Langevin Trajectories between Fixed Concentrations

We consider the trajectories of particles diffusing between two infinite baths of fixed concentrations connected by a channel, e.g. a protein channel of a biological membrane. The steady state influx and efflux of Langevin trajectories at the boundaries of a finite volume containing the channel and parts of the two baths is replicated by termination of outgoing trajectories and injection according to a residual phase space density. We present a simulation scheme that maintains averaged fixed concentrations without creating spurious boundary layers, consistent with the assumed physics

Ions in Fluctuating Channels: Transistors Alive

Ion channels are proteins with a hole down the middle embedded in cell membranes. Membranes form insulating structures and the channels through them allow and control the movement of charged particles, spherical ions, mostly Na+, K+, Ca++, and Cl-. Membranes contain hundreds or thousands of types of channels, fluctuating between open conducting, and closed insulating states. Channels control an enormous range of biological function by opening and closing in response to specific stimuli using mechanisms that are not yet understood in physical language. Open channels conduct current of charged particles following laws of Brownian movement of charged spheres rather like the laws of electrodiffusion of quasi-particles in semiconductors. Open channels select between similar ions using a combination of electrostatic and 'crowded charge' (Lennard-Jones) forces. The specific location of atoms and the exact atomic structure of the channel protein seems much less important than certain properties of the structure, namely the volume accessible to ions and the effective density of fixed and polarization charge. There is no sign of other chemical effects like delocalization of electron orbitals between ions and the channel protein. Channels play a role in biology as important as transistors in computers, and they use rather similar physics to perform part of that role. Understanding their fluctuations awaits physical insight into the source of the variance and mathematical analysis of the coupling of the fluctuations to the other components and forces of the system.Comment: Revised version of earlier submission, as invited, refereed, and published by journa

Software for interpreting cardiopulmonary exercise tests

<p>Abstract</p> <p>Background</p> <p>Cardiopulmonary exercise testing (CPET) has become an important modality for the evaluation and management of patients with a diverse array of medical problems. However, interpreting these tests is often difficult and time consuming, requiring significant expertise.</p> <p>Methods</p> <p>We created a computer software program (XINT) that assists in CPET interpretation. The program uses an integrative approach as recommended in the Official Statement of the American Thoracic Society/American College of Chest Physicians (ATS/ACCP) on Cardiopulmonary Exercise Testing. In this paper we discuss the principles behind the software. We also provide the detailed logic in an accompanying file (Additional File <supplr sid="S1">1</supplr>). The actual program and the open source code are also available free over the Internet at <url>http://www.xint.org</url>. For convenience, the required download files can also be accessed from this article.</p> <suppl id="S1"> <title> <p>Additional file 1</p> </title> <text> <p>XINTlogic. This file provides the detailed logic used by the XINT program. The variable names are described in Table <tblr tid="T1">1</tblr>. The actual source code may also be read directly simply by opening the source code with a text editor.</p> </text> <file name="1471-2466-7-15-S1.doc"> <p>Click here for file</p> </file> </suppl> <p>Results</p> <p>To test the clinical usefulness of XINT, we present the computer generated interpretations of the case studies discussed in the ATS/ACCP document in another accompanying file (Additional File <supplr sid="S2">2</supplr>). We believe the interpretations are consistent with the document's criteria and the interpretations given by the expert panel.</p> <suppl id="S2"> <title> <p>Additional file 2</p> </title> <text> <p>XINTinterpretations. These are the XINT generated reports based on the five examples provided in the ATS/ACCP statement on cardiopulmonary exercise testing <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>.</p> </text> <file name="1471-2466-7-15-S2.doc"> <p>Click here for file</p> </file> </suppl> <p>Conclusion</p> <p>Computers have become an integral part of modern life. Peer-reviewed scientific journals are now able to present not just medical concepts and experimental studies, but actual functioning medical interpretive software. This has enormous potential to improve medical diagnoses and patient care. We believe XINT is such a program that will give clinically useful interpretations when used by the medical community at large.</p

Galois covers of the open p-adic disc

This paper investigates Galois branched covers of the open $p$-adic disc and their reductions to characteristic $p$. Using the field of norms functor of Fontaine and Wintenberger, we show that the special fiber of a Galois cover is determined by arithmetic and geometric properties of the generic fiber and its characteristic zero specializations. As applications, we derive a criterion for good reduction in the abelian case, and give an arithmetic reformulation of the local Oort Conjecture concerning the liftability of cyclic covers of germs of curves.Comment: 19 pages; substantial organizational and expository changes; this is the final version corresponding to the official publication in Manuscripta Mathematica; abstract update

Roving vehicle motion control Quarterly report, 1 Mar. - 31 May 1967

System and subsystem requirements for remote control of roving space vehicle motio

A Quantum-mechanical description of ion motion within the confining potentials of voltage gated ion channels

Voltage gated channel proteins cooperate in the transmission of membrane potentials between nerve cells. With the recent progress in atomic-scaled biological chemistry it has now become established that these channel proteins provide highly correlated atomic environments that may maintain electronic coherences even at warm temperatures. Here we demonstrate solutions of the Schr\"{o}dinger equation that represent the interaction of a single potassium ion within the surrounding carbonyl dipoles in the Berneche-Roux model of the bacterial \textit{KcsA} model channel. We show that, depending on the surrounding carbonyl derived potentials, alkali ions can become highly delocalized in the filter region of proteins at warm temperatures. We provide estimations about the temporal evolution of the kinetic energy of ions depending on their interaction with other ions, their location within the oxygen cage of the proteins filter region and depending on different oscillation frequencies of the surrounding carbonyl groups. Our results provide the first evidence that quantum mechanical properties are needed to explain a fundamental biological property such as ion-selectivity in trans-membrane ion-currents and the effect on gating kinetics and shaping of classical conductances in electrically excitable cells.Comment: 12 pages, 8 figure

Roving vehicle motion control Final report

Roving vehicle motion control for unmanned planetary and lunar exploratio

A kinetic study of cation transport in erythrocytes from uremic patients

A kinetic study of cation transport from uremic patients. We previously described in red blood cells (RBCs) from uremic patients on dialysis a reduction in sodium (Na) efflux through the Na, potassium (K) cotransport system (Na,K CoT) while Na efflux through the Na,K pump was normal. We then examined Na efflux in fresh cells and in cells loaded to obtain one level of intracellular sodium (Nai) concentration at about 25 mmol/liter cell. In the present study we used similar cation flux methodology to examine the kinetics of cation efflux through the Na,K pump and Na,K CoT in uremic patients on dialysis. RBCs were Na-loaded to attain five different levels of Nat concentration over a range of 5 to 50 mmol/liter cells using the ionophore nystatin. At each level of Na-loading, the Nai achieved was similar in RBCs from controls and patients. Ouabain–sensitive Na efflux through the Na,K pump showed no difference in rate between normals and dialysis patients. When the kinetic parameters of this transport pathway were considered, the apparent affinity (K0.5) for sodium was not significantly different between controls and patients (18.4 ± 2.3 vs. 20.0 ± 2.6 mmol/liter cell) and the maximal velocity of efflux (Vmax) was also not different between controls and patients (9.6 ± 0.7 vs. 8.5 ± 1.2 mmol&sol;liter cell&sol;hr). Comparison of Nai-activated Na versus K efflux rates through the Na,K CoT in normal subjects demonstrated similar saturation kinetics, (K0.5 15.8 ± 3.3 vs. 12.2 ± 2.8 mmol/liter cell, Vmax0.81 ± 0.1 vs. 0.78 ± 0.1 mmol/liter cell/hr) consistent with the known stoichiometric ratio of 1 Na:l K:2 C1 described for this mechanism. In dialysis patients Nai-activated, Na,K CoT-mediated Na efflux was markedly reduced. Analysis of the kinetic parameters of Na1-activated Na efflux showed that the reduced RBC Na,K CoT is due to reduction in Vmax and not to a change in K0.5 Maximum furosemide–sensitive K efflux rate was also reduced in dialysis patients. However, instead of exhibiting the anticipated saturation kinetics observed for Na, the K efflux rates were high at low levels of Nai and remained unchanged with increasing Nai concentrations. Ouabain- and furosemide-resistant Na and K effluxes were not significantly different between normals and dialysis patients. We conclude that Na efflux through RBC Na,K pump is intact over a wide range of Nai concentrations in dialysis patients. On the other hand, the furosemide–sensitive co-efflux of Na and K, which in normal RBCs displayed a typical 1 Na to 1 K transport characteristic, was quantitatively and qualitatively altered in dialysis patients. The maximum efflux rate of both Na and K was reduced and in addition, the usual stoichiometric ratio for Na and K exit through this furosemide–sensitive pathway was no longer observed

Alveolar macrophages in lung cancer: opportunities challenges

Alveolar macrophages (AMs) are critical components of the innate defense mechanism in the lung. Nestled tightly within the alveoli, AMs, derived from the yolk-sac or bone marrow, can phagocytose foreign particles, defend the host against pathogens, recycle surfactant, and promptly respond to inhaled noxious stimuli. The behavior of AMs is tightly dependent on the environmental cues whereby infection, chronic inflammation, and associated metabolic changes can repolarize their effector functions in the lungs. Several factors within the tumor microenvironment can re-educate AMs, resulting in tumor growth, and reducing immune checkpoint inhibitors (ICIs) efficacy in patients treated for non-small cell lung cancer (NSCLC). The plasticity of AMs and their critical function in altering tumor responses to ICIs make them a desirable target in lung cancer treatment. New strategies have been developed to target AMs in solid tumors reprograming their suppressive function and boosting the efficacy of ICIs. Here, we review the phenotypic and functional changes in AMs in response to sterile inflammation and in NSCLC that could be critical in tumor growth and metastasis. Opportunities in altering AMs’ function include harnessing their potential function in trained immunity, a concept borrowed from memory response to infections, which could be explored therapeutically in managing lung cancer treatment