411 results on '"Gibson KM"'
Search Results
2. Aerosol Exposure of Cynomolgus Macaques to SARS-CoV-2 Results in More Severe Pathology than Existing Models
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Bixler Sl, Joshua A. Johnson, Keersten M. Ricks, Gibson Km, Ondraya Frick, Pitt Mlm, David N Dyer, Franco Rossi, Moreau Am, Jeffrey M. Smith, Timothy D. Minogue, Heather L. Esham, Bloomfield H, Aysegul Nalca, Kuehnert Pa, Xiankun Zeng, DiPinto N, Jun Liu, Delp Kl, Jeffrey W. Koehler, Alexandra Jay, Tostenson S, Charles J. Shoemaker, Kristen Akers, Brian J. Kearney, Kerry Berrier, Coyne, Jay W. Hooper, Christopher P. Stefan, and Clements Tl
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Pathology ,medicine.medical_specialty ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Respiratory disease ,Severe disease ,Disease ,medicine.disease ,Nonhuman primate ,medicine ,Clinical endpoint ,Small particles ,business - Abstract
The emergence of SARS-CoV-2 pandemic has highlighted the need for animal models that faithfully recapitulate the salient features of COVID-19 disease in humans; these models are necessary for the rapid down-selection, testing, and evaluation of medical countermeasures. Here we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure, combined intratracheal/intranasal and small particle aerosol, in two nonhuman primate species: rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at the time of necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models were suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.
- Published
- 2021
3. Animal Model Prescreening: Pre-exposure to SARS-CoV-2 impacts responses in the NHP model
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Akers Ks, Keersten M. Ricks, Andrew S. Herbert, Timothy D. Minogue, Jeffrey W. Koehler, Jay W. Hooper, Sara C. Johnston, Gibson Km, Kuehnert Pa, Delp Kl, Brett Beitzel, Kugelman, Cecilia M. O’Brien, Clements Tl, Charles J. Shoemaker, Jeffrey M. Smith, Ana I. Kuehne, John M. Dye, and Coyne
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medicine.medical_specialty ,Animal model ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Disease outcome ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Animal disease ,medicine ,African Green Monkey ,Viral disease ,Intensive care medicine ,business - Abstract
COVID-19 presents herculean challenges to research and scientific communities for producing diagnostic and treatment solutions. Any return to normalcy requires rapid development of countermeasures, with animal models serving as a critical tool in testing vaccines and therapeutics. Animal disease status and potential COVID-19 exposure prior to study execution may severely bias efficacy testing. We developed a toolbox of immunological and molecular tests to monitor countermeasure impact on disease outcome and evaluate pre-challenge COVID-19 status. Assay application showed critical necessity for animal pre-screening. Specifically, real-time PCR results documented pre-exposure of an African Green Monkey prior to SARS-CoV-2 challenge with sequence confirmation as a community-acquired exposure. Longitudinal monitoring of nasopharyngeal swabs and serum showed pre-exposure impacted both viral disease course and resulting immunological response. This study demonstrates utility in a comprehensive pre-screening strategy for animal models, which captured the first documented case of community-acquired, non-human primate infection.One Sentence SummaryPre-exposure to SARS-CoV-2 affects biomarker responses in animal models, highlighting a need for robust pre-screening protocols prior to medical countermeasure studies.
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- 2020
4. Aberrant mTOR signaling and disrupted autophagy: The missing link in potential vigabatrin-associated ocular toxicity?
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Vogel, KR, primary, Ainslie, GR, additional, Pearl, PL, additional, and Gibson, KM, additional
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- 2017
- Full Text
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5. DETECTION OF 1,4-BUTANEDIOL (1,4-BD) IN URINE BY GAS CHROMATOGRAPHY-MASS SPECTROMETRY (GC/MS) AND RAPID IN VIVO CONVERSION TO GH
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Lewis-Younger, C, Gibson, KM, Burlingame, TG, and Horowitz, Z
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Toxicology -- Research ,Environmental issues ,Health ,Pharmaceuticals and cosmetics industries - Abstract
Background: The gamma-hydroxybutyrate (GHB) precursors gamma-butyrolactone (GBL) and 1,4-BD are available as non-regulated substitutes for GHB. We demonstrate reliable GC/MS detection of 1,4-BD in human urine and rapid in vivo conversion to GHB in 2 human ingestions. Case 1: A 41-year-old male body-builder ingested 50 B 60 drops of liquid Rejov-at-nite[TM] (1,4-BD) associated with nausea and lost consciousness. Upon arrival at hospital, he was comatose with seizure activity, and a core temperature of 35 [degrees] C. He remained comatose and hypothermic for 8 hours. Urine samples were obtained 1 and 9 hours post contact for GC/MS analysis. Case 2: A 25-year-old male body-builder ingested 32 ounces of Rejoov[TM] leading to respiratory depression, non-reactive pupils, and coma. Urine was collected 13 hours post admission for GC/MS analysis. Both cases recovered spontaneously within 24 hours and were discharged. Method: GC/MS methodology for detection, separation and semi-quantification of 1,4-BD and GHB in urine followed established methods (Pediatr Res (2000) 47, 830-833). Representative chromatograms and mass spectra will be presented. Conclusion: Our data indicate that 1,4-BD is rapidly converted to GHB in vivo. Reliable identification in physiologic fluids can be made for diagnostic and legal purposes., Lewis-Younger C, Gibson KM, Burlingame TG, Horowitz Z. Oregon Poison Control Center and Department of Molecular and Medical Genetics, Oregon Health Science University, Portland, [...]
- Published
- 2001
6. Succinic semialdehyde dehydrogenase deficiency: Clinical, biochemical and molecular characterization of a new patient with severe phenotype and a novel mutation [4]
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Blasi, P, Palmerio, F, Caldarola, S, Rizzo, C, Carrozzo, R, Gibson, Km, Novelletto, A, Deodato, F, Cappa, M, Dionisi_vici, C, and Malaspina, P
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Genotype ,phenotype ,letter ,speech disorder ,reverse transcription polymerase chain reaction ,consanguinity ,Mental Retardation ,case report ,Humans ,succinate semialdehyde dehydrogenase ,gene mutation ,human ,gene location ,family history ,muscle hypotonia ,Base Sequence ,brain cortex atrophy ,chemical analysis ,clinical feature ,disease severity ,electroencephalogram ,electroencephalography ,enzyme deficiency ,female ,genotype ,infant ,molecular genetics ,priority journal ,psychomotor disorder ,strabismus ,DNA ,Female ,Infant ,Mutation ,Phenotype ,Succinate-Semialdehyde Dehydrogenase ,Settore BIO/18 - Genetica - Published
- 2006
7. Molecular and Enzymatic Methods for Detection of Genetic Defects in Distal Pathways of Branched-Chain Amino Acid Metabolism
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Magdalena Ugarte, Fukao T, Mitchell Ga, and Gibson Km
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chemistry.chemical_classification ,chemistry.chemical_compound ,Enzyme ,Biochemistry ,Chemistry ,Branched-chain amino acid ,Metabolism ,Amino acid - Published
- 2000
8. Regulatory adaptation of isoprenoid biosynthesis and the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency
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R K Keller, Gibson Km, Wiesmann Un, Hoffmann Gf, and S. U. Brendel
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medicine.medical_specialty ,Glycosylation ,Protein Prenylation ,Reductase ,chemistry.chemical_compound ,Dolichol ,Biosynthesis ,Internal medicine ,Dolichols ,medicine ,Carbohydrate Conformation ,Humans ,Lymphocytes ,Cells, Cultured ,Dolichol Phosphates ,Mevalonate kinase deficiency ,biology ,Cholesterol ,Stem Cells ,Mevalonate kinase ,Fibroblasts ,medicine.disease ,Adaptation, Physiological ,Endocrinology ,chemistry ,Biochemistry ,Receptors, LDL ,Pediatrics, Perinatology and Child Health ,LDL receptor ,HMG-CoA reductase ,biology.protein ,lipids (amino acids, peptides, and proteins) - Abstract
In a search for the pathophysiologic mechanisms, we estimated isoprenoid synthesis and concentration, cellular growth, and the activity of the LDL receptor pathway in fibroblasts from patients with mevalonate kinase deficiency (MKD), a severe multisystemic disorder of cholesterol and non-sterol isoprenoid biosynthesis. In response to different concentrations of LDL and non-lipoprotein-bound cholesterol, MKD cells partially counteracted their enzyme defect by increased activities of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase (results from earlier studies) and the LDL receptor pathway, responses similar to the pharmacologic effects seen upon administration of HMG-CoA reductase inhibitors. Rates of N-linked protein glycosylation, estimated as the amount of [14C]galactose-labeled macromolecules secreted into cell culture medium, were significantly decreased in MKD fibroblasts in comparison with control cells which may indicate alterations in the dolichol or dolichol phosphate pool. In response to exogenous cholesterol, the major feedback inhibitor of isoprenoid biosynthesis, growth velocities of MKD fibroblasts declined in comparison with control cells, further suggesting an impairment of non-sterol isoprenoid biosynthesis in MKD. Our results suggest an imbalance in the multilevel regulation of the biosynthesis of cholesterol and non-sterol isoprenoids in MKD, representing an additional causative factor responsible for the pre- and postnatal pathology of MKD.
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- 1997
9. 3-Methylglutaconic aciduria in the Iraqi-Jewish 'optic atrophy plus' (Costeff) syndrome
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Hanan Costeff, Gibson Km, Joseph A, Weitz R, Shental Y, and Orly Elpeleg
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Costeff syndrome ,Meglutol ,Glutarates ,Atrophy ,Developmental Neuroscience ,medicine ,Humans ,Child ,Gynecology ,Movement Disorders ,Syndrome ,3-Methylglutaconic Aciduria ,medicine.disease ,Surgery ,Optic Atrophy ,Child, Preschool ,Jews ,Pediatrics, Perinatology and Child Health ,Iraq ,Female ,Neurology (clinical) ,Psychology ,Cognition Disorders - Abstract
SUMMARY Eleven new patients of Iraqi-Jewish origin with bilateral optic atrophy, neurological abnormalities (‘optic atrophy plus’ syndrome) and 3-methylglutaconic aciduria (type III) are described. Clinical abnormalities in decreasing order of frequency were bilateral optic atrophy, extrapyramidal signs, spasticity, ataxia, dysarthria and cognitive deficit. An association with age was found only for spasticity. Spasticity, extrapyramidal signs and optic atrophy frequently led to major disability, in contrast to ataxia, dysarthria and cognitive deficit. The combined excretion of 3-methylglutaconic and 3-methylglutaric acid ranged between 9 and 187mmol/mol creatinine. The primary enzymatic defect possibly may reside in the mitochondrial respiratory chain. RESUME L'adicurie 3-methylglutaconique dans le syndrome des juifs iraquiens ‘atrophie optique plus’ (Costeff) Onze nouveaux patients d'origine juif-irakien avec atrophie optique bilaterale, anomalies neurologiques (syndrome d“atrophie optique plus”) et acidurie 3-methyIglutaconique (type III) sont decrits. Les anomalies cliniques etaient, en ordre decroissant, une atrophie optique bilaterale, des signes extrapyramidaux, une spasticite, une ataxie, une dysarthrie et un defaut cognitif. Une association avec l‘âge n'a ete trouvee que pour la spasticite. La spasticite, les signes extrapyramidaux et l'atrophie optiques provoquaient frequemment une incapacite majeure, en contraste avec l'ataxie, la dysarthrie et le deficit cognitif. L'excretion combinee d'acide 3-methyIglutaconique et 3-methylglutarique se situait entre 9 et 187mmol/mol de creatinine. Le defaut enzymatique primaire reside peut-etre dans la chalne rcspiratoire mitochondriale. ZUSAMMENFASSUNG 3-Methylglutaconsaureausscheidung beim ‘Opticus-Atrophie-Plus’ (Costeff) Syndrom irakischer Juden 11 neue Patienten irakisch-judischer Herkunft mit bilateraler Opticusatrophie, neurologischen Storungen (‘Opticus-Atrophie-Plus’ Syndrom) und 3-Methylglutaconsaureausscheidung (Typ III) werden beschrieben. Mit abnehmender Haufigkeit bestanden die klinischen Symptome in bilateraler Opticusatrophie, Extrapyramidalzeichen, Spastik, Ataxie, Dysarthrie und kognitiven Storungen. Eine Beziehung zum Alter fand sich nur bei der Spastik. Spastik, Extrapyramidalzeichen und Opticusatrophie fuhrten haufig zu schweren Behinderungen, was bei den Symptomen Ataxie, Dysarthrie und kognitive Storungen nicht beobachtet wurden. Die kombinierte Ausscheidung von 3-Methylglutaconsaure und 3-Methylglutarsaure betrug zwischen 9 und 187mmol/mol Kreatinin. Der primare Enzymdefekt liegt moglicherweise in der mitochondrialen Atmungskette. RESUMEN Aciduria 3-metilglutaconica en el sindrome iraqui-judio ‘atrofia optica mas’ de Costeff Se describen once nuevos pacientes de origen iraqui-judio con atrofia optica bilateral, anomalies neurologicas (sindrome de atrofia optica mas) y acidosis 3-metilglutaconica (tipo III). Las anomalies clinicas en orden decreciente eran atrofia optica bilateral, signos extrapiramidales, espasticidad, ataxia, disartria y deficit cognitivo. La asociacion con la edad solo se hallo para la espasticidad. La espasticidad, los signos extrapiramidales y la atrofia optica con frecuencia dieron lugar a incapacidades mayores, en contraste con la ataxia, disartria y deficit cognitivo. La excrecion de acido 3-metilglutaconica y 3-metilglutarico oscilaba entre 9 y 187mmoI/moI creatinina. El defecto enzimatico primario puede residir posiblemente en la cadena respiratoria mitocondrial.
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- 1994
10. Neurodevelopmental pattern of succinic semialdehyde dehydrogenase deficiency (γ-hydroxybutyric aciduria)
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Philippe, A, primary, MA, J Deron, additional, MD, D Geneviève, additional, Lonlay, P, additional, Gibson, KM, additional, Rabier, D, additional, and Munnich, A, additional
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- 2007
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11. Neurodevelopmental pattern of succinic semialdehyde dehydrogenase deficiency (γ-hydroxybutyric aciduria)
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Philippe, A, primary, Deron, J, additional, Geneviève, D, additional, de Lonlay, P, additional, Gibson, KM, additional, Rabier, D, additional, and Munnich, A, additional
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- 2004
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12. Genetic Predisposition to Neural Tube Defects?
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Bottiglieri T and Gibson Km
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Genetics ,medicine.anatomical_structure ,Methylenetetrahydrofolate reductase (NADPH) ,Polymorphism (computer science) ,Pediatrics, Perinatology and Child Health ,Neural tube ,medicine ,Genetic predisposition ,Biology ,Risk factor ,Genetic determinism - Published
- 2000
13. Abstract
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Michael E. Jung, Gibson Km, E.D. Murray, W.J. Wechter, and Darko Kantoci
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medicine.medical_specialty ,Natriuretic hormones ,Endocrinology ,Natriuretic Factors ,business.industry ,Internal medicine ,Internal Medicine ,medicine ,Endogeny ,Natriuretic hormone ,business - Published
- 1997
14. Polysomnographic abnormalities in succinic semialdehyde dehydrogenase (SSADH) deficiency.
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Pearl PL, Shamim S, Theodore WH, Gibson KM, Forester K, Combs SE, Lewin D, Dustin I, Reeves-Tyer P, Jakobs C, and Sato S
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- 2009
15. Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency.
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Pearl PL, Gibson KM, Quezado Z, Dustin I, Taylor J, Trzcinski S, Schreiber J, Forester K, Reeves-Tyer P, Liew C, Shamim S, Herscovitch P, Carson R, Butman J, Jakobs C, Theodore W, Pearl, P L, Gibson, K M, Quezado, Z, and Dustin, I
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- 2009
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16. Status epilepticus in mice deficient for succinate semialdehyde dehydrogenase: GABAA receptor-mediated mechanisms.
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Wu Y, Buzzi A, Frantseva M, Velazquez JP, Cortez M, Liu C, Shen L, Gibson KM, and Snead OC 3rd
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- 2006
17. Drug therapy. Gamma-hydroxybutyric acid [corrected] [published erratum appears in N ENGL J MED 2006 Feb 2;354(5):537].
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Snead OC III and Gibson KM
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- 2005
18. 3-Hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured fibroblasts from patients with mevalonate kinase deficiency: differential response to lipid supplied by fetal bovine serum in tissue culture medium.
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Gibson, KM, primary, Hoffmann, G, additional, Schwall, A, additional, Broock, RL, additional, Aramaki, S, additional, Sweetman, L, additional, Nyhan, WL, additional, Brandt, IK, additional, Wappner, RS, additional, and Lehnert, W, additional
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- 1990
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19. Effect of genetically caused excess of brain gamma-hydroxybutyric acid and GABA on sleep.
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Arnulf I, Konofal E, Gibson KM, Rabier D, Beauvais P, Derenne J, and Philippe A
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- 2005
20. Pressure sore prevention in hospital patients: a clinical audit.
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Grewal PS, Sawant NH, Deaney CN, Gibson KM, Gupta AM, Haverty PF, Panditaratne HG, Samarasinghe SR, Sharma A, Singh S, Turner SA, Wilkinson SL, Wood SP, and Glickman S
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- 1999
21. MEVALONATE KINASE-DEFICIENCY IN A CHILD WITH CEREBELLAR-ATAXIA, HYPOTONIA AND MEVALONICACIDURIA
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GIBSON, KM, HOFFMANN, G, NYHAN, WL, SWEETMAN, L, BERGER, R, LECOULTRE, R, and SMIT, GPA
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- 1988
22. Whole of Government Environmental Reporting
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Gibson, KM and Gibson, KM
23. Whole of Government Environmental Reporting
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Gibson, KM and Gibson, KM
24. Whole of Government Environmental Reporting
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Gibson, KM and Gibson, KM
25. 'Succinic semialdehyde dehydrogenase deficiency: phenotype evolution in an adolescent patient at 20-year follow-up'.
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Crutchfield SR, Haas RH, Nyhan WL, Gibson KM, Crutchfield, Susan R, Haas, Richard H, Nyhan, William L, and Gibson, K Michael
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- 2008
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26. Mevalonate kinase deficiency and autoinflammation.
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Hager EJ and Gibson KM
- Published
- 2007
27. Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine.
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Wolfe LA, Finegold DN, Vockley J, Walters N, Chambaz C, Suormala T, Koch HG, Matern D, Barshop BA, Cropcho LJ, Baumgartner MR, and Gibson KM
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- 2007
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28. Succinic semialdehyde dehydrogenase deficiency in children and adults.
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Pearl PL, Novotny EJ, Acosta MT, Jakobs C, and Gibson KM
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- 2003
29. Magnetic resonance spectroscopy of neurotransmitters in human brain.
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Novotny EJ Jr., Fulbright RK, Pearl PL, Gibson KM, and Rothman DL
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- 2003
30. THERAPEUTIC EFFICACY OF MAGNESIUM VALPROATE IN SUCCINIC SEMIALDEHYDE DEHYDROGENASE DEFICIENCY
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Francesca Vanadia, Emanuele Trapolino, K. Michael Gibson, Phillip L. Pearl, Elena Vanadia, Salvatore Mangano, Vanadia, E, Gibson, KM, Pearl, PL, Trapolino, E, Mangano, S, Vanadia, F, Vanadia E, Gibson KM, Pearl PL, Trapolino E, Mangano S, and Vanadia F .
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Succinic semialdehyde dehydrogenase deficiency ,SSADHD ,business.industry ,Symptomatic seizures ,THERAPEUTIC EFFICACY OF MAGNESIUM VALPROATE IN SUCCINIC SEMIALDEHYDE DEHYDROGENASE ,Status epilepticus ,Pharmacology ,medicine.disease ,Settore MED/39 - Neuropsichiatria Infantile ,Article ,Broad spectrum ,Epilepsy ,Neurodevelopmental disorder ,Concomitant ,MAGNESIUM VALPROATE ,medicine ,medicine.symptom ,GABA,MgVPA ,business ,Magnesium Valproate - Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD or gammahydroxybutyric aciduria), a disorder of γ-aminobutyric acid (GABA) metabolism, manifests as a slowly progressive or static encephalopathy. The latter encompasses prominent cognitive dysfunction, neuropsychiatric morbidity and epilepsy.We report safe and effective treatment with MgVPA in an adolescent female with SSADHD and seizures refractory to a broad spectrum of antiepileptics. MgVPA therapy (20 mg/Kg/day) was introduced at 7 years based upon behavioural difficulties and EEG alterations without adverse effects. Therapy was halted at age 13 years, and reintroduced at 14 years, due to new onset complex partial seizures. EEG demonstrated improvement in epileptiform activity, associated with behavioural improvement in disinhibition, aggression and coprolalia. Though typically avoided in SSADHD due to inhibitory effects on any residual enzymatic activity, valproate was effective and safe in our patient. Sodium valproate has previously demonstrated therapeutic utility in SSADHD, but the use of the magnesium conjugate has not been reported. Epilepsy remains well controlled in our patient, with concomitant improvements in behavioural symptoms . Our results suggest that MgVPA intervention may have utility in selected cases of SSADHD
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- 2012
31. Variation in human erythrocyte membrane unsaturated fatty acids: correlation with cardiovascular disease.
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Sepulveda JL, Tanhehco YC, Frey M, Guo L, Cropcho LJ, Gibson KM, and Blair HC
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- 2010
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32. NMR-Based Screening for Inborn Errors of Metabolism: Initial Results from a Study on Turkish Neonates
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Sitke Aygen, S. Ümit Sarici, Johannes Kunig, David Krings, Peter Hegele, H. İbrahim Aydin, Rahmi Örs, Resit Atalan, Selda Fatma Bulbul, Fang Fang, Birk Schütz, Mehmet Yalaz, Hartmut Schäfer, Oğuz Tuncer, Manfred Spraul, Claire Cannet, Ulrich Dürr, Selçuk Üniversitesi, Zschocke, J, Gibson, KM, Brown, G, Morava, E, Peters, V, and Ege Üniversitesi
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Pediatrics ,medicine.medical_specialty ,High prevalence ,business.industry ,Turkish ,Biotinidase deficiency ,MEDLINE ,medicine.disease ,Article ,language.human_language ,Congenital hypothyroidism ,language ,Medicine ,business - Abstract
WOS: 000376979100015, PubMed ID: 25012580, Approximately 1 in 400 neonates in Turkey is affected by inherited metabolic diseases. This high prevalence is at least in part due to consanguineous marriages. Standard screening in Turkey now covers only three metabolic diseases (phenylketonuria, congenital hypothyroidism, and biotinidase deficiency). Once symptoms have developed, tandem-MS can be used, although this currently covers only up to 40 metabolites. NMR potentially offers a rapid and versatile alternative. We conducted a multi-center clinical study in 14 clinical centers in Turkey. Urine samples from 989 neonates were collected and investigated by using NMR spectroscopy in two different laboratories. The primary objective of the present study was to explore the range of variation of concentration and chemical shifts of specific metabolites without clinically relevant findings that can be detected in the urine of Turkish neonates. The secondary objective was the integration of the results from a healthy reference population of neonates into an NMR database, for routine and completely automatic screening of congenital metabolic diseases. Both targeted and untargeted analyses were performed on the data. Targeted analysis was aimed at 65 metabolites. Limits of detection and quantitation were determined by generating urine spectra, in which known concentrations of the analytes were added electronically as well as by real spiking. Untargeted analysis involved analysis of the whole spectrum for abnormal features, using statistical procedures, including principal component analysis. Outliers were eliminated by model building. Untargeted analysis was used to detect known and unknown compounds and jaundice, proteinuria, and acidemia. The results will be used to establish a database to detect pathological concentration ranges and for routine screening.
- Published
- 2014
33. Enhancing Cardiomyocyte Resilience to Ischemia-Reperfusion Injury: The Therapeutic Potential of an Indole-Peptide-Tempo Conjugate (IPTC).
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Hou S, Yan X, Gao X, Jockusch S, Gibson KM, Shan Z, and Bi L
- Abstract
Ischemia/reperfusion (I/R) injury leads to apoptosis and extensive cellular and mitochondrial damage, triggered by the early generation and subsequent accumulation of mitochondrial reactive oxygen species (mtROS). This condition not only contributes to the pathology of I/R injury itself but is also implicated in a variety of other diseases, especially within the cardiovascular domain. Addressing mitochondrial oxidative stress thus emerges as a critical therapeutic target. In this context, our study introduces an indole-peptide-tempo conjugate (IPTC), a compound designed with dual functionalities: antioxidative properties and the ability to modulate autophagy. Our findings reveal that IPTC effectively shields H9C2 cardiomyocytes against hypoxia/reoxygenation (H/R) damage, primarily through counteracting mtROS overproduction linked to impaired mitophagy and mitochondrial dysfunction. We propose that IPTC operates by simultaneously reducing mtROS levels and inducing mitophagy, highlighting its potential as a novel therapeutic strategy for mitigating mitochondrial oxidative damage and, by extension, easing I/R injury and potentially other related cardiovascular conditions., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)
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- 2024
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34. Editorial Commentary on the Special Issue "Antioxidant Therapy for Cardiovascular Diseases"-Cutting-Edge Insights into Oxidative Stress and Antioxidant Therapy in Cardiovascular Health.
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Kwon G, Gibson KM, and Bi L
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Recent advances in cardiovascular research have increasingly emphasized oxidative stress as a central mechanism in the pathogenesis and progression of cardiovascular diseases [...].
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- 2024
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35. Improving departmental psychological safety through a medical school-wide initiative.
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Porter-Stransky KA, Horneffer-Ginter KJ, Bauler LD, Gibson KM, Haymaker CM, and Rothney M
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- Humans, Male, Female, Organizational Culture, Patient Safety, Surveys and Questionnaires, Leadership, Psychological Safety, Schools, Medical
- Abstract
Background: Psychological safety is a team-based phenomenon whereby group members are empowered to ask questions, take appropriate risks, admit mistakes, propose novel ideas, and candidly voice concerns. Growing research supports the benefits of psychological safety in healthcare and education for patient safety, learning, and innovation. However, there is a paucity of research on how to create psychological safety, especially within academic medicine. To meet this need, the present study describes and evaluates a multi-year, medical school-wide psychological safety initiative., Methods: We created, implemented, and assessed a multi-pronged psychological safety initiative including educational training sessions, departmental champions, videos, infographics, and targeted training for medical school leaders. Employees' perceptions of psychological safety at both the departmental and institutional levels were assessed annually. The impact of educational training sessions was quantified by post-session surveys., Results: Deidentified employee surveys revealed a statistically significant increase in departmental psychological safety between the first and second annual surveys. Perceived psychological safety remained lower at the institution-wide level than at the departmental level. No significant differences in psychological safety were observed based on gender, position, or employment length. Post-educational training session surveys showed that the sessions significantly increased knowledge of the topic as well as motivation to create a culture of psychological safety within the medical school., Conclusions: This study establishes an evidence-based method for increasing psychological safety within medical school departments and serves as a template for other health professions schools seeking to promote psychological safety. Training leadership, faculty, and staff is an important first step towards creating a culture of psychological safety for everyone, including trainees., (© 2024. The Author(s).)
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- 2024
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36. Succinic semialdehyde dehydrogenase deficiency: a metabolic and genomic approach to diagnosis.
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Glinton KE, Gijavanekar C, Rajagopal A, Mackay LP, Martin KA, Pearl PL, Gibson KM, Wilson TA, Sutton VR, and Elsea SH
- Abstract
Genomic sequencing offers an untargeted, data-driven approach to genetic diagnosis; however, variants of uncertain significance often hinder the diagnostic process. The discovery of rare genomic variants without previously known functional evidence of pathogenicity often results in variants being overlooked as potentially causative, particularly in individuals with undifferentiated phenotypes. Consequently, many neurometabolic conditions, including those in the GABA (gamma-aminobutyric acid) catabolism pathway, are underdiagnosed. Succinic semialdehyde dehydrogenase deficiency (SSADHD, OMIM #271980) is a neurometabolic disorder in the GABA catabolism pathway. The disorder is due to bi-allelic pathogenic variants in ALDH5A1 and is usually characterized by moderate-to-severe developmental delays, hypotonia, intellectual disability, ataxia, seizures, hyperkinetic behavior, aggression, psychiatric disorders, and sleep disturbances. In this study, we utilized an integrated approach to diagnosis of SSADHD by examining molecular, clinical, and metabolomic data from a single large commercial laboratory. Our analysis led to the identification of 16 patients with likely SSADHD along with three novel variants. We also showed that patients with this disorder have a clear metabolomic signature that, along with molecular and clinical findings, may allow for more rapid and efficient diagnosis. We further surveyed all available pathogenic/likely pathogenic variants and used this information to estimate the global prevalence of this disease. Taken together, our comprehensive analysis allows for a global approach to the diagnosis of SSADHD and provides a pathway to improved diagnosis and potential incorporation into newborn screening programs. Furthermore, early diagnosis facilitates referral to genetic counseling, family support, and access to targeted treatments-taken together, these provide the best outcomes for individuals living with either GABA-TD or SSADHD, as well as other rare conditions., Competing Interests: Authors KEG, CG, AR, TAW, VRS and SHE are employees of Baylor College of Medicine, which receives revenue from clinical testing in association with Baylor Genetics. Author KM was employed by NeoGenomics Laboratories. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Glinton, Gijavanekar, Rajagopal, Mackay, Martin, Pearl, Gibson, Wilson, Sutton and Elsea.)
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- 2024
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37. Genetically engineered Lactococcus lactis strain constitutively expresses GABA-producing genes and produces high levels of GABA.
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Monteiro MP, Kohl HM, Roullet JB, Gibson KM, Ochoa-Repáraz J, and Castillo AR
- Subjects
- Genetic Engineering, Plasmids genetics, Glutamic Acid metabolism, Metabolic Engineering, Bacterial Proteins genetics, Bacterial Proteins metabolism, Lactococcus lactis genetics, Lactococcus lactis metabolism, gamma-Aminobutyric Acid metabolism, gamma-Aminobutyric Acid biosynthesis, Promoter Regions, Genetic, Glutamate Decarboxylase genetics, Glutamate Decarboxylase metabolism
- Abstract
γ-Aminobutyric acid (GABA) is an inhibitory neurotransmitter of the central nervous system that impacts physical and mental health. Low GABA levels have been documented in several diseases, including multiple sclerosis and depression, and studies suggest that GABA could improve disease outcomes in those conditions. Probiotic bacteria naturally produce GABA and have been engineered to enhance its synthesis. Strains engineered thus far use inducible expression systems that require the addition of exogenous molecules, which complicates their development as therapeutics. This study aimed to overcome this challenge by engineering Lactococcus lactis with a constitutive GABA synthesis gene cassette. GABA synthesizing and transport genes (gadB and gadC) were cloned onto plasmids downstream of constitutive L. lactis promoters [P2, P5, shortened P8 (P8s)] of different strengths and transformed into L. lactis. Fold increase in gadCB expression conferred by these promoters (P2, P5, and P8s) was 322, 422, and 627, respectively, compared to the unmodified strain (P = 0.0325, P8s). GABA synthesis in the highest gadCB expressing strain, L. lactis-P8s-glutamic acid decarboxylase (GAD), was dependent on media supplementation with glutamic acid and significantly higher than the unmodified strain (P < 0.0001, 125 mM, 200 mM glutamic acid). Lactococcus lactis-P8s-GAD is poised for therapeutic testing in animal models of low-GABA-associated disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)
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- 2024
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38. Succinic semialdehyde dehydrogenase deficiency in mice and in humans: An untargeted metabolomics perspective.
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Peters TMA, Engelke UFH, de Boer S, Reintjes JTG, Roullet JB, Broekman S, de Vrieze E, van Wijk E, Wamelink MMC, Artuch R, Barić I, Merx J, Boltje TJ, Martens J, Willemsen MAAP, Verbeek MM, Wevers RA, Gibson KM, and Coene KLM
- Subjects
- Adolescent, Animals, Child, Child, Preschool, Female, Humans, Infant, Male, Mice, Disease Models, Animal, Epilepsy metabolism, gamma-Aminobutyric Acid metabolism, Hydroxybutyrates, Language Development Disorders, Amino Acid Metabolism, Inborn Errors metabolism, Metabolomics methods, Succinate-Semialdehyde Dehydrogenase deficiency
- Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare neurometabolic disorder caused by disruption of the gamma-aminobutyric acid (GABA) pathway. A more detailed understanding of its pathophysiology, beyond the accumulation of GABA and gamma-hydroxybutyric acid (GHB), will increase our understanding of the disease and may support novel therapy development. To this end, we compared biochemical body fluid profiles from SSADHD patients with controls using next-generation metabolic screening (NGMS). Targeted analysis of NGMS data from cerebrospinal fluid (CSF) showed a moderate increase of aspartic acid, glutaric acid, glycolic acid, 4-guanidinobutanoic acid, and 2-hydroxyglutaric acid, and prominent elevations of GHB and 4,5-dihydroxyhexanoic acid (4,5-DHHA) in SSADHD samples. Remarkably, the intensities of 4,5-DHHA and GHB showed a significant positive correlation in control CSF, but not in patient CSF. In an established zebrafish epilepsy model, 4,5-DHHA showed increased mobility that may reflect limited epileptogenesis. Using untargeted metabolomics, we identified 12 features in CSF with high biomarker potential. These had comparable increased fold changes as GHB and 4,5-DHHA. For 10 of these features, a similar increase was found in plasma, urine and/or mouse brain tissue for SSADHD compared to controls. One of these was identified as the novel biomarker 4,5-dihydroxyheptanoic acid. The intensities of selected features in plasma and urine of SSADHD patients positively correlated with the clinical severity score of epilepsy and psychiatric symptoms of those patients, and also showed a high mutual correlation. Our findings provide new insights into the (neuro)metabolic disturbances in SSADHD and give leads for further research concerning SSADHD pathophysiology., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)
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- 2024
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39. Consensus guidelines for the diagnosis and management of succinic semialdehyde dehydrogenase deficiency.
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Tokatly Latzer I, Bertoldi M, Blau N, DiBacco ML, Elsea SH, García-Cazorla À, Gibson KM, Gropman AL, Hanson E, Hoffman C, Jeltsch K, Juliá-Palacios N, Knerr I, Lee HHC, Malaspina P, McConnell A, Opladen T, Oppebøen M, Rotenberg A, Walterfang M, Wang-Tso L, Wevers RA, Roullet JB, and Pearl PL
- Subjects
- Humans, Consensus, gamma-Aminobutyric Acid metabolism, Practice Guidelines as Topic, Succinate-Semialdehyde Dehydrogenase deficiency, Succinate-Semialdehyde Dehydrogenase genetics, Amino Acid Metabolism, Inborn Errors diagnosis, Amino Acid Metabolism, Inborn Errors therapy, Amino Acid Metabolism, Inborn Errors genetics, Developmental Disabilities
- Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD) (OMIM #271980) is a rare autosomal recessive metabolic disorder caused by pathogenic variants of ALDH5A1. Deficiency of SSADH results in accumulation of γ-aminobutyric acid (GABA) and other GABA-related metabolites. The clinical phenotype of SSADHD includes a broad spectrum of non-pathognomonic symptoms such as cognitive disabilities, communication and language deficits, movement disorders, epilepsy, sleep disturbances, attention problems, anxiety, and obsessive-compulsive traits. Current treatment options for SSADHD remain supportive, but there are ongoing attempts to develop targeted genetic therapies. This study aimed to create consensus guidelines for the diagnosis and management of SSADHD. Thirty relevant statements were initially addressed by a systematic literature review, resulting in different evidence levels of strength according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) criteria. The highest level of evidence (level A), based on randomized controlled trials, was unavailable for any of the statements. Based on cohort studies, Level B evidence was available for 12 (40%) of the statements. Thereupon, through a process following the Delphi Method and directed by the Appraisal of Guidelines for Research and Evaluation (AGREE II) criteria, expert opinion was sought, and members of an SSADHD Consensus Group evaluated all the statements. The group consisted of neurologists, epileptologists, neuropsychologists, neurophysiologists, metabolic disease specialists, clinical and biochemical geneticists, and laboratory scientists affiliated with 19 institutions from 11 countries who have clinical experience with SSADHD patients and have studied the disorder. Representatives from parent groups were also included in the Consensus Group. An analysis of the survey's results yielded 25 (83%) strong and 5 (17%) weak agreement strengths. These first-of-their-kind consensus guidelines intend to consolidate and unify the optimal care that can be provided to individuals with SSADHD., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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40. Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder.
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Tokatly Latzer I, Roullet JB, Afshar-Saber W, Lee HHC, Bertoldi M, McGinty GE, DiBacco ML, Arning E, Tsuboyama M, Rotenberg A, Opladen T, Jeltsch K, García-Cazorla À, Juliá-Palacios N, Gibson KM, Sahin M, and Pearl PL
- Subjects
- Adolescent, Animals, Child, Child, Preschool, Female, Humans, Male, Mice, Brain metabolism, Brain physiopathology, Disease Models, Animal, GABAergic Neurons metabolism, gamma-Aminobutyric Acid metabolism, Neurodevelopmental Disorders metabolism, Neurodevelopmental Disorders etiology, Neurodevelopmental Disorders genetics, Amino Acid Metabolism, Inborn Errors therapy, Amino Acid Metabolism, Inborn Errors physiopathology, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors complications, Amino Acid Metabolism, Inborn Errors metabolism, Developmental Disabilities, Induced Pluripotent Stem Cells metabolism, Succinate-Semialdehyde Dehydrogenase deficiency, Succinate-Semialdehyde Dehydrogenase metabolism, Succinate-Semialdehyde Dehydrogenase genetics
- Abstract
Background: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy., Methods: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy., Results: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation., Conclusions: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy., (© 2024. The Author(s).)
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- 2024
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41. Anti-LAMP-2 Antibody Seropositivity in Children with Primary Systemic Vasculitis Affecting Medium- and Large-Sized Vessels.
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Akbaba TH, Toor KK, Mann SK, Gibson KM, Alfaro GA, Balci-Peynircioglu B, Cabral DA, Morishita KA, and Brown KL
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- Adolescent, Child, Humans, Antibodies, Antineutrophil Cytoplasmic, Autoantigens, Myeloblastin, Retrospective Studies, Systemic Vasculitis
- Abstract
Chronic primary systemic vasculitis (PSV) comprises a group of heterogeneous diseases that are broadly classified by affected blood vessel size, clinical traits and the presence (or absence) of anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 (PR3) and myeloperoxidase (MPO). In small vessel vasculitis (SVV), ANCA are not present in all patients, and they are rarely detected in patients with vasculitis involving medium (MVV) and large (LVV) blood vessels. Some studies have demonstrated that lysosome-associated membrane protein-2 (LAMP-2/CD107b) is a target of ANCA in SVV, but its presence and prognostic value in childhood MVV and LVV is not known. This study utilized retrospective sera and clinical data obtained from 90 children and adolescents with chronic PSV affecting small (SVV, n = 53), medium (MVV, n = 16), and large (LVV, n = 21) blood vessels. LAMP-2-ANCA were measured in time-of-diagnosis sera using a custom electrochemiluminescence assay. The threshold for seropositivity was established in a comparator cohort of patients with systemic autoinflammatory disease. The proportion of LAMP-2-ANCA-seropositive individuals and sera concentrations of LAMP-2-ANCA were assessed for associations with overall and organ-specific disease activity at diagnosis and one-year follow up. This study demonstrated a greater time-of-diagnosis prevalence and sera concentration of LAMP-2-ANCA in MVV (52.9% seropositive) and LVV (76.2%) compared to SVV (45.3%). Further, LAMP-2-ANCA-seropositive individuals had significantly lower overall, but not organ-specific, disease activity at diagnosis. This did not, however, result in a greater reduction in disease activity or the likelihood of achieving inactive disease one-year after diagnosis. The results of this study demonstrate particularly high prevalence and concentration of LAMP-2-ANCA in chronic PSV that affects large blood vessels and is seronegative for traditional ANCA. Our findings invite reconsideration of roles for autoantigens other than MPO and PR3 in pediatric vasculitis, particularly in medium- and large-sized blood vessels.
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- 2024
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42. Phenotypic correlates of structural and functional protein impairments resultant from ALDH5A1 variants.
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Tokatly Latzer I, Roullet JB, Cesaro S, DiBacco ML, Arning E, Rotenberg A, Lee HHC, Opladen T, Jeltsch K, García-Cazorla À, Juliá-Palacios N, Gibson KM, Bertoldi M, and Pearl PL
- Subjects
- Child, Humans, Male, Female, Developmental Disabilities genetics, Phenotype, Succinate-Semialdehyde Dehydrogenase genetics, Succinate-Semialdehyde Dehydrogenase metabolism, Amino Acid Metabolism, Inborn Errors genetics, Amino Acid Metabolism, Inborn Errors metabolism, Amino Acid Metabolism, Inborn Errors pathology
- Abstract
To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
- Published
- 2023
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43. Reduced evoked cortical beta and gamma activity and neuronal synchronization in succinic semialdehyde dehydrogenase deficiency, a disorder of γ-aminobutyric acid metabolism.
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Papadelis C, Ntolkeras G, Tokatly Latzer I, DiBacco ML, Afacan O, Warfield S, Shi X, Roullet JB, Gibson KM, and Pearl PL
- Abstract
Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessively inherited metabolic disorder of γ-aminobutyric acid catabolism manifested by intellectual disability, expressive aphasia, movement disorders, psychiatric ailments and epilepsy. Subjects with succinic semialdehyde dehydrogenase deficiency are characterized by elevated γ-aminobutyric acid and related metabolites, such as γ-guanidinobutyric acid, and an age-dependent downregulation of cerebral γ-aminobutyric acid receptors. These findings indicate impaired γ-aminobutyric acid and γ-aminobutyric acid sub-type A (GABA
A ) receptor signalling as major factors underlying the pathophysiology of this neurometabolic disorder. We studied the cortical oscillation patterns and their relationship with γ-aminobutyric acid metabolism in 18 children affected by this condition and 10 healthy controls. Using high-density EEG, we recorded somatosensory cortical responses and resting-state activity. Using electrical source imaging, we estimated the relative power changes (compared with baseline) in both stimulus-evoked and stimulus-induced responses for physiologically relevant frequency bands and resting-state power. Stimulus-evoked oscillations are phase locked to the stimulus, whereas induced oscillations are not. Power changes for both evoked and induced responses as well as resting-state power were correlated with plasma γ-aminobutyric acid and γ-guanidinobutyric acid concentrations and with cortical γ-aminobutyric acid measured by proton magnetic resonance spectroscopy. Plasma γ-aminobutyric acid, γ-guanidinobutyric acid and cortical γ-aminobutyric acid were higher in patients than in controls ( P < 0.001 for both). Beta and gamma relative power were suppressed for evoked responses in patients versus controls ( P < 0.01). No group differences were observed for induced activity ( P > 0.05). The mean gamma frequency of evoked responses was lower in patients versus controls ( P = 0.002). Resting-state activity was suppressed in patients for theta ( P = 0.011) and gamma ( P < 0.001) bands. Evoked power changes were inversely correlated with plasma γ-aminobutyric acid and with γ-guanidinobutyric acid for beta ( P < 0.001) and gamma ( P < 0.001) bands. Similar relationships were observed between the evoked power changes and cortical γ-aminobutyric acid for all tested areas in the beta band ( P < 0.001) and for the posterior cingulate gyrus in the gamma band ( P < 0.001). We also observed a negative correlation between resting-state activity and plasma γ-aminobutyric acid and γ-guanidinobutyric acid for theta ( P < 0.001; P = 0.003), alpha ( P = 0.003; P = 0.02) and gamma ( P = 0.02; P = 0.01) bands. Our findings indicate that increased γ-aminobutyric acid concentration is associated with reduced sensory-evoked beta and gamma activity and impaired neuronal synchronization in patients with succinic semialdehyde dehydrogenase deficiency. This further elucidates the pathophysiology of this neurometabolic disorder and serves as a potential biomarker for therapeutic trials., Competing Interests: The authors report no competing interests., (Published by Oxford University Press on behalf of the Guarantors of Brain 2023.)- Published
- 2023
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44. Establishment and validation of a clinical severity scoring system for succinic semialdehyde dehydrogenase deficiency.
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Tokatly Latzer I, Roullet JB, Gibson KM, and Pearl PL
- Subjects
- Female, Male, Humans, Developmental Disabilities genetics, Succinate-Semialdehyde Dehydrogenase, Amino Acid Metabolism, Inborn Errors genetics, Epilepsy diagnosis, Epilepsy genetics
- Abstract
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder with a variable phenotype and rate of progression. We aimed to develop and validate a clinical severity scoring (CSS) system applicable to the clinical setting and composed of five domains reflecting the principal manifestations of this disorder: cognitive, communication, motor, epilepsy, and psychiatry. A prospectively characterized cohort of 27 SSADHD subjects (55% females, median [IQR] age 9.2 [4.6-16.2] years) who enrolled in the SSADHD Natural History Study were included. The CSS was validated by comparison to an objective severity scoring (OSS) system based on comprehensive neuropsychologic and neurophysiologic assessments, which mirror and complement the domains of the CSS. The total CSS was sex and age-independent, and 80% of its domains lacked interdependence. With increasing age, there was a significant improvement in communication abilities (p = 0.05) and a worsening of epilepsy and psychiatric manifestations (p = 0.004 and p = 0.02, respectively). There was a significant correlation between all the CSS and OSS domain scores, as well as between the total CSS and OSS (R = 0.855, p < 0.001). Additionally, there were no significant demographic or clinical differences in the ratio of individuals in the upper quartile to the lower three quartiles of the CSS and OSS. The SSADHD CSS is validated using objective measures and offers a reliable condition-specific instrument universally applicable in clinical settings. This severity score may be utilized for family and patient counseling, genotype-phenotype correlations, biomarker development, clinical trials, and objective descriptions of the natural history of SSADHD., (© 2023 SSIEM.)
- Published
- 2023
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45. Phenotypic Correlates of Structural and Functional Protein Impairments Resultant from ALDH5A1 Variants.
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Latzer IT, Roullet JB, Cesaro S, DiBacco ML, Arning E, Rotenberg A, Lee HHC, Opladen T, Jeltsch K, García-Cazorla À, Juliá-Palacios N, Gibson KM, Bertoldi M, and Pearl PL
- Abstract
Objective: To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism., Methods: Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics., Results: A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 ( p = 0.001), worse overall clinical outcomes ( p = 0.008) and specifically more severe cognitive deficits ( p = 0.01), epilepsy ( p = 0.04) and psychiatric morbidity ( p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome ( p = 0.02) and adaptive skills ( p = 0.04)., Conclusions: The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders., Competing Interests: Competing Interests The authors I.T.L, J.B.R., M.B., S.C., M.L.D., E.A., T.O., K.J., À.G.C., N.J.P., K.M.G. have no relevant financial or non- financial interests to discolose. The authors A.R. and H.H.C.L. are co-founders and have equity in Galibra Neuroscience, Inc., which develops treatments for SSADH deficiency, including gene replacement therapy mentioned in this study. The authors A.R., H.C.C.L., and P.L.P. are inventors of a filed SSADH deficiency gene therapy patent.
- Published
- 2023
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46. The presence and severity of epilepsy coincide with reduced γ-aminobutyrate and cortical excitatory markers in succinic semialdehyde dehydrogenase deficiency.
- Author
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Tokatly Latzer I, Bertoldi M, DiBacco ML, Arning E, Tsuboyama M, MacMullin P, Sachee D, Rotenberg A, Lee HHC, Aygun D, Opladen T, Jeltsch K, García-Cazorla À, Roullet JB, Gibson KM, and Pearl PL
- Subjects
- Humans, Child, Developmental Disabilities, gamma-Aminobutyric Acid metabolism, Aminobutyrates, Seizures, Sodium Oxybate, Amino Acid Metabolism, Inborn Errors complications, Amino Acid Metabolism, Inborn Errors metabolism, Epilepsy metabolism
- Abstract
Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare inherited metabolic disorder caused by a defect of γ-aminobutyrate (GABA) catabolism. Despite the resultant hyper-GABAergic environment facilitated by the metabolic defect, individuals with this disorder have a paradoxically high prevalence of epilepsy. We aimed to study the characteristics of epilepsy in SSADHD and its concordance with GABA-related metabolites and neurophysiologic markers of cortical excitation., Methods: Subjects in an international natural history study of SSADHD underwent clinical assessments, electroencephalography, transcranial magnetic stimulation (TMS), magnetic resonance spectroscopy for GABA/N-acetyl aspartate quantification, and plasma GABA-related metabolite measurements., Results: A total of 61 subjects with SSADHD and 42 healthy controls were included in the study. Epilepsy was present in 49% of the SSADHD cohort. Over time, there was an increase in severity in 33% of the subjects with seizures. The presence of seizures was associated with increasing age (p = .001) and lower levels of GABA (p = .002), γ-hydroxybutyrate (GHB; p = .004), and γ-guanidinobutyrate (GBA; p = .003). Seizure severity was associated with increasing age and lower levels of GABA-related metabolites as well as lower TMS-derived resting motor thresholds (p = .04). The cutoff values with the highest discriminative ability to predict seizures were age > 9.2 years (p = .001), GABA < 2.57 μmol·L
-1 (p = .002), GHB < 143.6 μmol·L-1 (p = .004), and GBA < .075 μmol·L-1 (p = .007). A prediction model for seizures in SSADHD was comprised of the additive effect of older age and lower plasma GABA, GHB, and GBA (area under the receiver operating characteristic curve of .798, p = .008)., Significance: Epilepsy is highly prevalent in SSADHD, and its onset and severity correlate with an age-related decline in GABA and GABA-related metabolite levels as well as TMS markers of reduced cortical inhibition. The reduction of GABAergic activity in this otherwise hyper-GABAergic disorder demonstrates a concordance between epileptogenesis and compensatory responses. These findings may furthermore inform the timing of molecular interventions for SSADHD., (© 2023 International League Against Epilepsy.)- Published
- 2023
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47. Association Between HLA-DPB1 and Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Children.
- Author
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Gibson KM, Drögemöller BI, Foell D, Benseler SM, Graham J, Hancock REW, Luqmani RA, Cabral DA, Brown KL, and Ross CJ
- Subjects
- Adult, Humans, Child, Genome-Wide Association Study, HLA-DP beta-Chains genetics, Genetic Predisposition to Disease, Peroxidase, Antibodies, Antineutrophil Cytoplasmic, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis genetics
- Abstract
Objective: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare, life-threatening inflammation of blood vessels that can affect both adults and children. Compared to adult-onset disease, AAV is especially rare in children, with an annual prevalence of 0.5-6.4 cases per million children. The etiology of AAV remains largely unknown, and both environmental and genetic factors are likely involved. The present study was undertaken to explore the genetic susceptibility factors recently identified in adult patients, including HLA-DP and HLA-DQ, in pediatric patients., Methods: We performed a genome-wide association study of pediatric AAV in patients of European ancestry (n = 63 AAV cases, n = 315 population-matched controls)., Results: We identified a significant genetic association between pediatric AAV and the HLA-DPB1*04:01 allele (P = 1.5 × 10
-8 , odds ratio [OR] 3.5), with a stronger association observed in children with proteinase 3-ANCA positivity than in children with myeloperoxidase-ANCA positivity. Among the HLA alleles, the HLA-DPB1*04:01 allele was the most highly associated with AAV, although not significantly, in a follow-up adult AAV cohort (P = 2.6 × 10-4 , OR 0.4). T cell receptor and interferon signaling pathways were also shown to be enriched in the pediatric AAV cohort., Conclusion: The HLA-DPB1 locus showed an association with pediatric AAV, as similarly shown previously in adult AAV. Despite the difference in the age of onset, these findings suggest that childhood- and adult-onset vasculitis share a common genetic predisposition. The identification of genetic variants contributing to AAV is an important step to improved classification tools and treatment strategies., (© 2022 American College of Rheumatology.)- Published
- 2023
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48. Allosteric modulation of α1β3γ2 GABA A receptors by farnesol through the neurosteroid sites.
- Author
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Gc JB, Szlenk CT, Diyaolu A, Obi P, Wei H, Shi X, Gibson KM, Natesan S, and Roullet JB
- Subjects
- Humans, Binding Sites, Farnesol pharmacology, gamma-Aminobutyric Acid pharmacology, Protein Domains, Neurosteroids, Receptors, GABA-A metabolism
- Abstract
In mammalian cells, all-trans farnesol, a 15-carbon isoprenol, is a product of the mevalonate pathway. It is the natural substrate of alcohol dehydrogenase and a substrate for CYP2E1, two enzymes implicated in ethanol metabolism. Studies have shown that farnesol is present in the human brain and inhibits voltage-gated Ca
2+ channels at much lower concentrations than ethanol. Here we show that farnesol modulates the activity of γ-aminobutyric acid type A receptors (GABAA Rs), some of which also mediate the sedative activity of ethanol. Electrophysiology experiments performed in HEK cells expressing human α1β3γ2 or α6β3γ2 GABAA Rs revealed that farnesol increased chloride currents through positive allosteric modulation of these receptors and showed dependence on both the alcoholic functional group of farnesol and the length of the alkyl chain for activity. In silico studies using long-timescale unbiased all-atom molecular dynamics (MD) simulations of the human α1β3γ2 GABAA receptors revealed that farnesol modulates the channel by directly binding to the transmembrane neurosteroid-binding site, after partitioning into the surrounding membrane and reaching the receptor by lateral diffusion. Channel activation by farnesol was further characterized by several structural and dynamic variables, such as global twisting of the receptor's extracellular domain, tilting of the transmembrane M2 helices, radius, cross-sectional area, hydration status, and electrostatic potential of the channel pore. Our results expand the pharmacological activities of farnesol to yet another class of ion channels implicated in neurotransmission, thus providing a novel path for understanding and treatment of diseases involving GABAA receptor dysfunction., Competing Interests: Declaration of interests The Authors declare no competing interests., (Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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49. Discovery and Optimization of 5-Hydroxy-Diclofenac toward a New Class of Ligands with Nanomolar Affinity for the CaMKIIα Hub Domain.
- Author
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Tian Y, Shehata MA, Gauger SJ, Ng CKL, Solbak S, Thiesen L, Bruus-Jensen J, Krall J, Bundgaard C, Gibson KM, Wellendorph P, and Frølund B
- Subjects
- Ligands, Long-Term Potentiation, Calcium-Calmodulin-Dependent Protein Kinase Type 2 metabolism, Diclofenac analogs & derivatives
- Abstract
The Ca
2+ /calmodulin-dependent protein kinase II α (CaMKIIα) is a brain-relevant kinase involved in long-term potentiation and synaptic plasticity. We have recently pinpointed the CaMKIIα hub domain as the long-sought-after high-affinity target of γ-hydroxybutyrate ligands substantiated with a high-resolution cocrystal of 5-hydroxydiclofenac ( 3 ). Herein, we employed in silico approaches to rationalize and guide the synthesis and pharmacological characterization of a new series of analogues circumventing chemical stability problems associated with 3 . The oxygen-bridged analogue 4d showed mid-nanomolar affinity and notable ligand-induced stabilization effects toward the CaMKIIα hub oligomer. Importantly, 4d displayed superior chemical and metabolic stability over 3 by showing excellent chemical stability in phosphate-buffered saline and high resistance to form reactive intermediates and subsequent sulfur conjugates. Altogether, our study highlights 4d as a new CaMKIIα hub high-affinity ligand with enhanced pharmacokinetic properties, representing a powerful tool compound for allosteric regulation of kinase activity with subtype specificity.- Published
- 2022
- Full Text
- View/download PDF
50. Exposure Route Influences Disease Severity in the COVID-19 Cynomolgus Macaque Model.
- Author
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Bixler SL, Stefan CP, Jay AN, Rossi FD, Ricks KM, Shoemaker CJ, Moreau AM, Zeng X, Hooper JW, Dyer DN, Frick OM, Koehler JW, Kearney BJ, DiPinto N, Liu J, Tostenson SD, Clements TL, Smith JM, Johnson JA, Berrier KL, Esham HL, Delp KL, Coyne SR, Bloomfield HA, Kuehnert PA, Akers K, Gibson KM, Minogue TD, Nalca A, and Pitt MLM
- Subjects
- Aerosols, Animals, Disease Models, Animal, Macaca fascicularis, SARS-CoV-2, Severity of Illness Index, COVID-19
- Abstract
The emergence of SARS-CoV-2 and the subsequent pandemic has highlighted the need for animal models that faithfully replicate the salient features of COVID-19 disease in humans. These models are necessary for the rapid selection, testing, and evaluation of potential medical countermeasures. Here, we performed a direct comparison of two distinct routes of SARS-CoV-2 exposure-combined intratracheal/intranasal and small particle aerosol-in two nonhuman primate species, rhesus and cynomolgus macaques. While all four experimental groups displayed very few outward clinical signs, evidence of mild to moderate respiratory disease was present on radiographs and at necropsy. Cynomolgus macaques exposed via the aerosol route also developed the most consistent fever responses and had the most severe respiratory disease and pathology. This study demonstrates that while all four models produced suitable representations of mild COVID-like illness, aerosol exposure of cynomolgus macaques to SARS-CoV-2 produced the most severe disease, which may provide additional clinical endpoints for evaluating therapeutics and vaccines.
- Published
- 2022
- Full Text
- View/download PDF
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