2,171 results on '"A La Spada"'
Search Results
2. Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease.
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Matthews, Ian, Birnbaum, Allison, Gromova, Anastasia, Huang, Amy, Liu, Kailin, Liu, Eleanor, Coutinho, Kristen, McGraw, Megan, Patterson, Dalton, Banks, Macy, Nobles, Amber, Nguyen, Nhat, Merrihew, Gennifer, Wang, Lu, Baeuerle, Eric, Fernandez, Elizabeth, Musi, Nicolas, MacCoss, Michael, Miranda, Helen, Cortes, Constanza, and La Spada, Albert
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CP: Neuroscience ,TFEB ,aging ,brain ,exercise ,muscle ,neurodegeneration ,tau ,Mice ,Animals ,Neurodegenerative Diseases ,Transcription Factors ,Neuroinflammatory Diseases ,Muscle ,Skeletal ,Mice ,Transgenic ,Aging ,Central Nervous System ,Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - Abstract
Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.
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- 2023
3. Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity.
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Bennett, Craig, Dastidar, Somasish, Arnold, Frederick, McKinstry, Spencer, Stockford, Cameron, Freibaum, Brian, Sopher, Bryce, Wu, Meilin, Seidner, Glen, Joiner, William, Taylor, J, West, Ryan, and La Spada, Albert
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Amyotrophic lateral sclerosis ,C9orf72 ,Dipeptide repeat ,Drosophila ,Nucleolus ,Senataxin ,Humans ,Animals ,Amyotrophic Lateral Sclerosis ,Dipeptides ,C9orf72 Protein ,Arginine ,HEK293 Cells ,Motor Neurons ,Drosophila ,RNA ,Frontotemporal Dementia ,DNA Repeat Expansion ,DNA Helicases ,RNA Helicases ,Multifunctional Enzymes - Abstract
Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA-protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.
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- 2023
4. MAP4K3 inhibits Sirtuin-1 to repress the LKB1-AMPK pathway to promote amino acid-dependent activation of the mTORC1 complex.
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Branch, Mary Rose, Hsu, Cynthia L, Ohnishi, Kohta, Shen, Wen-Chuan, Lee, Elian, Meisenhelder, Jill, Winborn, Brett, Sopher, Bryce L, Taylor, J Paul, Hunter, Tony, and La Spada, Albert R
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Amino Acids ,Signal Transduction ,AMP-Activated Protein Kinases ,Sirtuin 1 ,Mechanistic Target of Rapamycin Complex 1 ,1.1 Normal biological development and functioning ,Underpinning research - Abstract
mTORC1 is the key rheostat controlling the cellular metabolic state. Of the various inputs to mTORC1, the most potent effector of intracellular nutrient status is amino acid supply. Despite an established role for MAP4K3 in promoting mTORC1 activation in the presence of amino acids, the signaling pathway by which MAP4K3 controls mTORC1 activation remains unknown. Here, we examined the process of MAP4K3 regulation of mTORC1 and found that MAP4K3 represses the LKB1-AMPK pathway to achieve robust mTORC1 activation. When we sought the regulatory link between MAP4K3 and LKB1 inhibition, we discovered that MAP4K3 physically interacts with the master nutrient regulatory factor sirtuin-1 (SIRT1) and phosphorylates SIRT1 to repress LKB1 activation. Our results reveal the existence of a novel signaling pathway linking amino acid satiety with MAP4K3-dependent suppression of SIRT1 to inactivate the repressive LKB1-AMPK pathway and thereby potently activate the mTORC1 complex to dictate the metabolic disposition of the cell.
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- 2023
5. Protocol for mapping double-stranded DNA break sites across the genome with translocation capture sequencing
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Delaney, Joe R and La Spada, Albert R
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Human Genome ,Biotechnology ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Cell Biology ,Genomics ,High-throughput Screening - Abstract
Translocation sequencing can be used to assess mechanisms of DNA repair and identify genome-wide double-strand breaks (DSBs) accessible to DNA repair machinery. Here, we present a protocol for mapping double-strand DNA break sites across the genome with translocation capture sequencing. Bait DSBs are introduced using a Cas9 nuclease and repaired by the host cell, connecting bait DSBs to other DSBs. Repair sites are detected by isolating bait site DNA, cleaving normal sequence to enrich off-site repair, and next-generation sequencing. For complete details on the use and execution of this protocol, please refer to Switonski et al. (2021).1.
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- 2023
6. X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease.
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Gromova, Anastasia, Cha, Byeonggu, Robinson, Erica M, Strickland, Laura M, Nguyen, Nhat, ElMallah, Mai K, Cortes, Constanza J, and La Spada, Albert R
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Motor Neurons ,Animals ,Mice ,Transgenic ,Humans ,Mice ,Nerve Degeneration ,Receptors ,Androgen ,Phenotype ,Aged ,Male ,Bulbo-Spinal Atrophy ,X-Linked ,Rare Diseases ,Genetics ,Orphan Drug ,Neurodegenerative ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Musculoskeletal ,Biochemistry and Cell Biology ,Clinical Sciences - Abstract
X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally.
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- 2023
7. Exploring eco-friendly solutions for Phytophthora disease management: Harnessing the anti-oomycete potential of a fermented lemon waste formulation
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Federico La Spada, Cristian Bua, Antonella Pane, Nunzio Tuccitto, Mario Riolo, and Santa Olga Cacciola
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Phytophthora spp. ,Citrus limon ,Phytophthora fruit rot ,Bioformulation ,Lactiplantibacillus plantarum ,Antifungal activity ,Agriculture (General) ,S1-972 ,Nutrition. Foods and food supply ,TX341-641 - Abstract
Phytophthora species pose significant challenges to agricultural and natural ecosystems due to their ecological plasticity and ability to cause diseases of various plant species. Effective control of Phytophthora diseases requires integrated approaches that consider specific agronomic practices, environmental factors, and the rationale use of chemicals. In response to the need for eco-friendly alternatives, this study investigated the anti-oomycete potential of a formulation derived from the fermentation of lemon wastes by Lactiplantibacillus plantarum ('bioact-LM'). In vitro assays demonstrated the significant anti-oomycete efficacy of bioact-LM against multiple Phytophthora species, both through direct contact inhibition and the release of volatile organic compounds (VOCs). In vivo assessments on orange and apple fruits further confirmed the effectiveness of bioact-LM in reducing Phytophthora rot severity. These findings suggest bioact-LM is promising as a sustainable alternative to synthetic fungicide for Phytophthora disease management, highlighting the importance of exploring eco-friendly solutions in a scenario of environmental challenges and restriction in the use of conventional chemical control methods.
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- 2024
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8. Geographical Overview of 137Cs Resampling Studies
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Porto, P., primary, Fulajtar, E., additional, Walling, D. E., additional, Callegari, G., additional, Cogliandro, V., additional, La Spada, C., additional, Gaspar, L., additional, Navas, A., additional, Yu, H. Q., additional, Liu, W. X., additional, Chappell, A., additional, Li, Y., additional, Benmansour, M., additional, Moustakim, M., additional, Damnati, B., additional, Moussadek, R., additional, Nouira, A., additional, Amenzou, N., additional, Mrabet, R., additional, and Kheng Heng, L., additional
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- 2024
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9. Selective vulnerability in Huntington's disease: From excitotoxicity, mitochondrial dysfunction, and transcription dysregulation to therapeutic opportunity
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Deyell, Jacob S., primary, Gulia, Ravinder, additional, and La Spada, Albert R., additional
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- 2024
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10. Contributors
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Aaronson, Jeffrey S., primary, Abramovich, Juliana, additional, Aronin, Neil, additional, Bañez-Coronel, Monica, additional, Bates, Gillian P., additional, Brodsky, Michael, additional, Chen, Richard Z., additional, Cleary, John Douglas, additional, Colwell, Christopher S., additional, Cristea, Ileana M., additional, Croce, Katherine R., additional, Deshmukh, Amit L., additional, Deyell, Jacob S., additional, DiFiglia, Marian, additional, Dionisio, Leonardo E., additional, Estevez-Fraga, Carlos, additional, Fienko, Sandra, additional, Finkbeiner, Steven, additional, Frydman, Judith, additional, Gall-Duncan, Terence, additional, Gantman, Emily C., additional, Goldman, Steven A., additional, Gray, Michelle, additional, Greco, Todd M., additional, Grosso Jasutkar, Hilary, additional, Gulia, Ravinder, additional, Gusella, James F., additional, Heiman, Myriam, additional, Khvorova, Anastasia, additional, Kleczko, Korbin, additional, Landles, Christian, additional, Langfelder, Peter, additional, La Spada, Albert R., additional, Leavitt, Blair R., additional, Lee, Jong-Min, additional, Lee, Seong Won, additional, Li, Xiao-Jiang, additional, Li, Shihua, additional, Liu, Jeh-Ping, additional, Long, Jeffrey D., additional, MacDonald, Marcy E., additional, Mackay, James, additional, Mansbach, Alexandra, additional, Massey, Thomas H., additional, Masto, Vincent, additional, Moran-Reyna, Aida, additional, Morton, A. Jennifer, additional, Nakajima, Mitsuko, additional, Oh, Young Mi, additional, Papadopoulou, Aikaterini-Smaragdi, additional, Pearson, Christopher E., additional, Pinto, Ricardo Mouro, additional, Ranum, Laura P.W., additional, Raymond, Lynn A., additional, Rosinski, Jim, additional, Sampaio, Cristina, additional, Sathitloetsakun, Suphinya, additional, Sena-Esteves, Miguel, additional, Sepers, Marja D., additional, Silva Ramos, Eduardo, additional, Smith, Charlene, additional, Steffan, Joan S., additional, Stone, Joseph C., additional, Tabrizi, Sarah J., additional, Tan, Weiyi, additional, Thompson, Leslie M., additional, Vogt, Thomas F., additional, Wanker, Erich E., additional, Wheeler, Vanessa C., additional, William Yang, X., additional, Yamamoto, Ai, additional, Yan, Sen, additional, Yoo, Andrew S., additional, and Zeitlin, Scott O., additional
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- 2024
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11. Antibody-assisted selective isolation of Purkinje cell nuclei from mouse cerebellar tissue
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Luke C. Bartelt, Mouad Fakhri, Grazyna Adamek, Magdalena Trybus, Anna Samelak-Czajka, Paulina Jackowiak, Agnieszka Fiszer, Craig B. Lowe, Albert R. La Spada, and Pawel M. Switonski
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CP: Neuroscience ,Biotechnology ,TP248.13-248.65 ,Biochemistry ,QD415-436 ,Science - Abstract
Summary: We developed a method that utilizes fluorescent labeling of nuclear envelopes alongside cytometry sorting for the selective isolation of Purkinje cell (PC) nuclei. Beginning with SUN1 reporter mice, we GFP-tagged envelopes to confirm that PC nuclei could be accurately separated from other cell types. We then developed an antibody-based protocol to make PC nuclear isolation more robust and adaptable to cerebellar tissues of any genotypic background. Immunofluorescent labeling of the nuclear membrane protein RanBP2 enabled the isolation of PC nuclei from C57BL/6 cerebellum. By analyzing the expression of PC markers, nuclear size, and nucleoli number, we confirmed that our method delivers a pure fraction of PC nuclei. To demonstrate its applicability, we isolated PC nuclei from spinocerebellar ataxia type 7 (SCA7) mice and identified transcriptional changes in known and new disease-associated genes. Access to pure PC nuclei offers insights into PC biology and pathology, including the nature of selective neuronal vulnerability. Motivation: Cerebellar Purkinje cells (PCs) play a central role in controlling voluntary movements, coordination, and motor learning. PC degeneration and death are hallmarks of many human neurological disorders, including multiple forms of spinocerebellar ataxia. Unfortunately, PCs comprise a relatively small population of cells in the cerebellum, constituting less than 1% of the total cell count. This makes studying PC-related pathology using omics approaches exceptionally challenging. Here, we introduce a protocol that addresses the need for obtaining pure fractions of PC nuclei for subsequent cell-specific analysis.
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- 2024
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12. Author Correction: Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4
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Campisi, Laura, Chizari, Shahab, Ho, Jessica SY, Gromova, Anastasia, Arnold, Frederick J, Mosca, Lorena, Mei, Xueyan, Fstkchyan, Yesai, Torre, Denis, Beharry, Cindy, Garcia-Forn, Marta, Jiménez-Alcázar, Miguel, Korobeynikov, Vladislav A, Prazich, Jack, Fayad, Zahi A, Seldin, Marcus M, De Rubeis, Silvia, Bennett, Craig L, Ostrow, Lyle W, Lunetta, Christian, Squatrito, Massimo, Byun, Minji, Shneider, Neil A, Jiang, Ning, La Spada, Albert R, and Marazzi, Ivan
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General Science & Technology - Published
- 2022
13. A portable fluorescence-based recombinase polymerase amplification assay for the detection of mal secco disease by Plenodomus tracheiphilus
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Rovetto, Ermes Ivan, Garbelotto, Matteo, Moricca, Salvatore, Amato, Marcos, La Spada, Federico, and Cacciola, Santa Olga
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- 2024
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14. Leaf volatile organic compounds profiles from two citrus genotypes differing in susceptibility to Phytophthora citrophthora infection
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Maserti, Biancaelena, Michelozzi, Marco, Cencetti, Gabriele, Riolo, Mario, La Spada, Federico, Aloi, Francesco, Pane, Antonella, Bartolini, Paola, Pecori, Francesco, de Andrade Silva, Edson Mario, da Silva Gesteira, Abelmon, Micheli, Fabienne, and Cacciola, Santa Olga
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- 2024
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15. Exploring eco-friendly solutions for Phytophthora disease management: Harnessing the anti-oomycete potential of a fermented lemon waste formulation
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La Spada, Federico, Bua, Cristian, Pane, Antonella, Tuccitto, Nunzio, Riolo, Mario, and Cacciola, Santa Olga
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- 2024
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16. Structure-based design of multitargeting ChEs-MAO B inhibitors based on phenyl ring bioisosteres: AChE/BChE selectivity switch and drug-like characterization
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La Spada, Gabriella, Miniero, Daniela Valeria, Rullo, Mariagrazia, Cipolloni, Marco, Delre, Pietro, Colliva, Carolina, Colella, Marco, Leonetti, Francesco, Liuzzi, Grazia Maria, Mangiatordi, Giuseppe Felice, Giacchè, Nicola, and Pisani, Leonardo
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- 2024
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17. Improving Cuticle Thickness and Quality Traits in Table Grape cv. ‘Italia’ Using Pre-Harvest Treatments
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Paolo La Spada, Alberto Continella, Eva Dominguez, Antonio Heredia, and Alessandra Gentile
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cracking ,cuticle ,calcium chloride ,phytohormones ,brown algae ,table grape ,Botany ,QK1-989 - Abstract
Table grape viticulture, due to the impact of climate change, will have to face many challenges in the coming decades, including resistance to pathogens and physiological disorders. Our attention was focused on fruit cracking due to its ubiquitous presence in several species. This study explores the effects of three different treatments on the epidermis and cuticle of table grape berries by evaluating the impact of the girdling technique on various fruit quality parameters, including cuticle thickness, sugar content, acidity, color, bunch weight, and rheological properties. The treatments were (1) calcium chloride (CaCl2), (2) calcium chloride + salicylic acid (CaCl2 + SA), and (3) calcium chloride + Ascophyllum nodosum (CaCl2 + AN), with and without girdling, plus an untreated control. This research was conducted over the 2021–2022 growing season in a commercial vineyard in Licodia Eubea, Sicily, Italy. The results indicate significant variations in cuticle thickness and other qualitative traits throughout the growth and ripening phases, with notable differences depending on the treatment used. This study’s findings suggest that specific treatments can influence the structural integrity of the grape cuticle, potentially impacting the fruit’s susceptibility to cracking and overall marketability. The findings provide valuable insights into the role of chemical treatments and cultural techniques in enhancing fruit quality and resistance to environmental stresses in table grape cultivation.
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- 2024
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18. Author Correction: Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy
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Badders, Nisha M., Korff, Ane, Miranda, Helen C., Vuppala, Pradeep K., Smith, Rebecca B., Winborn, Brett J., Quemin, Emmanuelle R., Sopher, Bryce L., Dearman, Jennifer, Messing, James, Kim, Nam Chul, Moore, Jennifer, Freibaum, Brian D., Kanagaraj, Anderson P., Fan, Baochang, Tillman, Heather, Chen, Ping-Chung, Wang, Yingzhe, Freeman, III, Burgess B., Li, Yimei, Kim, Hong Joo, La Spada, Albert R., and Taylor, J. Paul
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- 2024
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19. Defining short-term outcomes of minor ischemic stroke due to small artery occlusion in the era of dual antiplatelet treatment: A READAPT study sub-analysis
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Foschi, Matteo, De Matteis, Eleonora, De Santis, Federico, Romoli, Michele, Tassinari, Tiziana, Saia, Valentina, Cenciarelli, Silvia, Bedetti, Chiara, Padiglioni, Chiara, Censori, Bruno, Puglisi, Valentina, Vinciguerra, Luisa, Guarino, Maria, Barone, Valentina, Zedde, Marialuisa, Grisendi, Ilaria, Diomedi, Marina, Bagnato, Maria Rosaria, Petruzzellis, Marco, Mezzapesa, Domenico Maria, Di Viesti, Pietro, Inchingolo, Vincenzo, Cappellari, Manuel, Zivelonghi, Cecilia, Candelaresi, Paolo, Andreone, Vincenzo, Rinaldi, Giuseppe, Bavaro, Alessandra, Cavallini, Anna, Moraru, Stefan, Querzani, Pietro, Terruso, Valeria, Mannino, Marina, Pezzini, Alessandro, Frisullo, Giovanni, Muscia, Francesco, Paciaroni, Maurizio, Mosconi, Maria Giulia, Zini, Andrea, Leone, Ruggiero, Palmieri, Carmela, Cupini, Letizia Maria, Marcon, Michela, Tassi, Rossana, Sanzaro, Enzo, Paci, Cristina, Viticchi, Giovanna, Orsucci, Daniele, Falcou, Anne, Diamanti, Susanna, Tarletti, Roberto, Nencini, Patrizia, Rota, Eugenia, Sepe, Federica Nicoletta, Ferrandi, Delfina, Caputi, Luigi, Volpi, Gino, La Spada, Salvatore, Beccia, Mario, Rinaldi, Claudia, Mastrangelo, Vincenzo, Di Blasio, Francesco, Invernizzi, Paolo, Pelliccioni, Giuseppe, De Angelis, Maria Vittoria, Bonanni, Laura, Ruzza, Giampietro, Caggia, Emanuele Alessandro, Russo, Monia, Tonon, Agnese, Acciarri, Maria Cristina, Anticoli, Sabrina, Roberti, Cinzia, Manobianca, Giovanni, Scaglione, Gaspare, Pistoia, Francesca, Fortini, Alberto, De Boni, Antonella, Sanna, Alessandra, Chiti, Alberto, Barbarini, Leonardo, Caggiula, Marcella, Masato, Maela, Del Sette, Massimo, Passarelli, Francesco, Bongioanni, Maria Roberta, Toni, Danilo, Ricci, Stefano, Sacco, Simona, and Ornello, Raffaele
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- 2024
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20. Clonally expanded CD8 T cells characterize amyotrophic lateral sclerosis-4
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Campisi, Laura, Chizari, Shahab, Ho, Jessica SY, Gromova, Anastasia, Arnold, Frederick J, Mosca, Lorena, Mei, Xueyan, Fstkchyan, Yesai, Torre, Denis, Beharry, Cindy, Garcia-Forn, Marta, Jiménez-Alcázar, Miguel, Korobeynikov, Vladislav A, Prazich, Jack, Fayad, Zahi A, Seldin, Marcus M, De Rubeis, Silvia, Bennett, Craig L, Ostrow, Lyle W, Lunetta, Christian, Squatrito, Massimo, Byun, Minji, Shneider, Neil A, Jiang, Ning, La Spada, Albert R, and Marazzi, Ivan
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Biomedical and Clinical Sciences ,Immunology ,ALS ,Rare Diseases ,Neurodegenerative ,Neurosciences ,Brain Disorders ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Animals ,Mice ,Amyotrophic Lateral Sclerosis ,CD8-Positive T-Lymphocytes ,Clone Cells ,DNA Helicases ,Gene Knock-In Techniques ,Motor Neurons ,Multifunctional Enzymes ,Mutation ,RNA Helicases ,Humans ,General Science & Technology - Abstract
Amyotrophic lateral sclerosis (ALS) is a heterogenous neurodegenerative disorder that affects motor neurons and voluntary muscle control1. ALS heterogeneity includes the age of manifestation, the rate of progression and the anatomical sites of symptom onset. Disease-causing mutations in specific genes have been identified and define different subtypes of ALS1. Although several ALS-associated genes have been shown to affect immune functions2, whether specific immune features account for ALS heterogeneity is poorly understood. Amyotrophic lateral sclerosis-4 (ALS4) is characterized by juvenile onset and slow progression3. Patients with ALS4 show motor difficulties by the time that they are in their thirties, and most of them require devices to assist with walking by their fifties. ALS4 is caused by mutations in the senataxin gene (SETX). Here, using Setx knock-in mice that carry the ALS4-causative L389S mutation, we describe an immunological signature that consists of clonally expanded, terminally differentiated effector memory (TEMRA) CD8 T cells in the central nervous system and the blood of knock-in mice. Increased frequencies of antigen-specific CD8 T cells in knock-in mice mirror the progression of motor neuron disease and correlate with anti-glioma immunity. Furthermore, bone marrow transplantation experiments indicate that the immune system has a key role in ALS4 neurodegeneration. In patients with ALS4, clonally expanded TEMRA CD8 T cells circulate in the peripheral blood. Our results provide evidence of an antigen-specific CD8 T cell response in ALS4, which could be used to unravel disease mechanisms and as a potential biomarker of disease state.
- Published
- 2022
21. Biological control of green mold in simulated post-harvest chain of citrus Fruit: Efficacy of Candida oleophila strain O and molecular insight into elicitation of host immune system
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Rovetto, Ermes Ivan, La Spada, Federico, El boumlasy, Soumia, Conti Taguali, Sebastiano, Riolo, Mario, Pane, Antonella, and Cacciola, Santa Olga
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- 2024
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22. Alternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders
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Cui, Ya, Arnold, Frederick J., Peng, Fanglue, Wang, Dan, Li, Jason Sheng, Michels, Sebastian, Wagner, Eric J., La Spada, Albert R., and Li, Wei
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- 2023
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23. Financial Sanctions, SWIFT, and the Architecture of the International Payment System
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Cipriani, Marco, Goldberg, Linda S., and La Spada, Gabriele
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- 2023
24. Factors influencing fruit cracking: an environmental and agronomic perspective
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Paolo La Spada, Eva Dominguez, Alberto Continella, Antonio Heredia, and Alessandra Gentile
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cracking ,cuticle ,environmental factors ,agronomic factors ,precision farming ,Plant culture ,SB1-1110 - Abstract
Fruit cracking, a widespread physiological disorder affecting various fruit crops and vegetables, has profound implications for fruit quality and marketability. This mini review delves into the multifaceted factors contributing to fruit cracking and emphasizes the pivotal roles of environmental and agronomic factors in its occurrence. Environmental variables such as temperature, relative humidity, and light exposure are explored as determinants factors influencing fruit cracking susceptibility. Furthermore, the significance of mineral nutrition and plant growth regulators in mitigating fruit cracking risk is elucidated, being calcium deficiency identified as a prominent variable in various fruit species. In recent years, precision farming and monitoring systems have emerged as valuable tools for managing environmental factors and optimizing fruit production. By meticulously tracking parameters such as temperature, humidity, soil moisture, and fruit skin temperature, growers can make informed decisions to prevent or alleviate fruit cracking. In conclusion, effective prevention of fruit cracking necessitates a comprehensive approach that encompasses both environmental and agronomic factors.
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- 2024
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25. Senataxin helicase, the causal gene defect in ALS4, is a significant modifier of C9orf72 ALS G4C2 and arginine-containing dipeptide repeat toxicity
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Craig L. Bennett, Somasish Dastidar, Frederick J. Arnold, Spencer U. McKinstry, Cameron Stockford, Brian D. Freibaum, Bryce L. Sopher, Meilin Wu, Glen Seidner, William Joiner, J. Paul Taylor, Ryan J. H. West, and Albert R. La Spada
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Amyotrophic lateral sclerosis ,C9orf72 ,Senataxin ,Dipeptide repeat ,Drosophila ,Nucleolus ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Identifying genetic modifiers of familial amyotrophic lateral sclerosis (ALS) may reveal targets for therapeutic modulation with potential application to sporadic ALS. GGGGCC (G4C2) repeat expansions in the C9orf72 gene underlie the most common form of familial ALS, and generate toxic arginine-containing dipeptide repeats (DPRs), which interfere with membraneless organelles, such as the nucleolus. Here we considered senataxin (SETX), the genetic cause of ALS4, as a modifier of C9orf72 ALS, because SETX is a nuclear helicase that may regulate RNA–protein interactions involved in ALS dysfunction. After documenting that decreased SETX expression enhances arginine-containing DPR toxicity and C9orf72 repeat expansion toxicity in HEK293 cells and primary neurons, we generated SETX fly lines and evaluated the effect of SETX in flies expressing either (G4C2)58 repeats or glycine-arginine-50 [GR(50)] DPRs. We observed dramatic suppression of disease phenotypes in (G4C2)58 and GR(50) Drosophila models, and detected a striking relocalization of GR(50) out of the nucleolus in flies co-expressing SETX. Next-generation GR(1000) fly models, that show age-related motor deficits in climbing and movement assays, were similarly rescued with SETX co-expression. We noted that the physical interaction between SETX and arginine-containing DPRs is partially RNA-dependent. Finally, we directly assessed the nucleolus in cells expressing GR-DPRs, confirmed reduced mobility of proteins trafficking to the nucleolus upon GR-DPR expression, and found that SETX dosage modulated nucleolus liquidity in GR-DPR-expressing cells and motor neurons. These findings reveal a hitherto unknown connection between SETX function and cellular processes contributing to neuron demise in the most common form of familial ALS.
- Published
- 2023
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26. Nanohaloarchaea as beneficiaries of xylan degradation by haloarchaea
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Violetta La Cono, Enzo Messina, Oleg Reva, Francesco Smedile, Gina La Spada, Francesca Crisafi, Laura Marturano, Noa Miguez, Manuel Ferrer, Elena A. Selivanova, Olga V. Golyshina, Peter N. Golyshin, Manfred Rohde, Mart Krupovic, Alexander Y. Merkel, Dimitry Y. Sorokin, John E. Hallsworth, and Michail M. Yakimov
- Subjects
Biotechnology ,TP248.13-248.65 - Abstract
Abstract Climate change, desertification, salinisation of soils and the changing hydrology of the Earth are creating or modifying microbial habitats at all scales including the oceans, saline groundwaters and brine lakes. In environments that are saline or hypersaline, the biodegradation of recalcitrant plant and animal polysaccharides can be inhibited by salt‐induced microbial stress and/or by limitation of the metabolic capabilities of halophilic microbes. We recently demonstrated that the chitinolytic haloarchaeon Halomicrobium can serve as the host for an ectosymbiont, nanohaloarchaeon ‘Candidatus Nanohalobium constans’. Here, we consider whether nanohaloarchaea can benefit from the haloarchaea‐mediated degradation of xylan, a major hemicellulose component of wood. Using samples of natural evaporitic brines and anthropogenic solar salterns, we describe genome‐inferred trophic relations in two extremely halophilic xylan‐degrading three‐member consortia. We succeeded in genome assembly and closure for all members of both xylan‐degrading cultures and elucidated the respective food chains within these consortia. We provide evidence that ectosymbiontic nanohaloarchaea is an active ecophysiological component of extremely halophilic xylan‐degrading communities (although by proxy) in hypersaline environments. In each consortium, nanohaloarchaea occur as ectosymbionts of Haloferax, which in turn act as scavenger of oligosaccharides produced by xylan‐hydrolysing Halorhabdus. We further obtained and characterised the nanohaloarchaea–host associations using microscopy, multi‐omics and cultivation approaches. The current study also doubled culturable nanohaloarchaeal symbionts and demonstrated that these enigmatic nano‐sized archaea can be readily isolated in binary co‐cultures using an appropriate enrichment strategy. We discuss the implications of xylan degradation by halophiles in biotechnology and for the United Nation's Sustainable Development Goals.
- Published
- 2023
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27. Chitosan-based films grafted with citrus waste-derived antifungal agents: An innovative and sustainable approach to enhance post-harvest preservation of citrus fruit
- Author
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Arslan, Deniz, Tuccitto, Nunzio, Auditore, Alessandro, Licciardello, Antonino, Marletta, Giovanni, Riolo, Mario, La Spada, Federico, Conti Taguali, Sebastiano, Calpe, Jorge, Meca, Giuseppe, Pane, Antonella, Cacciola, Santa Olga, and Karakeçili, Ayşe
- Published
- 2024
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28. Bleeding stem cankers and root rot caused by Phytophthora multivora in Morus alba, Pistacia atlantica and Sterculia diversifolia trees in eastern Sicily
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Conti Taguali, Sebastiano, Bua, Cristian, Rovetto, Ermes Ivan, Pane, Antonella, La Spada, Federico, and Cacciola, Santa Olga
- Published
- 2024
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29. Altered H3 histone acetylation impairs high-fidelity DNA repair to promote cerebellar degeneration in spinocerebellar ataxia type 7
- Author
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Switonski, Pawel M, Delaney, Joe R, Bartelt, Luke C, Niu, Chenchen, Ramos-Zapatero, Maria, Spann, Nathanael J, Alaghatta, Akshay, Chen, Toby, Griffin, Emily N, Bapat, Jaidev, Sopher, Bryce L, and La Spada, Albert R
- Subjects
Biological Sciences ,Genetics ,Rare Diseases ,Eye Disease and Disorders of Vision ,Neurosciences ,Brain Disorders ,Neurodegenerative ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Acetylation ,Animals ,Ataxin-7 ,Cerebellar Diseases ,DNA Repair ,Female ,Histones ,Humans ,Male ,Mice ,Neurons ,Peptides ,Spinocerebellar Ataxias ,ChIP-seq ,DNA damage ,ataxin-7 ,cerebellum ,epigenetic dysregulation ,neurodegeneration ,polyglutamine ,repair ,spinocerebellar ataxia ,translocation ,Biochemistry and Cell Biology ,Medical Physiology ,Biological sciences - Abstract
A common mechanism in inherited ataxia is a vulnerability of DNA damage. Spinocerebellar ataxia type 7 (SCA7) is a CAG-polyglutamine-repeat disorder characterized by cerebellar and retinal degeneration. Polyglutamine-expanded ataxin-7 protein incorporates into STAGA co-activator complex and interferes with transcription by altering histone acetylation. We performed chromatic immunoprecipitation sequencing ChIP-seq on cerebellum from SCA7 mice and observed increased H3K9-promoter acetylation in DNA repair genes, resulting in increased expression. After detecting increased DNA damage in SCA7 cells, mouse primary cerebellar neurons, and patient stem-cell-derived neurons, we documented reduced homology-directed repair (HDR) and single-strand annealing (SSA). To evaluate repair at endogenous DNA in native chromosome context, we modified linear amplification-mediated high-throughput genome-wide translocation sequencing and found that DNA translocations are less frequent in SCA7 models, consistent with decreased HDR and SSA. Altered DNA repair function in SCA7 may predispose the subject to excessive DNA damage, leading to neuron demise and highlights DNA repair as a therapy target.
- Published
- 2021
30. Synthesis, Molecular Electron Density Theory Study, Molecular Docking, and Pharmacological Evaluation of New Coumarin–Sulfonamide–Nitroindazolyl–Triazole Hybrids as Monoamine Oxidase Inhibitors
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Mohammed Eddahmi, Gabriella La Spada, Luis R. Domingo, Gérard Vergoten, Christian Bailly, Marco Catto, and Latifa Bouissane
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coumarin–sulfonamide–nitroindazolyl–triazole hybrids ,MEDT ,electrophilic aromatic substitution ,AS ,AChE inhibitors ,MAO inhibitors ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Inhibitors of monoamine oxidases (MAOs) are of interest for the treatment of neurodegenerative disorders and other human pathologies. In this frame, the present work describes different synthetic strategies to obtain MAO inhibitors via the coupling of the aminocoumarin core with arylsulfonyl chlorides followed by copper azide-alkyne cycloaddition, leading to coumarin–sulfonamide–nitroindazolyl–triazole hybrids. The nitration position on the coumarin moiety was confirmed through nuclear magnetic resonance spectroscopy and molecular electron density theory in order to elucidate the molecular mechanism and selectivity of the electrophilic aromatic substitution reaction. The coumarin derivatives were evaluated for their inhibitory potency against monoamine oxidases and cholinesterases. Molecular docking calculations provided a rational binding mode of the best compounds in the series with MAO A and B. The work identified hybrids 14a–c as novel MAO inhibitors, with a selective action against isoform B, of potential interest to combat neurological diseases.
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- 2024
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31. Revisiting Glutamate Excitotoxicity in Amyotrophic Lateral Sclerosis and Age-Related Neurodegeneration
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Frederick J. Arnold, Alexandra F. Putka, Urmimala Raychaudhuri, Solomon Hsu, Richard S. Bedlack, Craig L. Bennett, and Albert R. La Spada
- Subjects
glutamate excitotoxicity ,AMPA receptors ,GluR2 editing ,astrocytes ,NMDA receptors ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder. While there are five FDA-approved drugs for treating this disease, each has only modest benefits. To design new and more effective therapies for ALS, particularly for sporadic ALS of unknown and diverse etiologies, we must identify key, convergent mechanisms of disease pathogenesis. This review focuses on the origin and effects of glutamate-mediated excitotoxicity in ALS (the cortical hyperexcitability hypothesis), in which increased glutamatergic signaling causes motor neurons to become hyperexcitable and eventually die. We characterize both primary and secondary contributions to excitotoxicity, referring to processes taking place at the synapse and within the cell, respectively. ‘Primary pathways’ include upregulation of calcium-permeable AMPA receptors, dysfunction of the EAAT2 astrocytic glutamate transporter, increased release of glutamate from the presynaptic terminal, and reduced inhibition by cortical interneurons—all of which have been observed in ALS patients and model systems. ‘Secondary pathways’ include changes to mitochondrial morphology and function, increased production of reactive oxygen species, and endoplasmic reticulum (ER) stress. By identifying key targets in the excitotoxicity cascade, we emphasize the importance of this pathway in the pathogenesis of ALS and suggest that intervening in this pathway could be effective for developing therapies for this disease.
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- 2024
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32. Spinocerebellar Ataxia Type 7: From Mechanistic Pathways to Therapeutic Opportunities
- Author
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Switonski, Pawel M., La Spada, Albert R., Manto, Mario, Series Editor, Soong, Bing-wen, editor, Brice, Alexis, editor, and Pulst, Stefan M., editor
- Published
- 2023
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33. X-linked SBMA model mice display relevant non-neurological phenotypes and their expression of mutant androgen receptor protein in motor neurons is not required for neuromuscular disease
- Author
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Anastasia Gromova, Byeonggu Cha, Erica M. Robinson, Laura M. Strickland, Nhat Nguyen, Mai K. ElMallah, Constanza J. Cortes, and Albert R. La Spada
- Subjects
Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a rare neuromuscular disorder characterized by adult-onset proximal muscle weakness and lower motor neuron degeneration. SBMA was the first human disease found to be caused by a repeat expansion mutation, as affected patients possess an expanded tract of CAG repeats, encoding polyglutamine, in the androgen receptor (AR) gene. We previously developed a conditional BAC fxAR121 transgenic mouse model of SBMA and used it to define a primary role for skeletal muscle expression of polyglutamine-expanded AR in causing the motor neuron degeneration. Here we sought to extend our understanding of SBMA disease pathophysiology and cellular basis by detailed examination and directed experimentation with the BAC fxAR121 mice. First, we evaluated BAC fxAR121 mice for non-neurological disease phenotypes recently described in human SBMA patients, and documented prominent non-alcoholic fatty liver disease, cardiomegaly, and ventricular heart wall thinning in aged male BAC fxAR121 mice. Our discovery of significant hepatic and cardiac abnormalities in SBMA mice underscores the need to evaluate human SBMA patients for signs of liver and heart disease. To directly examine the contribution of motor neuron-expressed polyQ-AR protein to SBMA neurodegeneration, we crossed BAC fxAR121 mice with two different lines of transgenic mice expressing Cre recombinase in motor neurons, and after updating characterization of SBMA phenotypes in our current BAC fxAR121 colony, we found that excision of mutant AR from motor neurons did not rescue neuromuscular or systemic disease. These findings further validate a primary role for skeletal muscle as the driver of SBMA motor neuronopathy and indicate that therapies being developed to treat patients should be delivered peripherally.
- Published
- 2023
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34. The Optimal Supply of Central Bank Reserves under Uncertainty
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Afonso, Gara, primary, La Spada, Gabriele, additional, Mertens, Thomas M., additional, and Williams, John C., additional
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- 2023
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35. Novel benzothiazole derivatives as multitargeted-directed ligands for the treatment of Alzheimer’s disease
- Author
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Donia E. Hafez, Mariam Dubiel, Gabriella La Spada, Marco Catto, David Reiner-Link, Yu-Ting Syu, Mohammad Abdel-Halim, Tsong-Long Hwang, Holger Stark, and Ashraf H. Abadi
- Subjects
Multitarget-directed ligands ,Alzheimer’s disease ,cholinesterase inhibitors ,histamine H3 receptor ligands ,monoamine oxidase inhibitors ,benzothiazole derivatives ,Therapeutics. Pharmacology ,RM1-950 - Abstract
Neurodegenerative diseases such as Alzheimer’s disease (AD) are multifactorial with several different pathologic mechanisms. Therefore, it is assumed that multitargeted-directed ligands (MTDLs) which interact with different biological targets relevant to the diseases, might offer an improved therapeutic alternative than using the traditional “one-target, one-molecule” approach. Herein, we describe new benzothiazole-based derivatives as a privileged scaffold for histamine H3 receptor ligands (H3R). The most affine compound, the 3-(azepan-1-yl)propyloxy-linked benzothiazole derivative 4b, displayed a Ki value of 0.012 μM. The multitargeting potential of these H3R ligands towards AChE, BuChE and MAO-B enzymes was evaluated to yield compound 3s (pyrrolidin-1-yl-(6-((5-(pyrrolidin-1-yl)pentyl)oxy)benzo[d]thiazol-2-yl)methanone) as the most promising MTDL with a Ki value of 0.036 μM at H3R and IC50 values of 6.7 µM, 2.35 µM, and 1.6 µM towards AChE, BuChE, and MAO-B, respectively. These findings suggest that compound 3s can be a lead structure for developing new multi-targeting anti-AD agents.
- Published
- 2023
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36. Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease
- Author
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Ian Matthews, Allison Birnbaum, Anastasia Gromova, Amy W. Huang, Kailin Liu, Eleanor A. Liu, Kristen Coutinho, Megan McGraw, Dalton C. Patterson, Macy T. Banks, Amber C. Nobles, Nhat Nguyen, Gennifer E. Merrihew, Lu Wang, Eric Baeuerle, Elizabeth Fernandez, Nicolas Musi, Michael J. MacCoss, Helen C. Miranda, Albert R. La Spada, and Constanza J. Cortes
- Subjects
CP: Neuroscience ,Biology (General) ,QH301-705.5 - Abstract
Summary: Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy. Muscle-specific TFEB overexpression significantly ameliorates proteotoxicity, reduces neuroinflammation, and promotes transcriptional remodeling of the aged CNS, preserving cognition and memory in aged mice. Our results implicate the maintenance of skeletal muscle function throughout aging in direct regulation of CNS health and disease and suggest that skeletal muscle originating factors may act as therapeutic targets against age-associated neurodegenerative disorders.
- Published
- 2023
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37. Alternative polyadenylation transcriptome-wide association study identifies APA-linked susceptibility genes in brain disorders
- Author
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Ya Cui, Frederick J. Arnold, Fanglue Peng, Dan Wang, Jason Sheng Li, Sebastian Michels, Eric J. Wagner, Albert R. La Spada, and Wei Li
- Subjects
Science - Abstract
Alternative polyadenylation (APA) contributes to the post-transcriptional regulation of most human genes, yet the effects of APA are largely overlooked by conventional transcriptome-wide association studies (TWAS). Here, the authors conduct an APA-TWAS for 11 brain disorders, identifying hundreds of APA-linked disease susceptibility genes.
- Published
- 2023
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- View/download PDF
38. Antagonistic roles of canonical and Alternative-RPA in disease-associated tandem CAG repeat instability
- Author
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Gall-Duncan, Terence, Luo, Jennifer, Jurkovic, Carla-Marie, Fischer, Laura A., Fujita, Kyota, Deshmukh, Amit L., Harding, Rachel J., Tran, Stephanie, Mehkary, Mustafa, Li, Vanessa, Leib, David E., Chen, Ran, Tanaka, Hikari, Mason, Amanda G., Lévesque, Dominique, Khan, Mahreen, Razzaghi, Mortezaali, Prasolava, Tanya, Lanni, Stella, Sato, Nozomu, Caron, Marie-Christine, Panigrahi, Gagan B., Wang, Peixiang, Lau, Rachel, Castel, Arturo López, Masson, Jean-Yves, Tippett, Lynette, Turner, Clinton, Spies, Maria, La Spada, Albert R., Campos, Eric I., Curtis, Maurice A., Boisvert, François-Michel, Faull, Richard L.M., Davidson, Beverly L., Nakamori, Masayuki, Okazawa, Hitoshi, Wold, Marc S., and Pearson, Christopher E.
- Published
- 2023
- Full Text
- View/download PDF
39. 4E-BP1 Protects Neurons from Misfolded Protein Stress and Parkinson's Disease Toxicity by Inducing the Mitochondrial Unfolded Protein Response
- Author
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Dastidar, Somasish Ghosh, Pham, Michael T, Mitchell, Matthew B, Yeom, Steven G, Jordan, Sarah, Chang, Angela, Sopher, Bryce L, and La Spada, Albert R
- Subjects
Neurodegenerative ,Parkinson's Disease ,Aging ,Brain Disorders ,Neurosciences ,Neurological ,Adaptor Proteins ,Signal Transducing ,Animals ,Animals ,Newborn ,Brefeldin A ,Cell Cycle Proteins ,Female ,Male ,Mice ,Mice ,Transgenic ,Mitochondria ,Neurons ,Parkinson Disease ,Secondary ,Primary Cell Culture ,Protein Biosynthesis ,Protein Synthesis Inhibitors ,Protein Unfolding ,Proteostasis Deficiencies ,Rotenone ,Uncoupling Agents ,alpha-Synuclein ,4E-BP1 ,alpha-synuclein ,mitochondrial unfolded protein response ,neuroprotection ,Parkinson's disease ,protein translation ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Decline of protein quality control in neurons contributes to age-related neurodegenerative disorders caused by misfolded proteins. 4E-BP1 is a key node in the regulation of protein synthesis, as activated 4E-BP1 represses global protein translation. Overexpression of 4E-BP1 mediates the benefits of dietary restriction and can counter metabolic stress, and 4E-BP1 disinhibition on mTORC1 repression may be neuroprotective; however, whether 4E-BP1 overexpression is neuroprotective in mammalian neurons is yet to be fully explored. To address this question, we generated 4E-BP1-overexpressing transgenic mice and confirmed marked reductions in protein translation in 4E-BP1-overexpressing primary neurons. After documenting that 4E-BP1-overexpressing neurons are resistant to proteotoxic stress elicited by brefeldin A treatment, we exposed primary neurons to three different Parkinson's disease (PD)-linked toxins (rotenone, maneb, or paraquat) and documented significant protection in neurons from newborn male and female 4E-BP1-OE transgenic mice. We observed 4E-BP1-dependent upregulation of genes encoding proteins that comprise the mitochondrial unfolded protein response, and noted 4E-BP1 overexpression required activation of the mitochondrial unfolded protein response for neuroprotection against rotenone toxicity. We also tested whether 4E-BP1 could prevent α-synuclein neurotoxicity by treating 4E-BP1-overexpressing primary neurons with α-synuclein preformed fibrils, and we observed marked reductions in α-synuclein aggregation and neurotoxicity, thus validating that 4E-BP1 is a powerful suppressor of PD-linked pathogenic insults. Our results indicate that increasing 4E-BP1 expression or enhancing 4E-BP1 activation can robustly induce the mitochondrial unfolded protein response and thus could be an appealing strategy for treating a variety of neurodegenerative diseases, including especially PD.SIGNIFICANCE STATEMENT In neurodegenerative disease, misfolded proteins accumulate and overwhelm normal systems of homeostasis and quality control. One mechanism for improving protein quality control is to reduce protein translation. Here we investigated whether neuronal overexpression of 4E-BP1, a key repressor of protein translation, can protect against misfolded protein stress and toxicities linked to Parkinson's disease, and found that 4E-BP1 overexpression prevented cell death in neurons treated with brefeldin A, rotenone, maneb, paraquat, or preformed fibrils of α-synuclein. When we sought the basis for 4E-BP1 neuroprotection, we discovered that 4E-BP1 activation promoted the mitochondrial unfolded protein response. Our findings highlight 4E-BP1 as a therapeutic target in neurodegenerative disease and underscore the importance of the mitochondrial unfolded protein response in neuroprotection against various insults.
- Published
- 2020
40. DYSREGULATED LIPID ACCUMULATION IN THE CORTEX AND LUMBAR CORD OF METABOLICALLY PERTURBED TDP-43Q331K-LOW MICE
- Author
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Hsiao-Jou Cortina Chen, Fredrick Arnold, Martin Geira, Andrian Yang, Albert La Spada, and Florian Merkle
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Published
- 2023
- Full Text
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41. Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave
- Author
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F.J. Arnold, A.D. Nguyen, R.S. Bedlack, C.L. Bennett, and A.R. La Spada
- Subjects
ALS ,Cell-to-cell propagation ,Oligomerization ,Extracellular-vesicles ,Endocytosis ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
ABSTRACT: In patients with amyotrophic lateral sclerosis (ALS), disease symptoms and pathology typically spread in a predictable spatiotemporal pattern beginning at a focal site of onset and progressing along defined neuroanatomical tracts. Like other neurodegenerative diseases, ALS is characterized by the presence of protein aggregates in postmortem patient tissue. Cytoplasmic, ubiquitin-positive aggregates of TDP-43 are observed in approximately 97% of sporadic and familial ALS patients, while SOD1 inclusions are likely specific to cases of SOD1-ALS. Additionally, the most common subtype of familial ALS, caused by a hexanucleotide repeat expansion in the first intron of the C9orf72 gene (C9-ALS), is further characterized by the presence of aggregated dipeptide repeat proteins (DPRs). As we will describe, cell-to-cell propagation of these pathological proteins tightly correlates with the contiguous spread of disease. While TDP-43 and SOD1 are capable of seeding protein misfolding and aggregation in a prion-like manner, C9orf72 DPRs appear to induce (and transmit) a ‘disease state’ more generally. Multiple mechanisms of intercellular transport have been described for all of these proteins, including anterograde and retrograde axonal transport, extracellular vesicle secretion, and macropinocytosis. In addition to neuron-to-neuron transmission, transmission of pathological proteins occurs between neurons and glia. Given that the spread of ALS disease pathology corresponds with the spread of symptoms in patients, the various mechanisms by which ALS-associated protein aggregates propagate through the central nervous system should be closely examined.
- Published
- 2023
- Full Text
- View/download PDF
42. Bioisosteric replacement based on 1,2,4-oxadiazoles in the discovery of 1H-indazole-bearing neuroprotective MAO B inhibitors
- Author
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Rullo, Mariagrazia, La Spada, Gabriella, Miniero, Daniela Valeria, Gottinger, Andrea, Catto, Marco, Delre, Pietro, Mastromarino, Margherita, Latronico, Tiziana, Marchese, Sara, Mangiatordi, Giuseppe Felice, Binda, Claudia, Linusson, Anna, Liuzzi, Grazia Maria, and Pisani, Leonardo
- Published
- 2023
- Full Text
- View/download PDF
43. Chronic BMAA exposure combined with TDP-43 mutation elicits motor neuron dysfunction phenotypes in mice
- Author
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Arnold, F.J., Burns, M., Chiu, Y., Carvalho, J., Nguyen, A.D., Ralph, P.C., La Spada, A.R., and Bennett, C.L.
- Published
- 2023
- Full Text
- View/download PDF
44. Reduced C9ORF72 function exacerbates gain of toxicity from ALS/FTD-causing repeat expansion in C9orf72
- Author
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Zhu, Qiang, Jiang, Jie, Gendron, Tania F, McAlonis-Downes, Melissa, Jiang, Lulin, Taylor, Amy, Diaz Garcia, Sandra, Ghosh Dastidar, Somasish, Rodriguez, Maria J, King, Patrick, Zhang, Yongjie, La Spada, Albert R, Xu, Huaxi, Petrucelli, Leonard, Ravits, John, Da Cruz, Sandrine, Lagier-Tourenne, Clotilde, and Cleveland, Don W
- Subjects
Genetics ,Neurosciences ,Neurodegenerative ,Aging ,Orphan Drug ,Dementia ,Rare Diseases ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Alzheimer's Disease Related Dementias (ADRD) ,Frontotemporal Dementia (FTD) ,ALS ,Acquired Cognitive Impairment ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Amyotrophic Lateral Sclerosis ,Animals ,C9orf72 Protein ,DNA Repeat Expansion ,Female ,Frontotemporal Dementia ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Psychology ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
Hexanucleotide expansions in C9orf72, which encodes a predicted guanine exchange factor, are the most frequent genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although repeat expansion has been established to generate toxic products, mRNAs encoding the C9ORF72 protein are also reduced in affected individuals. In this study, we tested how C9ORF72 protein levels affected repeat-mediated toxicity. In somatic transgenic mice expressing 66 GGGGCC repeats, inactivation of one or both endogenous C9orf72 alleles provoked or accelerated, respectively, early death. In mice expressing a C9orf72 transgene with 450 repeats that did not encode the C9ORF72 protein, inactivation of one or both endogenous C9orf72 alleles exacerbated cognitive deficits, hippocampal neuron loss, glial activation and accumulation of dipeptide-repeat proteins from translation of repeat-containing RNAs. Reduced C9ORF72 was shown to suppress repeat-mediated elevation in autophagy. These efforts support a disease mechanism in ALS/FTD resulting from reduced C9ORF72, which can lead to autophagy deficits, synergizing with repeat-dependent gain of toxicity.
- Published
- 2020
45. Autophagy gene haploinsufficiency drives chromosome instability, increases migration, and promotes early ovarian tumors.
- Author
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Delaney, Joe R, Patel, Chandni B, Bapat, Jaidev, Jones, Christian M, Ramos-Zapatero, Maria, Ortell, Katherine K, Tanios, Ralph, Haghighiabyaneh, Mina, Axelrod, Joshua, DeStefano, John W, Tancioni, Isabelle, Schlaepfer, David D, Harismendy, Olivier, La Spada, Albert R, and Stupack, Dwayne G
- Subjects
Cell Line ,Tumor ,Animals ,Mice ,Ovarian Neoplasms ,Chromosomal Instability ,Microtubule-Associated Proteins ,Cell Movement ,Female ,Metabolome ,Haploinsufficiency ,Carcinogenesis ,Beclin-1 ,Ovarian Cancer ,Genetics ,Cancer ,Human Genome ,Breast Cancer ,Rare Diseases ,2.1 Biological and endogenous factors ,Developmental Biology - Abstract
Autophagy, particularly with BECN1, has paradoxically been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, studying the specific role of BECN1 at the genetic level is complicated due to its genomic proximity to BRCA1 on both human (chromosome 17) and murine (chromosome 11) genomes. In human breast and ovarian cancers, the monoallelic deletion of these genes is often co-occurring. To investigate the potential tumor suppressor roles of two of the most commonly deleted autophagy genes in ovarian cancer, BECN1 and MAP1LC3B were knocked-down in atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cells. Ultra-performance liquid chromatography mass-spectrometry metabolomics revealed reduced levels of acetyl-CoA which corresponded with elevated levels of glycerophospholipids and sphingolipids. Migration rates of ovarian cancer cells were increased upon autophagy gene knockdown. Genomic instability was increased, resulting in copy-number alteration patterns which mimicked high grade serous ovarian cancer. We further investigated the causal role of Becn1 haploinsufficiency for oncogenesis in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Tumors were evident earlier among the Becn1+/- mice, and this correlated with an increase in copy-number alterations per chromosome in the Becn1+/- tumors. The results support monoallelic loss of BECN1 as permissive for tumor initiation and potentiating for genomic instability in ovarian cancer.
- Published
- 2020
46. Runs and Flights to Safety: Are Stablecoins the New Money Market Funds?
- Author
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Anadu, Kenechukwu, primary, Azar, Pablo D., additional, Cipriani, Marco, additional, Eisenbach, Thomas M., additional, Huang, Catherine, additional, Landoni, Mattia, additional, La Spada, Gabriele, additional, Macchiavelli, Marco, additional, Malfroy-Camine, Antoine, additional, and Wang, J. Christina, additional
- Published
- 2023
- Full Text
- View/download PDF
47. Intercellular transmission of pathogenic proteins in ALS: Exploring the pathogenic wave
- Author
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Arnold, F.J., Nguyen, A.D., Bedlack, R.S., Bennett, C.L., and La Spada, A.R.
- Published
- 2023
- Full Text
- View/download PDF
48. Towards Alzheimer’s disease-related targets: One-pot Cu(I)- mediated synthesis of new nitroindazolyltriazoles
- Author
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Eddahmi, Mohammed, La Spada, Gabriella, Hafid, Abderrafia, Khouili, Mostafa, Catto, Marco, and Bouissane, Latifa
- Published
- 2023
- Full Text
- View/download PDF
49. Protocol for mapping double-stranded DNA break sites across the genome with translocation capture sequencing
- Author
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Joe R. Delaney and Albert R. La Spada
- Subjects
Cell Biology ,Genomics ,High-throughput Screening ,Science (General) ,Q1-390 - Abstract
Summary: Translocation sequencing can be used to assess mechanisms of DNA repair and identify genome-wide double-strand breaks (DSBs) accessible to DNA repair machinery. Here, we present a protocol for mapping double-strand DNA break sites across the genome with translocation capture sequencing. Bait DSBs are introduced using a Cas9 nuclease and repaired by the host cell, connecting bait DSBs to other DSBs. Repair sites are detected by isolating bait site DNA, cleaving normal sequence to enrich off-site repair, and next-generation sequencing.For complete details on the use and execution of this protocol, please refer to Switonski et al. (2021).1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.
- Published
- 2023
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- View/download PDF
50. Functional diversity of nanohaloarchaea within xylan-degrading consortia
- Author
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Oleg Reva, Enzo Messina, Violetta La Cono, Francesca Crisafi, Francesco Smedile, Gina La Spada, Laura Marturano, Elena A. Selivanova, Manfred Rohde, Mart Krupovic, and Michail M. Yakimov
- Subjects
nanohaloarchaeal-haloarchaeal symbioses ,ecology of nanohaloarchaea ,CRISPR ,ncRNA ,methylomics ,Microbiology ,QR1-502 - Abstract
Extremely halophilic representatives of the phylum Candidatus Nanohaloarchaeota (members of the DPANN superphyla) are obligately associated with extremely halophilic archaea of the phylum Halobacteriota (according to the GTDB taxonomy). Using culture-independent molecular techniques, their presence in various hypersaline ecosystems around the world has been confirmed over the past decade. However, the vast majority of nanohaloarchaea remain uncultivated, and thus their metabolic capabilities and ecophysiology are currently poorly understood. Using the (meta)genomic, transcriptomic, and DNA methylome platforms, the metabolism and functional prediction of the ecophysiology of two novel extremely halophilic symbiotic nanohaloarchaea (Ca. Nanohalococcus occultus and Ca. Nanohalovita haloferacivicina) stably cultivated in the laboratory as members of a xylose-degrading binary culture with a haloarchaeal host, Haloferax lucentense, was determined. Like all known DPANN superphylum nanoorganisms, these new sugar-fermenting nanohaloarchaea lack many fundamental biosynthetic repertoires, making them exclusively dependent on their respective host for survival. In addition, given the cultivability of the new nanohaloarchaea, we managed to discover many unique features in these new organisms that have never been observed in nano-sized archaea both within the phylum Ca. Nanohaloarchaeota and the entire superphylum DPANN. This includes the analysis of the expression of organism-specific non-coding regulatory (nc)RNAs (with an elucidation of their 2D-secondary structures) as well as profiling of DNA methylation. While some ncRNA molecules have been predicted with high confidence as RNAs of an archaeal signal recognition particle involved in delaying protein translation, others resemble the structure of ribosome-associated ncRNAs, although none belong to any known family. Moreover, the new nanohaloarchaea have very complex cellular defense mechanisms. In addition to the defense mechanism provided by the type II restriction-modification system, consisting of Dcm-like DNA methyltransferase and Mrr restriction endonuclease, Ca. Nanohalococcus encodes an active type I-D CRISPR/Cas system, containing 77 spacers divided into two loci. Despite their diminutive genomes and as part of their host interaction mechanism, the genomes of new nanohaloarchaea do encode giant surface proteins, and one of them (9,409 amino acids long) is the largest protein of any sequenced nanohaloarchaea and the largest protein ever discovered in cultivated archaea.
- Published
- 2023
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