Polarizability Plays a Decisive Role in Modulating Association Between Molecular Cations and Anions

Electrostatic interactions involving proteins depend not just on the ionic charges involved but also on their chemical identities. Here we examine the origins of incompletely understood differences in the strength of association of different pairs of monovalent molecular ions that are relevant to protein-protein and protein-ligand interactions. Cationic analogues of the basic amino acid side chains are simulated along with oxyanionic analogues of cation-exchange (CEX) ligands and acidic amino acids. Experimentally observed association trends with respect to the cations, but not anions, are captured by a non-polarizable model. A polarizable model proves decisive in capturing experimentally-suggested trends with respect to both cations and anions. Crucially, relative to a non-polarizable model, polarizability changes the free energy surface for ion-pair association, altering configurational sampling itself. An effective continuum correction to account for electronic polarizability can also capture the experimentally-suggested trends, but at the expense of fidelity to the underlying free energy surface

Modeling and Analysis of the Intrinsic Cardiac Nervous System in Closed-Loop Cardiovascular Control

The baroreceptor reflex is a multi-input, multi-output physiological control system that regulates short-term blood pressure by modulating nerve activity between the brainstem and the heart. The computational model by Park et al. (2020) is the most recent iteration in our exploration of the system. However, the contributions of”the little brain of the heart”, the intrinsic cardiac nervous system (ICN), to local control of the heart and to the integration of sensory information is unknown and has been overlooked in previous models. We have incorporated a high-fidelity representation of the ICN into a model of the baroreceptor reflex based on anatomical, molecular, and physiological evidence. The model consists of (1) differential equations to represent the cardiovascular system, and (2) transfer functions to represent neural control components, connected in a closed-loop control circuit. We use the model to evaluate the impact of alternative ICN network structures on overall cardiovascular control in response to mean arterial pressure and lung tidal volume perturbations. Our results show that the local circuit neurons that integrate sensory information into the ICN strengthen the response of ICN neuron activity, especially at low blood pressures, suggesting that the ICN amplifies the brainstem\u27s response to perturbations

Closed-Loop Modeling of Central and Intrinsic Cardiac Nervous System Circuits Underlying Cardiovascular Control

The baroreflex is a multi-input, multi-output physiological control system that regulates blood pressure by modulating nerve activity between the brainstem and the heart. Existing computational models of the baroreflex do not explicitly incorporate the intrinsic cardiac nervous system (ICN), which mediates central control of heart function. We developed a computational model of closed-loop cardiovascular control by integrating a network representation of the ICN within central control reflex circuits. We examined central and local contributions to the control of heart rate, ventricular functions, and respiratory sinus arrhythmia (RSA). Our simulations match the experimentally observed relationship between RSA and lung tidal volume. Our simulations predicted the relative contributions of the sensory and the motor neuron pathways to the experimentally observed changes in the heart rate. Our closed-loop cardiovascular control model is primed for evaluating bioelectronic interventions to treat heart failure and renormalize cardiovascular physiology

Generation of Covalently Closed Circular DNA of Hepatitis B Viruses via Intracellular Recycling Is Regulated in a Virus Specific Manner

Persistence of hepatitis B virus (HBV) infection requires covalently closed circular (ccc)DNA formation and amplification, which can occur via intracellular recycling of the viral polymerase-linked relaxed circular (rc) DNA genomes present in virions. Here we reveal a fundamental difference between HBV and the related duck hepatitis B virus (DHBV) in the recycling mechanism. Direct comparison of HBV and DHBV cccDNA amplification in cross-species transfection experiments showed that, in the same human cell background, DHBV but not HBV rcDNA converts efficiently into cccDNA. By characterizing the distinct forms of HBV and DHBV rcDNA accumulating in the cells we find that nuclear import, complete versus partial release from the capsid and complete versus partial removal of the covalently bound polymerase contribute to limiting HBV cccDNA formation; particularly, we identify genome region-selectively opened nuclear capsids as a putative novel HBV uncoating intermediate. However, the presence in the nucleus of around 40% of completely uncoated rcDNA that lacks most if not all of the covalently bound protein strongly suggests a major block further downstream that operates in the HBV but not DHBV recycling pathway. In summary, our results uncover an unexpected contribution of the virus to cccDNA formation that might help to better understand the persistence of HBV infection. Moreover, efficient DHBV cccDNA formation in human hepatoma cells should greatly facilitate experimental identification, and possibly inhibition, of the human cell factors involved in the process