The transmission of mutation effects in a multiprotein machine: A comprehensive metadynamics study of the cardiac thin filament.

The binding of Ca ions within the troponin core of the cardiac thin filament (CTF) regulates normal contraction and relaxation. Mutations within the troponin complexes are known to alter normal functions and result in the eventual development of cardiomyopathy. However, despite the importance of the problem, detailed microscopic knowledge of the mechanism of pathogenic effect of point mutations and their effects on the conformational free energy surface of CTF remains elusive.

Transition Path Sampling Based Free Energy Calculations of Evolution's Effect on Rates in β-Lactamase: The Contributions of Rapid Protein Dynamics to Rate.

β-Lactamases are one of the primary enzymes responsible for antibiotic resistance and have existed for billions of years. The structural differences between a modern class A TEM-1 β-lactamase compared to a sequentially reconstructed Gram-negative bacteria β-lactamase are minor. Despite the similar structures and mechanisms, there are different functions between the two enzymes.

The Evolution of the Acylation Mechanism in -Lactamase and Rapid Protein Dynamics.

-Lactamases are a class of well-studied enzymes that are known to have existed since billions of years ago, starting as a defense mechanism to stave off competitors and are now enzymes responsible for antibiotic resistance. Using ancestral sequence reconstruction, it is possible to study the crystal structure of a laboratory resurrected 2-3 billion year-old -lactamase. Comparing the ancestral enzyme to its modern counterpart, a TEM-1 -lactamase, the structural changes are minor, and it is probable that dynamic effects play an important role in the evolution of function.

Unexplained Acute Total Loss of Vision After Primary Scleral Buckle Surgery.

To present 2 cases of acute total loss of vision after scleral buckle surgery for rhegmatogenous retinal detachment. A retrospective chart review of 2 cases and an analysis of the literature were performed. An 18-year-old woman and a 67-year-old woman suffered complete loss of vision in their operative eye after primary scleral buckle surgery with encircling bands.

Unstable right ventricular hypertension in pulmonary atresia and intact ventricular septum: a case report.

Arterial oxygen saturation in single ventricle patients is dependent on systemic cardiac output. Here, we describe a case of a newborn with single ventricle physiology and an unusual mechanism to explain poor cardiac output and cyanosis. This case highlights the importance of identifying and considering ventricular morphology and ventricular-ventricular interactions to understand clinical challenges.

Rethinking the role of surgical resection in the management of primary pituitary lymphoma.

Background: Primary pituitary lymphoma (PPL) is a rare finding in immunocompetent patients, with only 54 patients reported to date (including ours). It presents most often with headache and hypopituitarism, with MRI findings comparable to more common pituitary tumours, making the diagnosis challenging. There is no consensus on the ideal management for these lesions with the role of surgical resection not clearly established.

Diffuse large B-cell lymphoma in the C8 root mimicking a schwannoma: illustrative case.

Background: Primary lymphomas arising in peripheral nerves are extremely rare, with just a few case reports documented in the literature.

Observations: The authors present the case of a 62-year-old female with C8 radiculopathy, initially suspected to have a schwannoma based on imaging but later diagnosed with primary C8 nerve root B-cell lymphoma. Following histopathological confirmation, the patient underwent 5 courses of chemotherapy, resulting in a decrease in the size of her lesion on magnetic resonance imaging.

Human cardiac β-myosin powerstroke energetics: Thin filament, Pi displacement, and mutation effects.

The powerstroke of human cardiac β-myosin is an important stage of the cross-bridge cycle that generates force for muscle contraction. However, the starting structure of this process has never been resolved, and the relative timing of the powerstroke and inorganic phosphate (Pi) release is still controversial. In this study, we generated an atomistic model of myosin on the thin filament and utilized metadynamics simulations to predict the absent starting structure of the powerstroke.

Myosin-Catalyzed ATP Hydrolysis in the Presence of Disease-Causing Mutations: Mavacamten as a Way to Repair Mechanism.

Hypertrophic cardiomyopathy is one of the most common forms of genetic cardiomyopathy. Mavacamten is a first-in-class myosin modulator that was identified via activity screening on the wild type, and it is FDA-approved for the treatment of obstructive hypertrophic cardiomyopathy (HCM). The drug selectively binds to the cardiac β-myosin, inhibiting myosin function to decrease cardiac contractility.

Transition Path Sampling Study of Engineered Enzymes That Catalyze the Morita-Baylis-Hillman Reaction: Why Is Enzyme Design so Difficult?

It is hoped that artificial enzymes designed in laboratories can be efficient alternatives to chemical catalysts that have been used to synthesize organic molecules. However, the design of artificial enzymes is challenging and requires a detailed molecular-level analysis to understand the mechanism they promote in order to design efficient variants. In this study, we computationally investigate the mechanism of proficient Morita-Baylis-Hillman enzymes developed using a combination of computational design and directed evolution.

Longitudinal Follow-Up of Children With HLHS and Association Between Norwood Shunt Type and Long-Term Outcomes: The SVR III Study.

Objective: In the SVR trial (Single Ventricle Reconstruction), newborns with hypoplastic left heart syndrome were randomly assigned to receive a modified Blalock-Taussig-Thomas shunt (mBTTS) or a right ventricle-to-pulmonary artery shunt (RVPAS) at Norwood operation. Transplant-free survival was superior in the RVPAS group at 1 year, but no longer differed by treatment group at 6 years; both treatment groups had accumulated important morbidities. In the third follow-up of this cohort (SVRIII [Long-Term Outcomes of Children With Hypoplastic Left Heart Syndrome and the Impact of Norwood Shunt Type]), we measured longitudinal outcomes and their risk factors through 12 years of age.

Atomistic description of the relationship between protein dynamics and catalysis with transition path sampling.

Despite initial resistance, it has been increasingly accepted that protein dynamics plays a role in enzymatic catalysis. There have been two lines of research. Some works study slow conformational motions that are not coupled to the reaction coordinate, but guide the system towards catalytically competent conformations.

Frosted Branch Angiitis in the Setting of Active COVID-19 Infection and Underlying Mixed Connective Tissue Disease.

Frosted branch angiitis (FBA) is an uncommon form of retinal vasculitis and is typically associated with vision loss. We report a unique case of FBA that manifested in the setting of an active COVID-19 infection in a patient with Mixed Connective Tissue Disease (MCTD). A 34-year-old female with a history of MCTD, including overlapping findings of dermatomyositis, systemic lupus erythematosus, and rheumatoid arthritis, on immunosuppressive medications, presented for left-sided vision loss.

Protein Dynamics and Enzymatic Catalysis.

This Perspective presents a review of our work and that of others in the highly controversial topic of the coupling of protein dynamics to reaction in enzymes. We have been involved in studying this topic for many years. Thus, this perspective will naturally present our own views, but it also is designed to present an overview of the variety of viewpoints of this topic, both experimental and theoretical.

Methods to Enhance Causal Inference for Assessing Impact of Clinical Informatics Platform Implementation.

Background: Hospitals are increasingly likely to implement clinical informatics tools to improve quality of care, necessitating rigorous approaches to evaluate effectiveness. We leveraged a multi-institutional data repository and applied causal inference methods to assess implementation of a commercial data visualization software in our pediatric cardiac intensive care unit.

Methods: Natural experiment in the University of Michigan (UM) Cardiac Intensive Care Unit pre and postimplementation of data visualization software analyzed within the Pediatric Cardiac Critical Care Consortium clinical registry; we identified N=21 control hospitals that contributed contemporaneous registry data during the study period.

Classical Molecular Dynamics Simulation of Glyonic Liquids: Structural Insights and Relation to Conductive Properties.

Rhamnolipids are biosurfactants that have obtained wide industrial and environmental interests with their biodegradability and great surface activity. Besides their important roles as surfactants, they are found to function as a new type of glycolipid-based protic ionic liquids (ILs)─glyonic liquids (GLs). GLs are reported to have impressive physicochemical properties, especially superionic conductivity, and it was reported in experiments that specific ion selections and the fraction of water content have a strong effect on the conductivity.

Development of the Residual Lesion Score for congenital heart surgery: the RAND Delphi methodology.

Background And Objective: The Residual Lesion Score is a novel tool for assessing the achievement of surgical objectives in congenital heart surgery based on widely available clinical and echocardiographic characteristics. This article describes the methodology used to develop the Residual Lesion Score from the previously developed Technical Performance Score for five common congenital cardiac procedures using the RAND Delphi methodology.

Methods: A panel of 11 experts from the field of paediatric and congenital cardiology and cardiac surgery, 2 co-chairs, and a consultant were assembled to review and comment on validity and feasibility of measuring the sub-components of intraoperative and discharge Residual Lesion Score for five congenital cardiac procedures.

Connecting Conformational Motions to Rapid Dynamics in Human Purine Nucleoside Phosphorylase.

The influence of protein motions on enzyme catalysis remains a topic of active discussion. Protein motions occur across a variety of time scales, from vibrational fluctuations in femtoseconds, to collective motions in milliseconds. There have been numerous studies that show conformational motions may assist in catalysis, protein folding, and substrate specificity.

Insights into the Mechanism of the Cardiac Drug Omecamtiv Mecarbil─A Computational Study.

Omecamtiv mecarbil (OM) is a positive inotrope that is thought to bind directly to an allosteric site of the β-cardiac myosin. The drug is under investigation for the treatment of systolic heart failure. The drug is classified as a cardiac myosin modulator and has been observed to affect multiple vital steps of the cross-bridge cycle including the recovery stroke and the chemical step.

Perspective: Path Sampling Methods Applied to Enzymatic Catalysis.

This Perspective reviews the use of Transition Path Sampling methods to study enzymatically catalyzed chemical reactions. First applied by our group to an enzymatic reaction over 15 years ago, the method has uncovered basic principles in enzymatic catalysis such as the protein promoting vibration, and it has also helped harmonize such ideas as electrostatic preorganization with dynamic views of enzyme function. It is now being used to help uncover principles of protein design necessary to artificial enzyme creation.