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Full-Text Articles in Biomedical Engineering and Bioengineering
Alterations In Cardiac Motions Of The Failing Heart During Direct Mechanical Ventricular Actuation, Benjamin Allyn Schmitt
Alterations In Cardiac Motions Of The Failing Heart During Direct Mechanical Ventricular Actuation, Benjamin Allyn Schmitt
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Objectives: Heart failure (HF) refractory to medical management can be effectively treated with mechanical support. However, available devices are frequently associated with complications due to blood contact. Direct cardiac compression (DCC) devices augment LV systolic pump function by externally compressing the heart surface. Direct Mechanical Ventricular Actuation (DMVA) is a unique DCC method providing not only systolic but, importantly, diastolic support. However, DCC in general remains a relatively poorly understood modality. The purpose of this study was to examine DMVA’s effect on restoration of physiologic function in the failing heart. Methods: Global ischemic HF was induced with 5 mins of …
Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda
Altered Skeletal Muscle Excitation-Contraction Coupling In The R6/2 Transgenic Mouse Model For Huntington's Disease, Daniel R. Miranda
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Huntington’s disease (HD) has classically been categorized as a neurodegenerative disorder. However, the expression of the disease-causing mutated huntingtin gene in skeletal muscle may contribute to the symptoms of HD, namely those that involve involuntary muscle contraction. In the R6/2 transgenic mouse model of HD, we previously observed ion channel defects that could contribute to involuntary muscle contraction. Here, in R6/2 muscle we investigated the consequence of these ion channel defects on action potentials (APs), the first step in excitation-contraction (EC) coupling. We found that the ion channel defects were associated with depolarizing the baseline membrane potential during AP trains. …
Augmenting Structure/Function Relationship Analysis With Deep Learning For The Classification Of Psychoactive Drug Activity At Class A G Protein-Coupled Receptors, Hannah Willow Shows
Augmenting Structure/Function Relationship Analysis With Deep Learning For The Classification Of Psychoactive Drug Activity At Class A G Protein-Coupled Receptors, Hannah Willow Shows
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G protein-coupled receptors (GPCRs) initiate intracellular signaling pathways via interaction with external stimuli. [1-5] Despite sharing similar structure and cellular mechanism, GPCRs participate in a uniquely broad range of physiological functions. [6] Due to the size and functional diversity of the GPCR family, these receptors are a major focus for pharmacological applications. [1,7] Current state-of-the-art pharmacology and toxicology research strategies rely on computational methods to efficiently design highly selective, low toxicity compounds. [9], [10] GPCR-targeting therapeutics are associated with low selectivity resulting in increased risk of adverse effects and toxicity. Psychoactive drugs that are active at Class A GPCRs used …
Acute Oxygen-Sensing By The Carotid Bodies : The Thermal Microdomain Model, Ryan Joseph Rakoczy
Acute Oxygen-Sensing By The Carotid Bodies : The Thermal Microdomain Model, Ryan Joseph Rakoczy
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The carotid bodies (CB) are peripheral chemoreceptors that detect changes in arterial oxygenation and, via afferent inputs to the brainstem, correct the pattern of breathing to restore blood gas homeostasis. Elucidating the “signal” that couples carotid body sensory type I cell (CBSC) hypoxic mitochondrial inhibition with potassium channel closure has proven to be an arduous task; to date, a multitude of oxygen-sensing chemotransduction mechanisms have been described and altercated (Varas, Wyatt & Buckler, 2007; Gao et al, 2017; Rakoczy & Wyatt, 2018). Herein, we provide preliminary evidence supporting a novel oxygen-sensing hypothesis suggesting CBSC hypoxic chemotransductive signaling may in part …
Regulation Of Δnp63Α By Tip60 Promotes Cellular Proliferation, Andrew Jared Stacy
Regulation Of Δnp63Α By Tip60 Promotes Cellular Proliferation, Andrew Jared Stacy
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ΔNp63α is a p53 transcription factor family member that promotes cellular proliferation and survival. In squamous cell carcinoma (SCC), ΔNp63α overexpression is associated with poor prognosis and survival, implicating it as a proto-oncogene. Despite its importance in SCC, the mechanisms regulating ΔNp63α expression are poorly understood. We have identified the acetyltransferase TIP60 as a novel upstream regulator of ΔNp63α levels. We discovered that TIP60 regulates ΔNp63α via two mechanisms. First, TIP60 upregulates ΔNp63α mRNA levels. Moreover, pharmacological inhibition of TIP60 activity reduces ΔNp63α transcript levels, indicating that TIP60-cataltyic activity is vital to amplified transcription of ΔNp63α. Second, we have demonstrated …
Host-Parasite Interactions: Comparative Analyses Of Population Genomics, Disease-Associated Genomic Regions, And Host Use, Sara Rose Seibert
Host-Parasite Interactions: Comparative Analyses Of Population Genomics, Disease-Associated Genomic Regions, And Host Use, Sara Rose Seibert
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Birds are major vectors and reservoir hosts of pathogens across our globe. Pathogens can be spread through the dispersal and seasonal movements of migratory and resident wild birds. Although biogeographic barriers have the potential to restrict completely or in part gene flow in wild birds, variation in ecological drivers of dispersal likely influences the effectiveness of these barriers amongst different species. This dissertation seeks to enhance our knowledge of Southern Hemisphere waterfowl species’ dispersal, population genomics, and disease ecology using population genomic techniques (double-digest restriction-site associated DNA sequencing (ddRADseq)) and multi-variate statistics. First, we investigated the roles of dispersal behavior …
Renca Macrobeads Inhibit Tumor Cell Growth Via Egfr Activation And Regulation Of Mef2 Isoform Expression, Prithy Caroline Martis
Renca Macrobeads Inhibit Tumor Cell Growth Via Egfr Activation And Regulation Of Mef2 Isoform Expression, Prithy Caroline Martis
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Tumors are heterogeneous systems, whose growth is influenced by intrinsic properties of malignant cells, external systemic factors (i.e. immune, neural, endocrine, etc.), and the dynamic interactions between tumor cells and their microenvironment. Given the inherent complexity of cancers, combined with the continual evolution of tumors and the development of treatment resistance, a precision medicine approach may not provide an optimal clinical response. Exploring a new paradigm that focuses on regulating cancer as a system may not only control tumor progression but also address the extraordinary challenges of tumor heterogeneity and disease recurrence in order to improve clinical outcomes. As a …
Ultraviolet-B Radiation Induces Release Of Bioactive Microvesicle Particles In Keratinocytes Via Platelet-Activating Factor And Acid Sphingomyelinase, Langni Liu
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Ultraviolet-B (UV-B) radiation is one of the most common environmental factors and is known to induce the production of bioactive agents that cause several diseases including skin cancer. UVB exposure stimulates the production of a phospholipid activator, platelet-activating factor (PAF), and its analogs in keratinocytes that activate the PAF receptor (PAF-R) resulting in acute inflammatory and delayed systematic immunosuppressive effects. However, as UVB only penetrates into the skin epidermal layer, the detailed mechanisms of how UVB exerts systematic effects remains unclear. Previously we found that UVB induces keratinocytes to release large numbers of microvesicle particles (MVPs). These small membrane-bound particles …
Global Identification Of Human Modifier Genes Of Alpha-Synuclein Toxicity, Ishita Haider
Global Identification Of Human Modifier Genes Of Alpha-Synuclein Toxicity, Ishita Haider
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Alpha-synuclein is a small lipid binding protein abundantly expressed in the brain. Lewy body or Lewy-like pathology, primarily composed of misfolded alpha-synuclein, is a pathological feature shared by several neurodegenerative disorders, including Parkinson's disease (PD). Both missense mutations and increased copy numbers of the SNCA gene, encoding the alpha-synuclein protein, have been genetically linked to autosome dominant PD. Other genetic variations affecting the expression of the SNCA gene have been associated with sporadic PD. Although the physiological function of alpha-synuclein is not well understood, its localization to plasma and vesicular membranes at the presynaptic terminals suggests a role in neurotransmission. …
Biomarker-Performance Associations During Nutritional And Exercise Intervention In Air Force Personnel, Jennifer Jurcsisn
Biomarker-Performance Associations During Nutritional And Exercise Intervention In Air Force Personnel, Jennifer Jurcsisn
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This study evaluated the combined effects of an exercise intervention and nutritional supplement on biomarkers of stress and resilience, and the relationships of those markers with physical and cognitive performance. 130 healthy Active-Duty Air Force (AF) personnel were recruited to participate in a double-blind, placebo controlled 12-week exercise and nutritional intervention. Serum was collected at basal and high stress conditions pre- and post-intervention to track the following biomarkers: cortisol, dehydroepiandrosterone-sulfate (DHEA-S), norepinephrine (NE), neuropeptide Y (NPY), and serotonin. The exercise intervention significantly attenuated the cortisol response and peak stress cortisol levels. The nutritional intervention decreased peak stress NE. The selected …
Mitochondria-Dependent Cellular Toxicity Of Α-Synuclein Modeled In Yeast, Rajalakshmi Santhanakrishnan
Mitochondria-Dependent Cellular Toxicity Of Α-Synuclein Modeled In Yeast, Rajalakshmi Santhanakrishnan
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Parkinson’s disease is the second most common neurodegenerative disease. This disease is caused by the degeneration of dopaminergic neurons, leading to debilitating motor symptoms and early mortality. The protein α-synuclein (α-syn), encoded by SNCA, misfolds and forms inclusions in Parkinson’s disease brains. When α-syn is overexpressed in yeast, it causes cellular toxicity and an increased number of aggregates, recapitulating the toxic phenotypes observed in humans and animal models. Yeast models are a powerful tool to perform high-throughput overexpression screening to identify modifiers of α-syn toxicity. α-syn causes mitochondrial dysfunction by inhibiting complex I and inducing mitochondrial fragmentation. Prior screening of …
Adenovirus Co-Opts Neutrophilic Inflammation In Order To Enhance Entry Into Epithelial Cells, James Matthew Readler
Adenovirus Co-Opts Neutrophilic Inflammation In Order To Enhance Entry Into Epithelial Cells, James Matthew Readler
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Human adenoviruses (AdV) are double-stranded DNA viruses that can cause a range of diseases. While AdV respiratory infections are often mild and self-limited, severe manifestations such as fulminant pneumonia and acute respiratory distress syndrome (ARDS) are not uncommon. In order to identify potential modalities to treat AdV infections and potentially enhance the effectiveness of AdV vector delivery, a thorough mechanistic understanding of how AdV enters host cells is needed. Previous studies have revealed polarized epithelia, one of the primary targets for AdV respiratory infections, are highly resistant to AdV entry from the apical (luminal) surface. However, upon exposure to interleukin …
Rescue Of Als Protein Fus Toxicity By Taf, Elliott Hayden
Rescue Of Als Protein Fus Toxicity By Taf, Elliott Hayden
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Amyotrophic Lateral Scleroses (ALS) is a neurodegenerative disease characterized by the degeneration of upper and lower motor neurons in the brain and spinal cord leading to progressive paralysis and ultimately death within 5 years of symptom onset. Only two drugs are approved by the Food and Drug Administration (FDA) for treating ALS that slow the disease progression by about 3 months. Mutations in the gene Fused in Sarcoma (FUS) cause inherited forms of ALS. FUS is a nuclear, multifunctional RNA-binding protein (RBP) involved in multiple RNA metabolic pathways. Mutations in FUS cause mislocalization of the protein from the nucleus to …
Differential Microrna Expression In Barrett's Esophagus Correlates With Regulation Of Posterior Homeotic Genes, Reilly June Clark
Differential Microrna Expression In Barrett's Esophagus Correlates With Regulation Of Posterior Homeotic Genes, Reilly June Clark
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Barrett’s Esophagus (BE) is characterized by the appearance of an intestinal-like epithelium in the distal esophagus. The molecular mechanisms behind BE development are unknown. BE is often preceded by Gastroesophageal Reflux Disease (GERD) and predisposes patients to esophageal adenocarcinoma (EAC). Due to the high mortality rate associated with EAC, BE patients are continuously monitored through upper endoscopy with biopsy for progression to low grade dysplasia (LGD), high grade dysplasia, and EAC. This monitoring technique poses numerous risks, so alternative surveillance and diagnostic techniques for BE pathogenesis are continually studied. microRNA biomarkers in BE pathogenesis may provide alternative means of diagnosis …
Type 2 Diabetes Leads To Impairment Of Cognitive Flexibility And Disruption Of Excitable Axonal Domains In The Brain, Leonid M. Yermakov
Type 2 Diabetes Leads To Impairment Of Cognitive Flexibility And Disruption Of Excitable Axonal Domains In The Brain, Leonid M. Yermakov
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Type 2 diabetes is a metabolic disease affecting millions of people around the world. Cognitive and mood impairments are among its many debilitating complications, but disease mechanism(s) remain elusive. Here, we present a series of behavioral tasks that demonstrate impairment of cognitive flexibility in db/db mice, a commonly used type 2 diabetes model. Using immunohistochemistry, we demonstrate disruption of axon initial segments (AIS) and nodes of Ranvier, excitable axonal domains regulating neuronal output, in brain regions associated with cognitive and mood impairments. Finally, we present results of exercise treatment that ameliorates AIS disruption in these animals. Establishing cognitive flexibility deficits …
The Pattern Of Sensory Axonal Endings Together With Synaptic Transmission Influence The Development Of Proprioceptive Circuits In The Spinal Cord, Yiyun Dai
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Proprioceptive circuits provide information regarding limb position and movement status, and are essential to producing correctly executed motor behaviors. Exploring the mechanisms underlying the formation of proprioceptive circuits is therefore critical for understanding neurological disorders with altered motor coordination and for restoring circuits damaged by injury. One important proprioceptive circuit, the stretch reflex circuit, is formed between proprioceptive sensory neurons (PSNs) and motor neurons (MNs) that innervate the same muscle. Progress has been made in understanding the spatial organization of MNs based on their muscle-specific subpopulation identities, which contributes to the specificity of stretch reflex circuit formation. However, whether PSNs …
Regulation Of The Motor Output Of The Spinal Cord: Burst Firing Generation And Sensorimotor Integration, Amr A. Mahrous
Regulation Of The Motor Output Of The Spinal Cord: Burst Firing Generation And Sensorimotor Integration, Amr A. Mahrous
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Spinal motoneurons are the final common path for motor signals. Thus, the firing activity recorded from spinal motoneurons or their axons in the ventral roots represents the motor output of the nervous system. This dissertation investigates two major phenomena that help generate and shape the neuronal motor output. Specialized groups of spinal neurons called central pattern generators (CPGs) are capable of orchestrating rhythmic bursting activity without involvement of the brain. This activity underlies stereotyped movements such as locomotion. If known, the ionic mechanisms responsible for generating this activity can offer new pharmacological interventions to restore walking in paralyzed patients with …
Consequences Of Trpm7 Kinase Inactivation In Immune Cells, Pavani Beesetty
Consequences Of Trpm7 Kinase Inactivation In Immune Cells, Pavani Beesetty
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The characteristic feature of ubiquitously expressed transient receptor potential melastatin 7 (TRPM7) protein is the presence of a C-terminal atypical kinase domain fused to a cation channel domain. Even though this protein has been implicated in a number of physiological and pathological processes, the mechanisms regulating TRPM7 channel activity are poorly understood. In the present study, regulation of TRPM7 channel by its kinase activity was investigated using the TRPM7 kinase-dead knock-in mouse (KD mouse). These mice have a point mutation Lys1646Arg in the kinase region abrogating the kinase activity. Examining TRPM7 channel activity in KD peritoneal macrophages revealed that TRPM7 …
A Novel Approach For Cancer Characterization Using Latent Dirichlet Allocation And Disease-Specific Genomic Analysis, Hima Bindu Yalamanchili
A Novel Approach For Cancer Characterization Using Latent Dirichlet Allocation And Disease-Specific Genomic Analysis, Hima Bindu Yalamanchili
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Two challenging problems in the clinical study of cancer are the characterization of cancer subtypes and the classification of individual patients according to those subtypes. Further, understanding the role of differential gene expression in the development of and molecular response to cancer is a complex problem that remains challenging, in part due to the sheer number of genes and gene products involved. Traditional statistical approaches addressing these problems are hindered by within-class heterogeneity and challenges inherent in data integration across high-dimensional data. In addition, many current machine learning methods do not lend themselves to biological interpretation. We have developed a …
Context-Dependence Of Physiological Systems: Environment-Physiology Interactions In The Respiratory Control System, Joseph M. Santin
Context-Dependence Of Physiological Systems: Environment-Physiology Interactions In The Respiratory Control System, Joseph M. Santin
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We know that animals are tuned to survive different environmental conditions or else life would not exist. Unfortunately, this is often forgotten or ignored when designing experiments. As Marsh Tenney articulated, "The physiologist keeps the whole always in mind. He accepts the tactical necessity of reductionism to understand parts, but, once done, for him it is only the beginning, never the end” (from Remmers, 2005). In an era when it is all too common to take environmental complexity out of the organism to understand physiology, my work puts some of that complexity back in the study of organisms. I take …
Regulation Of The Expression And Activity Of Extracellular Signal-Regulated Kinase 3 (Erk3), Lobna Elkhadragy
Regulation Of The Expression And Activity Of Extracellular Signal-Regulated Kinase 3 (Erk3), Lobna Elkhadragy
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Mitogen-activated protein kinases (MAPKs) are Ser/Thr kinases that regulate diverse cellular processes. Extracellular signal-regulated kinase 3 (ERK3) is an atypical MAPK that has recently gained interest for its roles in cancer. ERK3 promotes cancer cell migration, invasion and drug resistance, and its expression is upregulated in multiple cancers. However, little is known about the molecular mechanisms that regulate ERK3’s expression and kinase activity. Here, we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by inhibiting the expression of the tumor suppressor microRNA (miRNA) let-7i, which …
Glycolytic Metabolism And Pregnancy Parameters In The Murine Placenta, Renee Elizabeth Albers
Glycolytic Metabolism And Pregnancy Parameters In The Murine Placenta, Renee Elizabeth Albers
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The placenta is a complex and essential organ composed largely of fetal-derived cells, including several different trophoblast subtypes that work in unison to support nutrient transport to the fetus during pregnancy. Abnormal placental development can lead to pregnancy-associated disorders that often involve metabolic dysfunction. The scope of dysregulated metabolism during placental development may not be fully representative of the in vivo state in defined culture systems, such as cell lines or isolated primary cells. Thus, assessing metabolic function in intact placental tissue would provide a better assessment of placental metabolism. In this study, we describe a methodology for assaying glycolytic …
Phospholipase D: Key Player In Macrophage-Mediated Inflammation And Resolution, Ramya Ganesan
Phospholipase D: Key Player In Macrophage-Mediated Inflammation And Resolution, Ramya Ganesan
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Phospholipase D (PLD) is a cell membrane remodeling and signaling protein implicated in the pathology of chronic inflammation. As PLD is also central to macrophage cell migration, we investigated the molecular basis of PLD's involvement and regulation in macrophage-initiated inflammation (atherosclerosis) and resolution. We have found that PLD is associated with signaling proteins and positively affects cell movement, phagocytosis and NADPH-initiated release of Reactive Oxygen Species (ROS). We found that PLD2 but not PLD1 is important for foam cell formation that causes atherogenesis. We have also found a novel way of inducing macrophage class-switch (polarization) by PLD overexpression. PLD induces …
Proteomic Analysis Of Ischemic Stroke Blood Biomarkers, April Arnold Daubenspeck
Proteomic Analysis Of Ischemic Stroke Blood Biomarkers, April Arnold Daubenspeck
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Stroke is a global burden that claims 6 million lives and permanently disables another 5 million each year. The risk of morbidity and mortality following stroke decreases when early diagnosis and treatment are achieved. However there is no blood test to diagnose ischemic stroke because biomarkers to date have not shown adequate sensitivity and specificity to be adopted into hospital protocols. The overall objective of this dissertation was to identify novel blood protein biomarkers of ischemic stroke. We achieved this by using a number of proteomic and statistical techniques to investigate the differential abundance of proteins in the blood of …
Making Meaning: Shifts In Meaningfulness Across Three Modeling Units, Jeannette Manger
Making Meaning: Shifts In Meaningfulness Across Three Modeling Units, Jeannette Manger
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Recent reform calls for a more comprehensive approach to science education that positions learners as constructors of knowledge via scientific practices (NRC, 2012; Osborne, 2014). This 'practice turn' shifts from passive science learning to incorporating science actions with epistemic thinking (Duschl & Grandy, 2013; Ford & Forman, 2006; Osborne, 2014; Shouse, Schweingruber, & Duschl, 2007). Teachers are often underprepared in understanding the nuances of scientific practices, and frequently struggle with supporting students in meaningful practice engagement (Abd-El-Khalick & Akerson, 2004; Crawford, 1999; Davis, Petish, & Smithey, 2006; Duschl & Gitomer, 1997). Here, I draw upon the Berland et al. Epistemologies …
Analytical-Based Methodologies To Examine In Vitro Nanokinetics Of Silver Nanoparticles, Sesha Lakshmi Arathi Paluri
Analytical-Based Methodologies To Examine In Vitro Nanokinetics Of Silver Nanoparticles, Sesha Lakshmi Arathi Paluri
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Advancements in the nanotechnology have taken a huge leap in 21st century resulting in 1814 consumer products containing nanomaterials. About 47% of these products belong to the health and fitness sector and ~24% utilize silver nanoparticles (AgNPs). Despite the promising biomedical applications of AgNPs (e.g. bone cements, contrasting agents, and drug-carriers), lack of standardized methods for examining their nanokinetics (i.e., Absorption, Distribution, Metabolism, and Elimination (ADMEs)) limit their clinical implementation. The current work addresses this knowledge gap by developing analytical-based approaches for studying in vitro ADMEs of AgNPs. To demonstrate the versatility of these methodologies, two in vitro kidney study …
Dysregulation Of Phospholipase D (Pld) Isoforms Increases Breast Cancer Cell Invasion, Kristen Fite
Dysregulation Of Phospholipase D (Pld) Isoforms Increases Breast Cancer Cell Invasion, Kristen Fite
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Breast cancer remains the second most prevalent cancer among women in the U.S. with metastatic breast cancer having the worst prognosis. A rapidly proliferating tumor under various stressors will promote phenotypic cellular changes, known as epithelial-to-mesenchymal transition (EMT), which allows cells to begin to invade surrounding tissue, enter the circulatory system, and eventually seed a distant metastatic site. The phospholipase D (PLD) enzymes are critical regulators of cell signaling pathways necessary for cell migration. While the importance of PLD enzymes in cancer cell invasion is well known, clinically applicable methods of PLD inhibition are not yet available. The best-studied isoforms …
Identification Of Novel Ligands And Structural Requirements For Heterodimerization Of The Liver X Receptor Alpha, Shimpi Bedi
Identification Of Novel Ligands And Structural Requirements For Heterodimerization Of The Liver X Receptor Alpha, Shimpi Bedi
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LXRs, LXRa (NR1H3) and LXRß (NR1H2), are ligand-activated transcription factors that are members of the nuclear receptor superfamily. Oxysterols and nonsteroidal synthetic compounds bind directly to LXRs and influence the expression of LXR dependent genes. The use of murine models and LXR-selective agonists have established the important role of LXRs as sterol sensors that govern the absorption, transport, and catabolism of cholesterol. Upon activation, these receptors have been shown to increase reverse cholesterol transport from the macrophage back to the liver to aid in the removal of excess cholesterol. Not surprisingly, LXR dysregulation is a feature of several human diseases, …
A Novel System For Detection Of Dna Double Strand Breaks And Repair In Human Cells, Todd Warren Lewis
A Novel System For Detection Of Dna Double Strand Breaks And Repair In Human Cells, Todd Warren Lewis
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Imperative to genomic stability is the ability of the cell to repair damaged DNA which can occur from numerous endogenous byproducts of metabolism or exogenous components from the environment. The Fanconi anemia pathway is a DNA repair mechanism used by human cells to resolve multiple forms of DNA damage including interstrand crosslinks (ICL). Fanconi anemia (FA) is an autosomal recessive inherited disorder characterized by genome instability, developmental abnormalities, cancer predisposition and bone marrow failure. FA is attributed to a mutations in at least 18 genes (FANCA-FANCT) that play a concerted role in DNA repair. FANCT is the latest discovery in …
Persistent Inward Currents Play A Role In Muscle Dysfunction Seen In Myotonia Congenita, Ahmed Alaa Hawash
Persistent Inward Currents Play A Role In Muscle Dysfunction Seen In Myotonia Congenita, Ahmed Alaa Hawash
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Myotonia congenita is a rare skeletal muscle channelopathy caused by a reduced chloride channel (ClC-1) current, which results in debilitating muscle hyperexcitability, prolonged contractions, and transient episodes of weakness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. My in vitro intracellular recordings from a mouse homozygous knockout of ClC-1 revealed a slow after-depolarization (AfD) that triggers myotonic action potentials. The AfD is well-explained by a tetrododoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, thus providing the first mechanistic explanation for the …