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Full-Text Articles in Medicine and Health Sciences
Dopamine-Dependent Transcriptional Dynamics In Striatal Physiology And Cocaine Reward, Morgan Elizabeth Zipperly
Dopamine-Dependent Transcriptional Dynamics In Striatal Physiology And Cocaine Reward, Morgan Elizabeth Zipperly
All ETDs from UAB
Exposure to drugs of abuse alters transcriptional programs and neuronal activity, leading to long-lasting cellular and behavioral adaptations that may contribute to addiction. The nucleus accumbens (NAc), part of the mesocorticolimbic dopamine pathway, plays a central role in motivation, reward, and reward-related learning, and this brain region is highly implicated in the development and maintenance of addiction. However, the specific contributions of defined cell populations in the NAc to drug reward processes is still poorly understood. Here, we used electrophysiological, optogenetic, and single-nucleus RNA-sequencing (snRNA-seq) approaches in a rodent model system to define the acute physiological and transcriptional responses of …
Exploring The Roles Of Long Non-Coding Rnas In Glioblastoma Tumor Recurrence And Therapy Resistance, Christian Tyler Stackhouse
Exploring The Roles Of Long Non-Coding Rnas In Glioblastoma Tumor Recurrence And Therapy Resistance, Christian Tyler Stackhouse
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ABSTRACT Glioblastoma (GBM) is the most common and devastating primary CNS brain tumor with a median survival time of around 14 months. Most patients succumb to re-current disease which is often more malignant than the primary tumor and is frequently therapy resistant. There have not been significant advances in the treatment of GBM despite decades of research. This is partly due to the lack of accurate preclinical models and of the focus on primary rather than recurrent tumors. We created a 350 gene custom GBM-specific panel which contains 16 molecular signatures including molecular sub-typing signatures. We have demonstrated concordance of …
Exploring The Mechanism Of Cleavage And Secretion Of The Major Sperm Protein (Msp) Domain Of The Vapb/Vpr-1 Protein, Hala Zein-Sabatto
Exploring The Mechanism Of Cleavage And Secretion Of The Major Sperm Protein (Msp) Domain Of The Vapb/Vpr-1 Protein, Hala Zein-Sabatto
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VAPB is one of three mammalian VAP proteins. It is a type-II ER transmembrane protein whose N-terminal major sperm protein domain (MSPd) is cleaved and secreted. Since the MSPd faces the cytosol, rather than the ER lumen, how it is cleaved and secreted is not yet known. In humans, P56S is a substitution mutation within the VAPB protein that segregates with cases of familial Amyotrophic Lateral Sclerosis (ALS) and prevents the secretion of VAPB MSPd. The work described in this thesis uses C. elegans to study how the N-terminal MSPd of VAPB is proteolytically processed, secreted, and regulated. C. elegans …
From Pathology To Circuits: Loss Of Pink1 Function In Parkinson’S Disease, Rose Berthe Creed
From Pathology To Circuits: Loss Of Pink1 Function In Parkinson’S Disease, Rose Berthe Creed
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Parkinson’s disease (PD) is the most common neurogenerative motor disorder, affecting over 10 million people worldwide. Clinically, PD is diagnosed by presentation of hypokinetic movements such as bradykinesia, rigidity, and resting tremor. Additionally, PD patients have non-motor symptoms that include anosmia, constipation, and hypophonia. Current therapeutics have been successful in treating many of the locomotor symptoms, however no therapies stop or slow disease progression and the effectiveness of current medications diminishes as the symptoms invariably become more severe over the course of many years. Histopathologically, PD diagnosis is confirmed postmortem by two pathological hallmarks: 1. loss of dopaminergic neurons in …
Molecular Regulation Of Glioblastoma Spatial Heterogeneity And Therapeutic Resistance, Soniya Bastola
Molecular Regulation Of Glioblastoma Spatial Heterogeneity And Therapeutic Resistance, Soniya Bastola
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Glioblastoma multiforme (GBM) is a highly invasive, highly vascularized, and heterogeneous malignant tumor of the brain. Due to the highly infiltrative phenotype of GBM, surgery often leaves behind residual tumor cells. In many cases, recurrence occurs close to the surgical margin suggesting the role of these remaining cells in promoting tumor aggressiveness. Rapidly growing tumor creates subsequent hypoxic, and hypovascular core due to limited nutrients, whereas tumor cells in the leading edge have access to nutrients from vasculature enriched microenvironment. Studies have identified the cellular and molecular heterogeneity between the tumors in core and edge. Still, their mechanisms of intercellular …
Copper Dependent Inhibitors Subvert Common Resistance Mechanisms In Staphylococcus Aureus And Inhibit Crucial Metabolic Pathways, Cameron Crawford
Copper Dependent Inhibitors Subvert Common Resistance Mechanisms In Staphylococcus Aureus And Inhibit Crucial Metabolic Pathways, Cameron Crawford
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The effective antibiotic pool is shrinking with antibiotic resistance a constant problem that threatens to make our current therapies obsolete. To combat this, new drug screening methodologies are required since the traditional drug screens are offering limited results or only improvements upon current treatments. This work expands upon the idea that transition metal toxicity can be preferentially targeted towards bacteria. Specifically, the focus is on copper dependent inhibitors that quickly work to eliminate Staphylococcus aureus. S. aureus is a particularly threatening bacteria with high strain variability, a litany of survival and virulence factors, and multiple drug resistance mechanisms that are …
Diurnal Dysfunction In Control Of Sodium Excretion In Diet-Induced Obesity, Reham Soliman
Diurnal Dysfunction In Control Of Sodium Excretion In Diet-Induced Obesity, Reham Soliman
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The renal endothelin system plays a key role in sodium excretion, particularly under high salt (HS) diet. HS stimulates renal endothelin-1 (ET-1), which binds and activates the endothelin receptor B (ETB) to excrete the excess salt. Loss of ETB receptor is linked to the development of hypertension under HS. Central clock genes are important in maintaining rhythmic patterns of sodium excretion and ET-1 is identified as a target for clock genes, including Period and Bmal1. ET-1 excretion follows a diurnal rhythm along with sodium excretion. Sexual dimorphism is evident in the diurnal regulation of endothelin-mediated natriuresis and its downstream targets. …
Mitochondrial Priming Of Tumor Initiating Cells Involves Repression Of Mitochondrial Fission Activity Towards Redox Regulation Of The Cell Cycle Regulator Cyclin E, Brian Spurlock
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Mitochondrial dynamics primarily refers to the opposing fission or fusion events between individual mitochondria, which maintains steady-state mitochondrial morphology in cells. Fission and fusion activities maintain the energetics of normal and neoplastic stem cells. We developed the novel approach mito-SinCe2 to study the bidirectional relationship between mitochondrial dynamics and energetics. Application of this method led to the hypothesis that mitochondria-dependent ovarian tumor initiating cells interconvert between 3 states with distinct mitochondrial energetics/dynamics relationships. Cells in one state, characterized by high mitochondrial ROS and low fission activity, appear to be primed for self-renewal by mitochondria. We call these cells mitochondria-primed stem …
Toxin Secretion By Mycobacterium Tuberculosis, Uday Tak
Toxin Secretion By Mycobacterium Tuberculosis, Uday Tak
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Mycobacterium tuberculosis (Mtb) is a highly infectious airborne bacterial pathogen, and the causative agent of human tuberculosis. Mtb infects approximately one-third of the human population, and is responsible for more deaths than any other infectious disease in the history of mankind. Mtb is an intracellular pathogen and primarily infects myeloid cells, such as macrophages in the human lung. In macrophages, Mtb establishes a replication niche within membrane-bound vacuoles named phagosomes, while subverting immunity. The intracellular survival of Mtb depends on manipulation of host cellular processes through secreted effector proteins. Ultimately, this intracellular vacuole is ruptured by the type VII secretion …
Immunopathogenesis In Fungal Asthma, Matthew Stephen Godwin
Immunopathogenesis In Fungal Asthma, Matthew Stephen Godwin
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Asthma patients are increasingly presenting with asthma that is more difficult to control and treat than in years past. A subset of these patients who are sensitive to fungal species are described as having severe asthma with fungal sensitization (SAFS). Given the severity of disease, there is ever increasing interest in identifying the immune processes underlying SAFS disease pathology and the development of novel therapeutics to improve management. While sensitivity to multiple fungal species has been described in SAFS, none is more common than Aspergillus fumigatus. Here, we describe two previously unrecognized contributors to the amelioration of disease pathology in …
Gp44, A Minor Protein With A Major Role In Bacteriophage 80Α Infection, Keith Allen Manning
Gp44, A Minor Protein With A Major Role In Bacteriophage 80Α Infection, Keith Allen Manning
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Bacteriophage 80α is a temperate double-stranded DNA phage that infects Staphylococcus aureus and is capable of mobilizing a variety of mobile genetic elements named S. aureus Pathogenicity Islands. The capsid of the mature virion is composed of subunits of the capsid protein, portal protein, and a minor capsid protein gp44 as well as packaged phage genomic DNA. The loss of the gp44 protein completely eliminates the phage titer of 80α but does not eliminate the transduction of the pathogenicity islands. In this dissertation, I show that the minor capsid protein is primarily active in a post-ejection role. Without gp44 the …
Downstream Pathways Of Glucagon Receptor Agonism In Obesity, Shelly Nason
Downstream Pathways Of Glucagon Receptor Agonism In Obesity, Shelly Nason
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Obesity is highly prevalent and strategies to improve weight loss maintenance are critical for healthcare. Behavioral interventions are effective but require major lifestyle changes that are often difficult to maintain long-term. Therefore, modifying energy balance with pharmacotherapy is a strategy to combine with lifestyle modifications for sustained weight loss. Glucagon, a hormone involved in maintaining glucose homeostasis, also regulates energy expenditure, food intake, and lipid metabolism. As such, glucagon-based therapies have gained attention as an attractive clinical target. Glucagon Receptor (GCGR) mono-agonism induces glucose intolerance; therefore, dissecting the mechanisms by which GCGR signaling mediates energy balance are clinically relevant to …
Deficiency Of Tumor Suppressor Merlin Induces Metabolic Reprogramming In Breast Cancer, Mateus Mota
Deficiency Of Tumor Suppressor Merlin Induces Metabolic Reprogramming In Breast Cancer, Mateus Mota
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The tumor suppressor Merlin is encoded by Neurofibromin 2 (NF2) gene. Merlin is predominantly located in the cell cortex where regulates cell proliferation by mediating cell contact-dependent growth inhibition. Metastatic breast cancer tissues presented with a remarkable loss of Merlin protein, revealing clinical relevance of Merlin. In order to examine the cellular effect of Merlin deficiency, breast cancer cell lines were silenced for NF2. Additionally, to assess the impact of Merlin loss at the organismal level, a mammary-specific NF2 knockout mouse mammary tumor model was engineered. Merlin deficiency induced a metabolic shift from mitochondrial oxidative phosphorylation to aerobic glycolysis. Furthermore, …
Novel Hiv Adaptation Strategy Against Host Cd8 T Cell Immunity, Kai Qin
Novel Hiv Adaptation Strategy Against Host Cd8 T Cell Immunity, Kai Qin
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Since the 1980s, HIV infection has caused millions of death and tremendous economic losses worldwide. Despite great scientific advances, the only effective therapy to date, antiretroviral therapy (ART), merely delays disease progression yet cannot eradicate viral infection. Therefore, an effective HIV vaccine that can prevent the acquisition of infection would be a desirable alternative. The critical role of CD8 T-cell immunity in HIV infection has been well documented and therefore not surprisingly a great deal of effort has been focused on developing an effective CD8 T-cell based HIV vaccine. However, by far, such CD8 T-cell based HIV vaccine trials have …
Noninvasive Neuromodulation Using A Benchtop Approach To Mri-Guided Focused Ultrasound Blood Brain Barrier Opening, Megan Rich
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Fundamental neuroscience research has provided a deeper understanding of the genes, molecules and cellular circuitry involved in neurological disorders, however translating discovery into clinical application remains a major challenge. This bench to bedside gap is in part due to the discrepancy in techniques used in the laboratory vs. the clinic for targeting the mechanisms that underlie disease. Ideally this discrepancy would be resolved not only by implementing novel clinical techniques to provide more precise targeting of disease foci, but also by using the same techniques in the clinic that are used at the lab bench to provide a direct bench …
Role Of Endogenous Tau In Lewy-Like Pathology, Lindsay Stoyka
Role Of Endogenous Tau In Lewy-Like Pathology, Lindsay Stoyka
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Lewy Body Diseases (LBDs) are a group of disorders characterized by intracellular inclusions of misfolded alpha-synuclein (α-synuclein). Of these, Parkinson’s Disease (PD) is the most common neurodegenerative movement disorder, and Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative dementia. PD is characterized clinically by bradykinesia, resting tremor, rigidity, and postural instability. In addition, up to 80% of patients eventually develop dementia, termed Parkinson’s Disease Dementia (PDD). DLB is characterized by onset of dementia before or concurrently with parkinsonism. Currently, no disease-modifying therapies exist for either of these diseases. Lewy pathology is found in regions important for cognition …
Distinct Tissue Specific Functions Of Bone Marrow Regulatory T Cells, And Their Therapeudic Applications In Myeloid Neoplasms, Virginia Camacho
Distinct Tissue Specific Functions Of Bone Marrow Regulatory T Cells, And Their Therapeudic Applications In Myeloid Neoplasms, Virginia Camacho
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In the bone marrow, Regulatory T cells (Tregs) constitute nearly 30% of CD4+ T cells, a significantly higher ratio than other tissues. Although a few of the mechanisms by which Tregs regulate normal hematopoiesis have been elucidated, our understanding of this process during leukemogenesis is ex-tremely limited. In this work, we define how Tregs maintain and support the bone marrow microenvironment. We propose that the role of Tregs extends be-yond their canonical immuno-suppressive function and that these cells are re-quired to maintain healthy hematopoiesis. We have defined tissue-specific roles for Tregs in the bone marrow including the maintenance of hematopoietic …
Understanding And Targeting Glucose Transporter 3 In Glioblastoma, Catherine Jeanne Libby
Understanding And Targeting Glucose Transporter 3 In Glioblastoma, Catherine Jeanne Libby
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Glioblastoma (GBM) is the most common adult primary malignant brain tumor with a median survival of about 15 months, even after aggressive treatment. Treatment of GBM is difficult for multiple reasons including the location of the tumor, tumor invasiveness, and the high degree of both inter-and intra-tumoral heterogeneity. Contributing to intratumoral heterogeneity are highly tumorigenic, stem-like tumor cells, with the capacity to self-renew and propagate the tumor, termed brain tumor initiating cells (BTICs). BTICs are also commonly therapy resistant, highly invasive, and metabolically plastic with elevated expression of glucose transporter 3 (GLUT3) allowing them to preferentially survive in low nutrient …
Cd8 T-Cell Responses To A Diverse Virus: Adaptation And Cross-Reactivity In Hiv Vaccination, Sushma Boppana
Cd8 T-Cell Responses To A Diverse Virus: Adaptation And Cross-Reactivity In Hiv Vaccination, Sushma Boppana
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In the four decades since human immunodeficiency virus (HIV) was discovered, significant progress has been made in treating HIV infection and in understanding the viral and immune dynamics underlying disease pathogenesis. However, in spite of scientific advances, HIV remains a significant global health issue, and an effective preventative vaccine has yet to be created. Many groups have demonstrated the importance of CD8 T cells in viral control during natural HIV infection and believe that CD8 T cells could contribute to vaccine efficacy by alleviating disease course in individuals who became infected despite vaccination. One major obstacle to inducing potent CD8 …
Impact Of Diet And Meal Timing On Time-Of-Day Dependent Hippocampal Function, Jennifer Davis
Impact Of Diet And Meal Timing On Time-Of-Day Dependent Hippocampal Function, Jennifer Davis
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Circadian rhythms are biological processes that cycle every ~24 hours and have allowed life to adapt for optimal function across the day. These rhythms are present in all tissues in the body and are coordinated to the light/dark cycle by the suprachiasmatic nucleus (SCN) in the hypothalamus. Along with active-rest cycles, cognitive performance fluctuates across the course of the day, peaking during the active phase. In addition to the light cycle, food and meal timing can provide signaling cues to extra-SCN tissues. Food access only during the inactive phase results in weight gain and memory impairment. High fat diet protocols …
Enhancer Rnas As Regulators Of Gene Expression And Neuronal Function, Nancy Verena Nicole Carullo
Enhancer Rnas As Regulators Of Gene Expression And Neuronal Function, Nancy Verena Nicole Carullo
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Genomic enhancers are cis-regulatory elements in the DNA that exhibit spatial and temporal control over intricate gene expression programs shaping fate and function of heterogeneous cell populations in the developing and adult brain. In addition to their role in cellular development and maintenance, enhancer activity drives transcriptional changes in response to stimulation. Active enhancers are subject to bidirectional transcription that yields non-coding enhancer RNAs (eR-NAs). However, the functional role of eRNAs in transcriptional regulation remains controversial. Therefore, we used primary neuronal cultures to investigate en-hancers and eRNAs in the rat genome. We identified and verified enhancer-gene pairs, characterized their response …
Pharmacodynamic Responses And Efficacies Associated With Lrrk2 Inhibition, Kaela Kelly
Pharmacodynamic Responses And Efficacies Associated With Lrrk2 Inhibition, Kaela Kelly
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Parkinson’s disease (PD) is an age-related, progressive, movement disorder pathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous aggregates, termed Lewy bodies, that are largely comprised of αSynuclein (αSyn). Missense mutations in the leucine-rich repeat kinase (LRRK2) gene are the most common genetic cause of PD and lead to gain-of-function increases in kinase activity. The G2019S-LRRK2 mutation is the most frequent mutation and elevates kinase activity by ~2-3 fold. Genetic and biochemical evidence suggest elevated LRRK2 kinase activity plays a pathogenic role in the development of PD, implicating LRRK2 …
Understanding The Impact Of Diet And Obesity On Anti-Tumor Immunity And Therapeutic Efficacy In Kidney Cancer, Rachael Miller Orlandella
Understanding The Impact Of Diet And Obesity On Anti-Tumor Immunity And Therapeutic Efficacy In Kidney Cancer, Rachael Miller Orlandella
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Obesity is regarded as a major risk factor for developing renal cell carcinoma (RCC). Advanced-stage RCC exhibits chemotherapeutic resistance, but is responsive to immunotherapies such as the immune checkpoint inhibitor anti-programmed cell death-1 (anti-PD-1). Despite some clinical successes, response rates remain low for anti-PD-1 monotherapy (20-30%). Preclinical evaluations of immunotherapeutic strategies typically use lean mice and do not account for patient comorbidities. This may explain the underwhelming success rates following clinical translation of new cancer treatments. Recent studies found that obesity was associated with favorable outcomes and responses to immunotherapy in melanoma. However, the effects of obesity on anti-tumor immunity …
Disease Specific Dysregulation Of Stat1 And Stat5 Activation In Mature Cd4+ And Cd8+ T Cells Influences Enhanced Kinetic Responses And Inflammation In Patients With Treatment-Naïve Relapsing Remitting Multiple Sclerosis (Rrms), Brandon Jay Pope
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Autoimmunity is propagated through the lack of effective mechanisms of central and peripheral tolerance. In relapsing remitting multiple sclerosis (RRMS), dysregulated adaptive immune cells have been shown to contribute to disease morbidity through the influence of immune-modulating cytokines in the peripheral blood. Interleukin-2 (IL-2) is a cytokine with several key functions in regulating homeostatic mechanisms within the human immune system. Interferon gamma (IFNγ) is a type II interferon that is needed for an effective response to intracellular bacteria infection through the actions of Th1 cells. IL-2 and IFNγ signaling occurs primarily through signal transducer and activator of transcription (STAT) activation. …
Novel Mechanisms Of Nitric Oxide Activation In The Kidney, Randee Sedaka
Novel Mechanisms Of Nitric Oxide Activation In The Kidney, Randee Sedaka
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Globally, adult sodium consumption has far exceeded daily intake recommendations, leading to one in ten cardiovascular deaths. Given the rise in hypertension prevalence, uncontrolled hypertension with antihypertensive medication use, and significant associations between high salt intake and high blood pressure, there is a need to better understand the mechanisms involved in hypertension. Nitric oxide synthase 1 (NOS1) is a well-established regulator of fluid and electrolyte balance in the renal collecting duct (CD) with highest activity in the inner medulla (IM). We previously reported that high salt (HS) intake stimulates CD endothelin B receptor (ETBR)/NOS1-dependent generation of NO, thereby inhibiting the …
Rab27 And 14-3-3 Mediated Regulation Of Alpha-Synuclein Pathology, Rachel Nicole Underwood
Rab27 And 14-3-3 Mediated Regulation Of Alpha-Synuclein Pathology, Rachel Nicole Underwood
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Alpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies (LBs) that pathologically define a group of disorders known as synucleinopathies, including Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn is thought to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it templates the misfolding of endogenous αsyn. Identifying regulators of this process is essential to understanding how αsyn propagates and furthers disease progression. In this study, we investigated Rab27 and 14-3-3θ …
Gene–Environment Interaction In Parkinson Disease: The Gut Microbiome, Zachary D. Wallen
Gene–Environment Interaction In Parkinson Disease: The Gut Microbiome, Zachary D. Wallen
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GENE–ENVIRONMENT INTERACTION IN PARKINSON DISEASE: THE GUT MICROBIOME ZACHARY D. WALLEN GENETICS, GENOMICS, AND BIOINFORMATICS ABSTRACTParkinson disease (PD) is a progressive neurodegenerative disease with no cure. Majority of cases are idiopathic, and the cause is unknown. Studies have been conducted in human and animals to identify PD risk factors, resulting in a list of genetic and environmental factors that modestly increases risk of PD. Still, no individual risk factor fully explains the cause of PD, and neither has the combination of these factors. Additional avenues of research are being investigated to find potential triggers of PD, and factors that might …
Co-Factors In Fgf Signaling, Christopher Yanucil
Co-Factors In Fgf Signaling, Christopher Yanucil
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The fibroblast growth factor (FGF) family consists of a group of proteins whose diverse biological functions are mediated by receptor tyrosine kinases, termed FGF receptors (FGFR) 1-4. While paracrine FGFs require heparin sulfate as a co-factor for FGFR bind-ing and signaling, it has been assumed that endocrine FGFs, such as FGF23, do not bind heparin but instead require klotho, a family of transmembrane proteins, as a co-receptor on specific target cells. FGF23 acts as bone-derived hormone that targets tubular epitheli-al cells in the kidney via FGFR1 and α-klotho to reduce renal phosphate uptake. In chron-ic kidney disease (CKD), the kidney …
Protective Effects Of Thioredoxin Reductase Inhibition In The Murine Lung: The Regulation And Contribution Of Heme Oxygenase-1, Katelyn Louise Dunigan
Protective Effects Of Thioredoxin Reductase Inhibition In The Murine Lung: The Regulation And Contribution Of Heme Oxygenase-1, Katelyn Louise Dunigan
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Endogenous antioxidant responses defend the lung against oxygen toxicity. In premature neonates, oxygen toxicity and impaired antioxidant defenses contribute to the development of bronchopulmonary dysplasia (BPD), the leading cause of long-term morbidity among premature infants. In adults, oxygen toxicity and impaired antioxidant defense contributes to the pathogenesis of acute lung injury (ALI). Acute Respiratory Distress Syndrome (ARDS), a severe form of ALI, can cause permeant lung damage and mortality. Our lab has established that pharmacologic thioredoxin reductase-1 (TXNRD1) inhibition attenuates lung injury in murine BPD and ALI models. The protective effects of TXNRD1 inhibition are mediated by the activation of …
Contribution Of Adaptive Immune Responses In Chronic Lung Diseases, Thi Kim Tran-Nguyen
Contribution Of Adaptive Immune Responses In Chronic Lung Diseases, Thi Kim Tran-Nguyen
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Immune dysregulation is a hallmark of various chronic lung diseases such as Chronic Obstructive Pulmonary Diseases (COPD) and Idiopathic Pulmonary Fibrosis (IPF). Previous studies in our lab have shown evidences of autoimmunity such as increases in autoantibodies, abnormal T cell profile, immune complex deposition and the presence of ectopic lymphoid structures in the lung of these patients. This thesis consolidates two separate projects about various aberrant immune responses in these diseases. The first project identified Glucose-Regulated-Protein 78 (GRP78) as the common autoantigen in COPD and characterized how GRP78 autoantibodies may increase COPD mortality via its atherogenic effects. I demonstrated that …