You Have the Right to Remain Silent, and It Can and Will Be Used Against You: Addressing Post-Arrest Pre-Miranda Silence

The right to remain silent has long been recognized by the Supreme Court as requiring a high degree of protection. Since Miranda v. Arizona was decided in 1966, procedural safeguards have been put in place to inform individuals of this right upon arrest. Yet, a gray area exists when it comes to the use of an individual\u27s silence post-arrest. It may surprise some that a point in time exists when an individual has not yet been read their Miranda rights post-arrest. Several circuit courts have taken the position that any silence that follows arrest but precedes the reading of Miranda rights can be used against an individual as evidence of their guilt. The unresolved circuit split on the issue of post-arrest pre-Miranda silence continues to pose a threat to one of the most fundamental rights afforded to individuals. Resolution is not out of the Court\u27s reach. By incorporating existing precedent and establishing a bright-line rule which would require formal arrest to immediately trigger Miranda\u27s procedural safeguards, the Court can ensure that the constitutional guarantees which are so deeply rooted in our justice system may continue to prosper

Multiscale computational modeling of the effects of 2’-deoxy-ATP on cardiac muscle calcium handling

2'-Deoxy-ATP (dATP), a naturally occurring near analog of ATP, is a well-documented myosin activator that has been shown to increase contractile force, improve pump function, and enhance lusitropy in the heart. Calcium transients in cardiomyocytes with elevated levels of dATP show faster calcium decay compared with cardiomyocytes with basal levels of dATP, but the mechanisms behind this are unknown. Here, we design and utilize a multiscale computational modeling framework to test the hypothesis that dATP acts on the sarcoendoplasmic reticulum calcium-ATPase (SERCA) pump to accelerate calcium re-uptake into the sarcoplasmic reticulum during cardiac relaxation. Gaussian accelerated molecular dynamics simulations of human cardiac SERCA2A in the E1 apo, ATP-bound and dATP-bound states showed that dATP forms more stable contacts in the nucleotide binding pocket of SERCA and leads to increased closure of cytosolic domains. These structural changes ultimately lead to changes in calcium binding, which we assessed using Brownian dynamics simulations. We found that dATP increases calcium association rate constants to SERCA and that dATP binds to apo SERCA more rapidly than ATP. Using a compartmental ordinary differential equation model of human cardiomyocyte excitation-contraction coupling, we found that these increased association rate constants contributed to the accelerated rates of calcium transient decay observed experimentally. This study provides clear mechanistic evidence of enhancements in cardiac SERCA2A pump function due to interactions with dATP

Multiscale analysis and visualization of biophysical structure and biochemical function with computational microscopy

The evasive source and cause of a disease is oftentimes smaller than you think. Imagine, though, chasing something that you can't actually see. Fortunately for the modern-day biomedical scientist, computational tools harnessing the power of physics using the language of mathematics are able to see the invisible. Computational microscopy is a tool developed to visualize the energetic behavior of biological systems. With progressive advancements in computer graphics and the development of mathematical theories to explain biological behavior, computational microscopy has become a useful tool used by many kinds scientists over the greater half of the last century to understand the energetic underpinnings of a system's behavior. Unlike most "microscopes," it allows us to visualize extremely small entities like atoms, molecules, proteins, and cells. More importantly, it allows us to spatiotemporally transcend scales to understand the dynamics of our systems. Like a biophysically detailed time-lapse, we are able to see through time, to understand chemical "butterfly effects" that transcend the time and space scale at which they operate. In this thesis, the computational microscope is applied to multiple systems to visualize and analyze the physicochemical mechanisms that underlie biological function. Specifically, the thesis is centered on the structure of proteins and subcellular mechanisms driving cardiac function and dysfunction. In the first chapter, we address the concept of multiscale biological simulations, integrating information from atomistic scales toward cellular models of Protein Kinase A. The second chapter demonstrates the ways that atomistic simulations can be applied to the study of the structural interactions in protein-protein complexes vital to the infectious mechanisms of Group-A Streptococcus. In the third chapter, two scales of biological simulation are used in tandem to understand the structure and the kinetic behavior of Protein Kinase A RIalpha. The final chapter incorporates the kinetic understanding of relevant species in a realistic subcellular geometry to investigate signaling mechanisms that underlie calcium activation in healthy and diseased hearts. Particular attention is paid to the way that structural alterations on the atomistic, molecular, and membranous level alter the behavior of biological systems. Holistically, this thesis is centered on the use of computational tools and the development of realistic models that can reproduce experimental findings and predict the behavior of systems, driving the creation of new hypotheses

Multiscale analysis and visualization of biophysical structure and biochemical function with computational microscopy

The evasive source and cause of a disease is oftentimes smaller than you think. Imagine, though, chasing something that you can't actually see. Fortunately for the modern-day biomedical scientist, computational tools harnessing the power of physics using the language of mathematics are able to see the invisible. Computational microscopy is a tool developed to visualize the energetic behavior of biological systems. With progressive advancements in computer graphics and the development of mathematical theories to explain biological behavior, computational microscopy has become a useful tool used by many kinds scientists over the greater half of the last century to understand the energetic underpinnings of a system's behavior. Unlike most "microscopes," it allows us to visualize extremely small entities like atoms, molecules, proteins, and cells. More importantly, it allows us to spatiotemporally transcend scales to understand the dynamics of our systems. Like a biophysically detailed time-lapse, we are able to see through time, to understand chemical "butterfly effects" that transcend the time and space scale at which they operate. In this thesis, the computational microscope is applied to multiple systems to visualize and analyze the physicochemical mechanisms that underlie biological function. Specifically, the thesis is centered on the structure of proteins and subcellular mechanisms driving cardiac function and dysfunction. In the first chapter, we address the concept of multiscale biological simulations, integrating information from atomistic scales toward cellular models of Protein Kinase A. The second chapter demonstrates the ways that atomistic simulations can be applied to the study of the structural interactions in protein-protein complexes vital to the infectious mechanisms of Group-A Streptococcus. In the third chapter, two scales of biological simulation are used in tandem to understand the structure and the kinetic behavior of Protein Kinase A RIalpha. The final chapter incorporates the kinetic understanding of relevant species in a realistic subcellular geometry to investigate signaling mechanisms that underlie calcium activation in healthy and diseased hearts. Particular attention is paid to the way that structural alterations on the atomistic, molecular, and membranous level alter the behavior of biological systems. Holistically, this thesis is centered on the use of computational tools and the development of realistic models that can reproduce experimental findings and predict the behavior of systems, driving the creation of new hypotheses

Testing the protracted lexical restructuring hypothesis: The effects of position and acoustic-phonetic clarity on sensitivity to mispronunciations in children and adults

Although developmental increases in the size of the position effect within a mispronunciation detection task have been interpreted as consistent with a view of the lexical restructuring process as protracted, the position effect itself might not be reliable. The current research examined the effects of position and clarity of acoustic-phonetic information on sensitivity to mispronounced onsets in 5- and 6-year-olds and adults. Both children and adults showed a position effect only when mispronunciations also differed in the amount of relevant acoustic-phonetic information. Adults' sensitivity to mispronounced second-syllable onsets also reflected the availability of acoustic-phonetic information. The implications of these findings are discussed in relation to the lexical restructuring hypothesis. (c) 2006 Elsevier Inc. All rights reserved

You Have the Right to Remain Silent, and It Can and Will Be Used Against You: Addressing Post-Arrest Pre-Miranda Silence

The right to remain silent has long been recognized by the Supreme Court as requiring a high degree of protection. Since Miranda v. Arizona was decided in 1966, procedural safeguards have been put in place to inform individuals of this right upon arrest. Yet, a gray area exists when it comes to the use of an individual\u27s silence post-arrest. It may surprise some that a point in time exists when an individual has not yet been read their Miranda rights post-arrest. Several circuit courts have taken the position that any silence that follows arrest but precedes the reading of Miranda rights can be used against an individual as evidence of their guilt. The unresolved circuit split on the issue of post-arrest pre-Miranda silence continues to pose a threat to one of the most fundamental rights afforded to individuals. Resolution is not out of the Court\u27s reach. By incorporating existing precedent and establishing a bright-line rule which would require formal arrest to immediately trigger Miranda\u27s procedural safeguards, the Court can ensure that the constitutional guarantees which are so deeply rooted in our justice system may continue to prosper

Molecular Simulations Reveal an Unresolved Conformation of the Type IA Protein Kinase A Regulatory Subunit and Suggest Its Role in the cAMP Regulatory Mechanism

We identify a previously unresolved, unrecognized, and highly stable conformation of the protein kinase A (PKA) regulatory subunit RIα. This conformation, which we term the “Flipback” structure, bridges conflicting characteristics in crystallographic structures and solution experiments of the PKA RIα heterotetramer. Our simulations reveal a hinge residue, G235, in the B/C helix that is conserved through all isoforms of RI. Brownian dynamics simulations suggest that the Flipback conformation plays a role in cAMP association to the A domain of the R subunit