 45 (T4). The TSB group showed significant reductions in alpha power (from T2 to T4) and increased HRV (from T3 to T4) compared with the PMR and CWL groups. Moreover, TSB and PMR both showed significant reductions in self-reported anxiety compared with CWL, with this effect being more evident in the TSB group. We concluded that a single session of TSB treatment was able to induce a more evident psychological/physiological relaxation response compared with PMR and CWL. TSB could be a relevant acute intervention in stressful situations or crisis intervention and while waiting for conventional interventions
Bortezomib Plus Dexamethasone Followed by Escalating Donor Lymphocyte Infusions for Patients with Multiple Myeloma Relapsing or Progressing after Allogeneic Stem Cell Transplantation
Abstract Multiple myeloma relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLIs) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of three VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled with a median age of 57 years (range, 33 to 67); 14 patients were allografted from human leukocyte antigen–identical siblings and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, but 3 patients did not: 2 patients because of disease progression and 1 refused. After the VD phase the response rate was 62%, with 1 complete remission, 6 very good partial remissions, 5 partial remissions, 2 patients with stable disease, and 5 with progressive disease. After the DLI phase, the response rate was 68%, but a significant upgrade of response was observed: 3 stringent complete remissions, 2 complete remissions, 5 very good partial remissions, 1 partial remission, 4 with stable disease, and 1 with progressive disease. With a median follow-up of 40 months (range, 29 to 68), the 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute graft-versus-host disease flares were observed. VD-DLIs is a safe treatment for multiple myeloma patients relapsing or progressing after alloSCT and may be effective
Identification of p38 MAPK and JNK as New Targets for Correction of Wilson Disease-Causing ATP7B Mutants
Wilson disease (WD) is an autosomal recessive disorder that is caused by the toxic accumulation of copper (Cu) in the liver. The ATP7B gene, which is mutated in WD, encodes a multitransmembrane domain adenosine triphosphatase that traffics from the trans-Golgi network to the canalicular area of hepatocytes, where it facilitates excretion of excess Cu into the bile. Several ATP7B mutations, including H1069Q and R778L that are two of the most frequent variants, result in protein products, which, although still functional, remain in the endoplasmic reticulum. Thus, they fail to reach Cu excretion sites, resulting in the toxic buildup of Cu in the liver of WD patients. Therefore, correcting the location of these mutants by leading them to the appropriate functional sites in the cell should restore Cu excretion and would be beneficial to help large cohorts of WD patients. However, molecular targets for correction of endoplasmic reticulum-retained ATP7B mutants remain elusive. Here, we show that expression of the most frequent ATP7B mutant, H1069Q, activates p38 and c-Jun N-terminal kinase signaling pathways, which favor the rapid degradation of the mutant. Suppression of these pathways with RNA interference or specific chemical inhibitors results in the substantial rescue of ATP7B(H1069Q) (as well as that of several other WD-causing mutants) from the endoplasmic reticulum to the trans-Golgi network compartment, in recovery of its Cu-dependent trafficking, and in reduction of intracellular Cu levels. Conclusion: Our findings indicate p38 and c-Jun N-terminal kinase as intriguing targets for correction of WD-causing mutants and, hence, as potential candidates, which could be evaluated for the development of novel therapeutic strategies to combat WD
Daily risk of adverse outcomes in patients undergoing complex lesions revascularization: a subgroup analysis from the RAIN-CARDIOGROUP VII study (veRy thin stents for patients with left mAIn or bifurcatioN in real life)
Introduction: Percutaneous coronary intervention (PCI) for complex lesions, including unprotected left main (ULM) and bifurcations, is gaining a relevant role in treating coronary artery disease with good outcomes, also thanks to new generation stents. The daily risk of adverse cardiovascular events and their temporal distribution after these procedures is not known.Methods: All consecutive patients presenting with a critical lesion of ULM or bifurcation treated with very thin struts stents, enrolled in the RAIN-Cardiogroup VII study, were analyzed. The daily risk of major acute cardiovascular events (MACE), target lesion revascularization (TLR) and stent thrombosis (ST) and their temporal distribution in the first year of follow-up was the primary endpoint. Differences among subgroups (ULM, patient presentation, kind of stent polymer) were the secondary endpoint.Results: 2745 patients were included, mean age 68 ± 11 years, 33.3% diabetics, 54.5% had an acute coronary syndrome (ACS); 88.5% of treated lesions were bifurcations, 27.2% ULM. Average daily risk was 0.022% for MACE, 0.005% for TLR and 0.004% for ST, in the first year. Bimodal distribution of adverse events, especially TLR, with an early peak in the first 50 days and a late one after 150 days, was observed. Patients with ULM presented a significantly higher daily risk of events, and ACS patients presented higher MACE risk. No difference emerged according to the type of stent polymer.Conclusions: The daily risk of adverse events in the first year after complex PCI in our study is acceptably low. PCI on ULM carries a higher risk of complications
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