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Hypervirulent Chlamydia Trachomatis Clinical Strain Is A Recombinant Between Lymphogranuloma Venereum (L(2)) And D Lineages, Naraporn Somboonna, Raymond Wan, David M. Ojcius, Matthew A. Pettengill, Sandeep J. Joseph, Alexander Chang, Ray Hsu, Timothy D. Read, Deborah Dean

All Dugoni School of Dentistry Faculty Articles

Chlamydia trachomatis is an obligate intracellular bacterium that causes a diversity of severe and debilitating diseases worldwide. Sporadic and ongoing outbreaks of lymphogranuloma venereum (LGV) strains among men who have sex with men (MSM) support the need for research on virulence factors associated with these organisms. Previous analyses have been limited to single genes or genomes of laboratory-adapted reference strain L₂/434 and outbreak strain L₂b/UCH-1/proctitis. We characterized an unusual LGV strain, termed L₂c, isolated from an MSM with severe hemorrhagic proctitis. L₂c developed nonfusing, grape-like inclusions and a cytotoxic phenotype in culture, …

The Natural Polyphenol Resveratrol Potentiates The Lethality Of Hdac Inhibitors In Acute Myelogenous Leukemia Cells Through Multiple Mechanisms., Alae Abod Yaseen

Theses and Dissertations

This study examined the mechanisms underlying the interactions between the natural polyphenol Resveratrol and HDAC inhibitors in both U937 myelomonocytic leukemia cell line and blood samples from AML patients and normal cord blood. Simultaneous exposure to Resveratrol and HDAC inhibitors (Vorinostat-SAHA or Panobinostat-LBH589) resulted in potentiating the lethality caused by any single agent of the combination, this interaction found to be synergistic at multiple concentrations. Exposing U937 cells to minimal toxic doses of Resveratrol and HDACIs results in release of mitochondrial pro-apoptotic proteins AIF and cytochrome c, pro-apoptotic caspase activation especially caspase-8, and induction of DNA damage. These events were …

The Effect Of Dopamine Therapy On Ventral And Dorsal Striatum-Mediated Cognition In Parkinson's Disease: Support From Functional Mri., Penny A Macdonald, Alex A Macdonald, Ken N Seergobin, Ruzbeh Tamjeedi, Hooman Ganjavi, Jean-Sebastien Provost, Oury Monchi

Brain and Mind Institute Researchers' Publications

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson's disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson's disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus …

Role Of Protein Kinase C Zeta (Pkcζ) In Regulation Of Epithelial Tight Junctions, Suneet Kumar Jain

Theses and Dissertations (ETD)

Occludin is hyperphosphorylated on Ser and Thr residues in intact epithelial tight junctions. The dynamics of epithelial tight junctions appear to involve reversible phosphorylation of occludin on Ser and Thr residues. In the present study we determined the role of PKCζ in occludin phosphorylation and the dynamics of tight junctions. Inhibition of PKCζ by specific PKCζ pseudo substrate rapidly reduced TER, increased inulin permeability and induced redistribution of occludin and ZO‑1 in Caco‑2 and MDCK cell monolayers without inducing cytotoxicity. Reduced expression of PKCζ also resulted in compromised tight junction integrity. Both PKCζ pseudo substrate and reduced expression of PKCζ …

Noise, Delays, And Resonance In A Neural Network, Austin Quan

HMC Senior Theses

A stochastic-delay differential equation (SDDE) model of a small neural network with recurrent inhibition is presented and analyzed. The model exhibits unexpected transient behavior: oscillations that occur at the boundary of the basins of attraction when the system is bistable. These are known as delay-induced transitory oscillations (DITOs). This behavior is analyzed in the context of stochastic resonance, an unintuitive, though widely researched phenomenon in physical bistable systems where noise can play in constructive role in strengthening an input signal. A method for modeling the dynamics using a probabilistic three-state model is proposed, and supported with numerical evidence. The potential …

The Association Between Hydroxyurea Treatment And Pain Intensity, Analgesic Use, And Utilization In Ambulatory Sickle Cell Anemia Patients., Wally R Smith, Samir K Ballas, William F Mccarthy, Robert L Bauserman, Paul S Swerdlow, Martin H Steinberg, Myron A Waclawiw, Investigators Of The Multicenter Study Of Hydroxyurea In Sickle Cell Anemia

Department of Medicine Faculty Papers

Background.  We compared daily pain, home analgesic use, and utilization among ambulatory adults in the randomized Multicenter Study of Hydroxyurea in Sickle Cell Anemia (MSH). We related the fetal hemoglobin (HbF) hydroxyurea response to these response variables. Methods.  Patients rated their sickle cell pain intensity (0-9), use of analgesics, and visits for pain daily. Diaries were collected biweekly, and intensity was collapsed into single interval ratings. The interval proportions of days of analgesic use and medical visits for pain were also calculated. Group comparisons were made by intention to treat as well as by HbF change levels from baseline to …

The Interplay Between Nf-Kappab And E2f1 Coordinately Regulates Inflammation And Metabolism In Human Cardiac Cells., Xavier Palomer, David Álvarez-Guardia, Mercy M Davidson, Tung O Chan, Arthur M Feldman, Manuel Vázquez-Carrera

Department of Medicine Faculty Papers

Pyruvate dehydrogenase kinase 4 (PDK4) inhibition by nuclear factor-κB (NF-κB) is related to a shift towards increased glycolysis during cardiac pathological processes such as cardiac hypertrophy and heart failure. The transcription factors estrogen-related receptor-α (ERRα) and peroxisome proliferator-activated receptor (PPAR) regulate PDK4 expression through the potent transcriptional coactivator PPARγ coactivator-1α (PGC-1α). NF-κB activation in AC16 cardiac cells inhibit ERRα and PPARβ/δ transcriptional activity, resulting in reduced PGC-1α and PDK4 expression, and an enhanced glucose oxidation rate. However, addition of the NF-κB inhibitor parthenolide to these cells prevents the downregulation of PDK4 expression but not ERRα and PPARβ/δ DNA binding activity, …

Δnp63 Regulates A Complex Network Of Target Genes In Limb And Epidermal Development, Min Soon Cho

Dissertations and Theses (Open Access)

The skin is composed of two major compartments, the dermis and epidermis. The epidermis forms a barrier to protect the body. The stratified epithelium has self-renewing capacity throughout life, and continuous turnover is mediated by stem cells in the basal layer. p63 is structurally and functionally related to p53. In spite of their structural similarities, p63 is critical for the development and maintenance of stratified epithelial tissues, unlike p53. p63 is highly expressed in the epidermis and previously has been shown to play a critical role in the development and maintenance of the epidermis. The study of p63 has been …

Microarray-Based Analysis Of Differential Gene Expression Between Infective And Noninfective Larvae Of Strongyloides Stercoralis., Roshan Ramanathan, Sudhir Varma, José M C Ribeiro, Timothy G Myers, Thomas J Nolan, David Abraham, James B Lok, Thomas B Nutman

Department of Microbiology and Immunology Faculty Papers

BACKGROUND: Differences between noninfective first-stage (L1) and infective third-stage (L3i) larvae of parasitic nematode Strongyloides stercoralis at the molecular level are relatively uncharacterized. DNA microarrays were developed and utilized for this purpose.

METHODS AND FINDINGS: Oligonucleotide hybridization probes for the array were designed to bind 3,571 putative mRNA transcripts predicted by analysis of 11,335 expressed sequence tags (ESTs) obtained as part of the Nematode EST project. RNA obtained from S. stercoralis L3i and L1 was co-hybridized to each array after labeling the individual samples with different fluorescent tags. Bioinformatic predictions of gene function were developed using a novel cDNA Annotation …

Comparison Of Human Memory Cd8 T Cell Responses To Adenoviral Early And Late Proteins In Peripheral Blood And Lymphoid Tissue., Amita Joshi, Biwei Zhao, Cara Romanowski, David Rosen, Phyllis Flomenberg

Department of Microbiology and Immunology Faculty Papers

Treatment of invasive adenovirus (Ad) disease in hematopoietic stem cell transplant (SCT) recipients with capsid protein hexon-specific donor T cells is under investigation. We propose that cytotoxic T cells (CTLs) targeted to the late protein hexon may be inefficient in vivo because the early Ad protein E3-19K downregulates HLA class I antigens in infected cells. In this study, CD8+ T cells targeted to highly conserved HLA A2-restricted epitopes from the early regulatory protein DNA polymerase (P-977) and late protein hexon (H-892) were compared in peripheral blood (PB) and tonsils of naturally infected adults. In tonsils, epitope-specific pentamers detected a significantly …

The Biochemical Pathway Leading To Lpa Generation Upon Blood Coagulation, Alyssa Lynn Jefferson Bolen

Theses and Dissertations (ETD)

Platelet activation initiates an upsurge in 18:2 and 20:4 lysophosphatidic acid (LPA) production. The biochemical pathway responsible for LPA production during blood clotting is not fully understood. We have purified a phospholipase A₁ (PLA₁) from thrombin-activated human platelets using sequential chromatographic steps followed by fluorophosphonate‑biotin affinity labeling and proteomics. We identified acyl‑protein thioesterase 1 (aka. lysophospholipase A1, accession code O75608) as a novel PLA₁. Addition of this recombinant PLA₁ significantly increased the production of sn‑2‑esterified polyunsaturated LPCs and the corresponding LPAs in plasma. We next examined the regioisomeric preference of lysophospholipase …

Characterization Of The Sigma Factor Proteins And The Dna Binding Protein Euo Of Chlamydia, Cory L. Blackwell

Theses and Dissertations (ETD)

Chlamydia spp. are prokaryotic obligate intracellular pathogens with a unique, biphasic developmental cycle in which an infectious, extracellular form termed the elementary body (EB) interconverts with a metabolically active intracellular reticulate body (RB) within host cells. Subsets of genes are differentially expressed during the developmental cycle, and these genes are believed to be responsible for the transitions between the EB and RB forms. The goal of these studies was to explore two potential mechanisms that may function in regulating developmental cycle stage‑specific gene expression in chlamydiae: a cascade of sigma factor expression and the binding of the early stage protein …

Insights Into P53-Dependent Apoptotic Signaling And Cell Fate Vis-A-Vis Functional Cooperation Among Bcl-Xl, Cytoplasmic P53, And Puma, John C. Fisher

Theses and Dissertations (ETD)

Following DNA damage, nuclear p53 induces the expression of PUMA (p53 upregulated modulator of apoptosis), a BH3‑only protein that binds and inhibits the anti‑apoptotic BCL‑2 repertoire, including BCL‑xL. Structural investigations of PUMA and the BCL‑xL×PUMA BH3 domain complex by X‑ray crystallography and nuclear magnetic resonance (NMR) spectroscopy reveal a novel, PUMA‑induced, domain‑swapped dimerization of BCL‑xL that requires a π‑stacking interaction between PUMA W71 and BCL‑xL H113. PUMA is an intrinsically disordered protein, but upon interaction with BCL‑xL, PUMA W71 and the PUMA BH3 domain residues fold into an alpha helix and subtly remodel BCL‑xL to trigger its dimerization. Wild type …

Novel Insights Into Ubiquitin-Like Protein E1-E2 Interactions, Asad Taherbhoy

Theses and Dissertations (ETD)

Posttranslational modification of macromolecules by ubiquitin-like proteins (UBLs) such as ubiquitin, Sumo and NEDD8 regulate a vast array of processes in the cell. Transfer of UBLs to their target generally occurs by a series of molecular handoffs down an E1‑E2‑E3 cascade. We are interested in understanding how E1‑E2 pairs interact and mediate UBL transfer. To this effect, we studied two E1‑E2 pairs: the Sumo pathway (Sumo utilizes a canonical E1 and E2) and the Atg8 pathway (Atg8 is a UBL involved in autophagy that utilizes a non-canonical E1‑E2 pair).

Sumo conjugation is initiated by the heterodimeric Aos1‑Uba2 E1 enzyme (in …

Mitostatin Is Down-Regulated In Human Prostate Cancer And Suppresses The Invasive Phenotype Of Prostate Cancer Cells., Matteo Fassan, Domenico D'Arca, Juraj Letko, Andrea Vecchione, Marina P Gardiman, Peter Mccue, Bernadette Wildemore, Massimo Rugge, Dolores Shupp-Byrne, Leonard G Gomella, Andrea Morrione, Renato V Iozzo, Raffaele Baffa

Kimmel Cancer Center Faculty Papers

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in …

Defining The Role Of Egfr Acetylation In Cellular Processes: Clinical Implications, Hui Song

Dissertations and Theses (Open Access)

Epidermal growth factor receptor (EGFR) is a cell membrane tyrosine kinase receptor and plays a pivotal role in regulating cell growth, differentiation, cell cycle, and tumorigenesis.  Deregulation of EGFR causes many diseases including cancers.  Intensive investigation of EGFR alteration in human cancers has led to profound progress in developing drugs to target EGFR-mediated cancers.  While exploring possible synergistic enhancement of therapeutic efficacy by combining EGFR tyrosine kinase inhibitors (TKI) with other anti-cancer agents, we observed that suberoylanilide hydroxamic acid (SAHA, a deacetylase inhibitor) enhanced TKI-induced cancer cell death, which further led us to question whether SAHA-mediated sensitization to TKI was …

Role Of Gsh Metabolism In Mediating Stromal-Leukemia Interaction And Promoting Cell Survival And Drug Resistance In Chronic Lymphocytic Leukemia, Wan Zhang

Dissertations and Theses (Open Access)

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the western countries. The interaction between CLL cells and the bone marrow stromal environment is thought to play a major role in promoting the leukemia cell survival and drug resistance. My dissertation works proved a novel biochemical mechanism by which the bone marrow stromal cells exert a profound influence on the redox status of primary CLL cells and enhance their ability to sustain oxidative stress and drug treatment. Fresh leukemia cells isolated from the peripheral blood of CLL patients exhibited two major redox alterations when they were cultured alone: …

Risk Of Second Malignant Neoplasms Following Proton Arc Therapy And Volumetric Modulated Arc Therapy For Prostate Cancer, Laura A. Rechner

Dissertations and Theses (Open Access)

The risk of second malignant neoplasms (SMNs) following prostate radiotherapy is a concern due to the large population of survivors and decreasing age at diagnosis. It is known that parallel-opposed beam proton therapy carries a lower risk than photon IMRT. However, a comparison of SMN risk following proton and photon arc therapies has not previously been reported. The purpose of this study was to predict the ratio of excess relative risk (RRR) of SMN incidence following proton arc therapy to that after volumetric modulated arc therapy (VMAT). Additionally, we investigated the impact of margin size and the effect …

The Effects Of Curcumin On Body Composition Of Patients With Advanced Pancreatic Cancer, Henrique A. Parsons Md

Dissertations and Theses (Open Access)

Cachexia is very common among patients with advanced pancreatic cancer and is a marker of poor prognosis. Weight loss in cachexia is due to both adipose and muscle compartments, and sarcopenia (severe muscle depletion) is associated with worse outcomes. Curcumin has shown a myriad of biological effects, including anti-cancer and anti-inflammatory. The ability of curcumin to attenuate cachexia and muscle loss has been tested in animal models, with conflicting results so far. The hypothesis of this study was that patients with advanced pancreatic cancer treated with curcumin for two months have less fat and muscle loss as compared to matched …

Prevalence Of Premature Ovarian Failure In Women With Tuberous Sclerosis, Emily Gabitzsch

Dissertations and Theses (Open Access)

Tuberous Sclerosis Complex (TSC) is an autosomal dominant tumor suppressor disorder characterized by hamartomas, or benign growths, in various organ systems. Inactivating mutations in either the TSC1 or the TSC2 gene cause most cases of TSC. Recently, the use of ovarian specific conditional knock-out mouse models has demonstrated a crucial role of the TSC genes in ovarian function. Mice with complete deletion of Tsc1 or Tsc2 showed accelerated ovarian follicle activation and subsequent premature follicular depletion, consistent with the human condition premature ovarian failure (POF). POF is defined in women as the cessation of menses before the age of 40 …

A Phase I/Iia Clinical Trial Of A Recombinant Rho Protein Antagonist In Acute Spinal Cord Injury., Michael G Fehlings, Nicholas Theodore, James Harrop, Gilles Maurais, Charles Kuntz, Chris I Shaffrey, Brian K Kwon, Jens Chapman, Albert Yee, Allyson Tighe, Lisa Mckerracher

Department of Neurosurgery Faculty Papers

Multiple lines of evidence have validated the Rho pathway as important in controlling the neuronal response to growth inhibitory proteins after central nervous system (CNS) injury. A drug called BA-210 (trademarked as Cethrin(®)) blocks activation of Rho and has shown promise in pre-clinical animal studies in being used to treat spinal cord injury (SCI). This is a report of a Phase I/IIa clinical study designed to test the safety and tolerability of the drug, and the neurological status of patients following the administration of a single dose of BA-210 applied during surgery following acute SCI. Patients with thoracic (T2-T12) or …

Identifying And Reducing Lead Exposure Associated With The Use Of Cultural Practices In Southern Nevada Hispanic Communities, Maria Castillo-Couch

UNLV Theses, Dissertations, Professional Papers, and Capstones

Despite large amounts of national data on lead and childhood lead poisoning, the status of childhood lead exposure in Nevada as a result of the use of cultural practices in the Hispanic population is unknown. The influx of immigrant Hispanic populations to Nevada, their low education level, the high number of them who are living in poverty present an increased risk for children to be exposed to lead through the use of imported consumables, home remedies and alternative medicine (i.e., healers/ sobadores).

A 61-question survey collected data from Hispanics over 18 years of age who have or take care …

Executive Function Profiles In Pediatric Traumatic Brain Injury, Erik Nelson Ringdahl

UNLV Theses, Dissertations, Professional Papers, and Capstones

Traumatic brain injury is a common cause of disability and death among children in the United States. Insult to the frontal and temporal lobes are frequent in closed head brain injury. Cognitive deficits in a variety of domains are common sequelae of brain trauma. In many cases, trauma to the frontal and temporal lobe regions engender prominent deficits in higher-order cognitive processing, memory, and attention.

Higher-order cognitive processing, or Executive Functions are the grouping of cognitive processes necessary for organization of thoughts and activities, attending to the activities, prioritizing tasks, managing time efficiently, and making decisions (Alvarez & Emory, 2006; …

The Variable Presentations Of Anaplastic Spindle Cell Squamous Carcinoma Associated With Tall Cell Variant Of Papillary Thyroid Carcinoma., Pallavi P Gopal, Kathleen T Montone, Zubair Baloch, Madalina Tuluc, Virginia Livolsi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

BACKGROUND: In 1976, Hawk and Hazard described the tall cell variant (TCV) of papillary thyroid carcinoma (PTC). While the lesions they described had cytologic features of papillary carcinoma, they showed more aggressive behavior with a greater propensity for extrathyroid extension and lymphovascular invasion than classic PTC. In 1991, Bronner and LiVolsi described a series of patients with TCV that progressed to spindle cell squamous carcinoma (SCSC), a unique form of anaplastic thyroid carcinoma. This study describes the variable clinical and pathologic presentations in 31 patients with anaplastic SCSC arising in association with TCV.

METHODS: The surgical pathology archives as well …

A Compact Guide To The Diagnosis And Management Of Neurofibromatosis Type 1, Timothy Beer, David Strayer, Md, Phd

Department of Pathology, Anatomy, and Cell Biology Resident's Posters

Brief Introduction

Neurofibromatosis type 1 (NF-1) is a multisystem neurocutaneous disorder resulting from mutations in the NF-1 gene on chromosome 17 (q11.2). Mutations in NF-1 result in deficient activity of the tumor suppresor protein neurofibromin, allowing for uncontrolled constitutive activity of the proliferative Raspathway in several neural cell types, including neurons, oligodendrocytes, astrocytes and Schawnn cells. Half of NF-1 cases are inherited in autosomal dominant fashion, while half develop sporadically. The syndrome has 100% penetrance but highly variable expressivity. The prevalence of this syndrome is 1/3,000, making it common enough to warrant YOU, the physician, taking a moment to learn …

Electrophysiological Characterization Of Enteric Neurons Isolated From The Immortomouse, Edward G. Hawkins

Theses and Dissertations

The availability of murine genetic models is extremely advantageous to studying gastrointestinal function, but the benefits afforded by studying enteric neurons in mice has been hindered by their accessibility. Fetal (E13) and 2 day post-natal (P2) enteric neuron cell lines (IM-FEN and IM-PEN, respectively) were recently developed from the H-2Kb-tsA58 immortomouse. Our goal was to identify the electrophysiological properties of these cell lines and clarify their utility as a model of enteric neurons. IM-PEN cells stained positively for the neuron specific markers βIII-tubulin and PGP9.5 and were negative for the glial cell marker S100. Detection of mRNA for TRPA1, TRPV1, …

Involvement Of P53 In The S-Phase Checkpoint During Nucleotide Deficiencies, Cortney Heyer

Theses and Dissertations

Several classes of antimetabolites have been developed for the treatment of cancer, including numerous inhibitors of nucleotide biosynthesis. N-(phosphonacetyl)-L-aspartate (PALA) and hydroxyurea (HU) are two antimetabolites that inhibit nucleotide biosynthesis; PALA inhibits de novo pyrimidine synthesis and HU inhibits the conversion of ribonucleotide diphosphates to deoxyribonucleotide diphosphates. Due to the similar mechanisms, it was thought that cancer cells would respond similarly to HU and PALA treatment. However, studies in this dissertation revealed strikingly different responses to either HU or PALA treatment in HCT116 cells. A cytoprotective S-phase arrest was activated upon HU treatment while PALA treatment failed to activate the …

Muc4 Stabilizes Her2 Expression And Maintains The Cancer Stem Cell Population In Ovarian Cancer Cells., Moorthy P. Ponnusamy, Parthasarathy Seshacharyulu, Arokia P. Vaz, Parama Dey, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Recent evidence has suggested that the capability of cancer to grow, propagate and relapse after therapy is dependent on a small subset of the cell population within the tumor, called cancer stem cells. Therefore, this subpopulation of cells needs to be targeted with different approaches by identification of unique stem-cell specific target antigens. One of the well known tumor antigens is the epithelial cell mucin MUC4, which is aberrantly expressed in ovarian cancer as compared to the normal ovary and plays a pivotal role in the aggressiveness and metastasis of ovarian cancer cells. In the present study, we aimed …

Incidence And Prevention Of Injury Of The Anterior Cruciate Ligament In Females, Arielle E. Gillie

Senior Honors Theses

According to the American College of Sports Medicine, women are two to eight times more likely to sustain an anterior cruciate ligament injury than men at the same level of performance. This high incidence of women with an ACL injury is thought to be due to a number of gender differences. This study examines the research that has been conducted to determine the reason for the disproportionate incidence of anterior cruciate ligament in female population. The study encompasses anatomical structure of the knee joint, structural differences in the male and female knee, hormonal influences, biomechanical influences, neuromuscular influences, and strategies …

The Effect Of Training On Motoneuron Survival In Amyotrophic Lateral Sclerosis: Which Motoneuron Type Is Saved?, Sherif M. Elbasiouny, Jenna E. Schuster

Neuroscience, Cell Biology & Physiology Faculty Publications

Amyotrophic lateral sclerosis (ALS) is characterized by selective and progressive degeneration of motoneurons (MNs). Although the etiology of the disease is unknown, glutamate toxicity and reactive oxygen species toxicity have been strongly implicated in ALS pathophysiology, Training exercise has been proposed to provide a beneficial therapy during the early or late stages of ALS; however, some studies showed deleterious effects of exercise on survival in ALS.