Papers by Sherry-ann Brown
Frontiers in Genetics, 2016
Nature reviews. Clinical oncology, Jan 13, 2015
Increased awareness of the cardiovascular toxic effects of chemotherapy has led to the emergence ... more Increased awareness of the cardiovascular toxic effects of chemotherapy has led to the emergence of cardio-oncology (or onco-cardiology), which focuses on screening, monitoring and treatment of patients with cardiovascular dysfunctions resulting from chemotherapy. Anthracyclines, such as doxorubicin, and HER2 inhibitors, such as trastuzumab, both have cardiotoxic effects. The biological rationale, mechanisms of action and cardiotoxicity profiles of these two classes of drugs, however, are completely different, suggesting that cardiotoxic effects can occur in a range of different ways. Advances in genomics and proteomics have implicated several genomic variants and biological pathways that can influence the susceptibility to cardiotoxicity from these, and other drugs. Established pathways include multidrug resistance proteins, energy utilization pathways, oxidative stress, cytoskeletal regulation and apoptosis. Gene-expression profiles that have revealed perturbed pathways have vastl...
Typescript. Thesis (M.A.)--Wesleyan University, 2004. Includes bibliographical references (leaves... more Typescript. Thesis (M.A.)--Wesleyan University, 2004. Includes bibliographical references (leaves 114-118).
SpringerPlus, 2015
Among kidney transplant recipients with acute kidney injury, the differential diagnosis must be b... more Among kidney transplant recipients with acute kidney injury, the differential diagnosis must be broadened to include conditions such as rejection, immunocompromised host infections, anatomic pathologies, and recurrent or de novo glomerular diseases. In this case report, we describe an unusual cause of acute renal allograft injury due to external compression of the allograft ureter. Retrospective review; case report. The patient developed acute kidney injury of the renal allograft due to external compression of the allograft ureter coincident with a cecal volvulus. The patient underwent lysis of adhesions, right hemicolectomy, and end ileostomy creation with resolution of acute kidney injury. Cecal volvulus is an uncommon cause of bowel obstruction and is often associated with adhesions following abdominal surgery. To our knowledge, cecal volvulus has not previously been reported as a direct contributor to acute kidney injury. This case highlights the need for a systematic approach to the patient with acute kidney injury and the special considerations involved in the diagnosis of renal failure in the kidney transplant population.
Southern medical journal, 2015
Frontiers in Neurology, 2015
Biophysical Journal, 2013
Frontiers in neuroscience, 2015
Hereditary ataxia, or motor incoordination, affects approximately 150,000 Americans and hundreds ... more Hereditary ataxia, or motor incoordination, affects approximately 150,000 Americans and hundreds of thousands of individuals worldwide with onset from as early as mid-childhood. Affected individuals exhibit dysarthria, dysmetria, action tremor, and diadochokinesia. In this review, we consider an array of computational studies derived from experimental observations relevant to human neuropathology. A survey of related studies illustrates the impact of integrating clinical evidence with data from mouse models and computational simulations. Results from these studies may help explain findings in mice, and after extensive laboratory study, may ultimately be translated to ataxic individuals. This inquiry lays a foundation for using computation to understand neurobiochemical and electrophysiological pathophysiology of spinocerebellar ataxias and may contribute to development of therapeutics. The interdisciplinary analysis suggests that computational neurobiology can be an important tool f...
Frontiers in neuroscience, 2014
A suite of models was developed to study the role of inositol 1,4,5-trisphosphate receptor 1 (IP3... more A suite of models was developed to study the role of inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in spinocerebellar ataxias (SCAs). Several SCAs are linked to reduced abundance of IP3R1 or to supranormal sensitivity of the receptor to activation by its ligand inositol 1,4,5-trisphosphate (IP3). Detailed multidimensional models have been created to simulate biochemical calcium signaling and membrane electrophysiology in cerebellar Purkinje neurons. In these models, IP3R1-mediated calcium release is allowed to interact with ion channel response on the cell membrane. Experimental findings in mice and clinical observations in humans provide data input for the models. The SCA modeling suite helps interpret experimental results and provides suggestions to guide experiments. The models predict IP3R1 supersensitivity in SCA1 and compensatory mechanisms in SCA1, SCA2, and SCA3. Simulations explain the impact of calcium buffer proteins. Results show that IP3R1-mediated calcium release act...
Computational Systems Neurobiology, 2012
Journal of Computational Neuroscience, 2011
Because of its highly branched dendrite, the Purkinje neuron requires significant computational r... more Because of its highly branched dendrite, the Purkinje neuron requires significant computational resources if coupled electrical and biochemical activity are to be simulated. To address this challenge, we developed a scheme for reducing the geometric complexity; while preserving the essential features of activity in both the soma and a remote dendritic spine. We merged our previously published biochemical model of calcium dynamics and lipid signaling in the Purkinje neuron, developed in the Virtual Cell modeling and simulation environment, with an electrophysiological model based on a Purkinje neuron model available in NEURON. A novel reduction method was applied to the Purkinje neuron geometry to obtain a model with fewer compartments that is tractable in Virtual Cell. Most of the dendritic tree was subject to reduction, but we retained the neuron's explicit electrical and geometric features along a specified path from spine to soma. Further, unlike previous simplification methods, the dendrites that branch off along the preserved explicit path are retained as reduced branches. We conserved axial resistivity and adjusted passive properties and active channel conductances for the reduction in surface area, and cytosolic calcium for the reduction in volume. Rallpacks are used to validate the reduction algorithm and show that it can be generalized to other complex neuronal geometries. For the Purkinje cell, we found that current injections at the soma were able to produce similar trains of action potentials and membrane potential propagation in the full and reduced models in NEURON; the reduced model produces identical spiking patterns in NEURON and Virtual Cell. Importantly, our reduced model can simulate communication between the soma and a distal spine; an alpha function applied at the spine to represent synaptic stimulation gave similar results in the full and reduced models for potential changes associated with both the spine and the soma. Finally, we combined phosphoinositol signaling and electrophysiology in the reduced model in Virtual Cell. Thus, a strategy has been developed to combine electrophysiology and biochemistry as a step toward merging neuronal and systems biology modeling.
BMC Systems Biology, 2012
Mutations in the smooth endoplasmic reticulum (sER) calcium channel Inositol Trisphosphate Recept... more Mutations in the smooth endoplasmic reticulum (sER) calcium channel Inositol Trisphosphate Receptor type 1 (IP3R1) in humans with the motor function coordination disorders Spinocerebellar Ataxia Types 15 and 16 (SCA15/16) and in a corresponding mouse model, the IP3R1delta18/delta18 mice, lead to reduced IP3R1 levels. We posit that increasing IP3R1 sensitivity to IP3 in ataxias with reduced IP3R1 could restore normal calcium response. On the other hand, in mouse models of the human polyglutamine (polyQ) ataxias, SCA2, and SCA3, the primary finding appears to be hyperactive IP3R1-mediated calcium release. It has been suggested that the polyQ SCA1 mice may also show hyperactive IP3R1. Yet, SCA1 mice show downregulated gene expression of IP3R1, Homer, metabotropic glutamate receptor (mGluR), smooth endoplasmic reticulum Ca-ATP-ase (SERCA), calbindin, parvalbumin, and other calcium signaling proteins. We create a computational model of pathological alterations in calcium signaling in cerebellar Purkinje neurons to investigate several forms of spinocerebellar ataxia associated with changes in the abundance, sensitivity, or activity of the calcium channel IP3R1. We find that increasing IP3R1 sensitivity to IP3 in computational models of SCA15/16 can restore normal calcium response if IP3R1 abundance is not too low. The studied range in IP3R1 levels reflects variability found in human and mouse ataxic models. Further, the required fold increases in sensitivity are within experimental ranges from experiments that use IP3R1 phosphorylation status to adjust its sensitivity to IP3. Results from our simulations of polyglutamine SCAs suggest that downregulation of some calcium signaling proteins may be partially compensatory. However, the downregulation of calcium buffer proteins observed in the SCA1 mice may contribute to pathology. Finally, our model suggests that the calcium-activated voltage-gated potassium channels may provide an important link between calcium metabolism and membrane potential in Purkinje cell function. Thus, we have established an initial platform for computational evaluation and prediction of ataxia pathophysiology. Specifically, the model has been used to investigate SCA15/16, SCA1, SCA2, and SCA3. Results suggest that experimental studies treating mouse models of any of these ataxias with appropriately chosen peptides resembling the C-terminal of IP3R1 could adjust receptor sensitivity, and thereby modulate calcium release and normalize IP3 response. In addition, the model supports the hypothesis of IP3R1 supersensitivity in SCA1.
Biophysical Journal, 2010
Biophysical Journal, 2009
Biophysical Journal, 2008
A 3D model was developed and used to explore dynamics of phosphatidylinositol-4,5-bisphosphate (P... more A 3D model was developed and used to explore dynamics of phosphatidylinositol-4,5-bisphosphate (PIP2) signaling in cerebellar Purkinje neurons. Long-term depression in Purkinje neurons depends on coincidence detection of climbing fiber stimulus evoking extracellular calcium flux into the cell and parallel fiber stimulus evoking inositol-1,4,5-trisphosphate (IP3)meditated calcium release from the endoplasmic reticulum. Experimental evidence shows that large concentrations of IP3 are required for calcium release. This study uses computational analysis to explore how the Purkinje cell provides sufficient PIP2 to produce large amounts of IP3. Results indicate that baseline PIP2 concentration levels in the plasma membrane are inadequate, even if the model allows for PIP2 replenishment by lateral diffusion from neighboring dendrite membrane. Lateral diffusion analysis indicates apparent anomalous diffusion of PIP2 in the spiny dendrite membrane, due to restricted diffusion through spine necks. Stimulated PIP2 synthesis and elevated spine PIP2 mediated by a local sequestering protein were explored as candidate mechanisms to supply sufficient PIP2. Stimulated synthesis can indeed lead to high IP3 amplitude of long duration; local sequestration produces high IP3 amplitude, but of short duration. Simulation results indicate that local sequestration could explain the experimentally observed finely tuned timing between parallel fiber and climbing fiber activation.
Mayo Clinic Proceedings, 2015
Quadrilateral space syndrome (QSS) arises from compression or mechanical injury to the axillary n... more Quadrilateral space syndrome (QSS) arises from compression or mechanical injury to the axillary nerve or the posterior circumflex humeral artery (PCHA) as they pass through the quadrilateral space (QS). Quadrilateral space syndrome is an uncommon cause of paresthesia and an underdiagnosed cause of digital ischemia in overhead athletes. Quadrilateral space syndrome can present with neurogenic symptoms (pain and weakness) secondary to axillary nerve compression. In addition, repeated abduction and external rotation of the arm is felt to lead to injury of the PCHA within the QSS. This often results in PCHA thrombosis and aneurysm formation, with distal emboli. Because of relative infrequency, QSS is rarely diagnosed on evaluation of athletes with such symptoms. We report on 9 patients who presented at Mayo Clinic with QSS. Differential diagnosis, a new classification system, and the management of QSS are discussed, with a comprehensive literature review. The following search terms were used on PubMed: axillary nerve, posterior circumflex humeral artery, quadrilateral space, and quadrangular space. Articles were selected if they described patients with symptoms from axillary nerve entrapment or PCHA thrombosis, or if related screening or imaging methods were assessed. References available within the obtained articles were also pursued. There was no date or language restriction for article inclusion; 5 studies in languages besides English were reported in German, French, Spanish, Turkish, and Chinese.
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Papers by Sherry-ann Brown