FlyBase: a guided tour of highlighted features

Genetics, Journal Year: 2022, Volume and Issue: 220(4)

Published: March 10, 2022

FlyBase provides a centralized resource for the genetic and genomic data of Drosophila melanogaster. As enters our fourth decade service to research community, we reflect on unique aspects look forward continued collaboration with larger model organism communities. In this study, emphasize dedicated reports tools have constructed meet specialized needs fly researchers but also facilitate use by other We highlight ways that support including an external resources page, help resources, multiple avenues which can interact FlyBase.

Language: Английский

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PANGEA: a new gene set enrichment tool for Drosophila and common research organisms

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(W1), P. W419 - W426

Published: May 1, 2023

Abstract Gene set enrichment analysis (GSEA) plays an important role in large-scale data analysis, helping scientists discover the underlying biological patterns over-represented a gene list resulting from, for example, ‘omics’ study. Ontology (GO) annotation is most frequently used classification mechanism definition. Here we present new GSEA tool, PANGEA (PAthway, Network and Gene-set Enrichment Analysis; https://www.flyrnai.org/tools/pangea/), developed to allow more flexible configurable approach using variety of sets. allows GO be performed on different sets annotations, example excluding high-throughput studies. Beyond GO, pathway protein complex from various resources as well expression disease Alliance Genome Resources (Alliance). In addition, visualizations results are enhanced by providing option view network relationships. The tool also comparison multiple input lists accompanying visualisation tools quick easy comparison. This will facilitate Drosophila other major model organisms based high-quality annotated information available these species.

Language: Английский

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Updates to the Alliance of Genome Resources central infrastructure

Genetics, Journal Year: 2024, Volume and Issue: 227(1)

Published: March 29, 2024

Abstract The Alliance of Genome Resources (Alliance) is an extensible coalition knowledgebases focused on the genetics and genomics intensively studied model organisms. organized as individual knowledge centers with strong connections to their research communities a centralized software infrastructure, discussed here. Model organisms currently represented in are budding yeast, Caenorhabditis elegans, Drosophila, zebrafish, frog, laboratory mouse, rat, Gene Ontology Consortium. project rapid development phase harmonize knowledge, store it, analyze present it community through web portal, direct downloads, application programming interfaces (APIs). Here, we focus developments over last 2 years. Specifically, added enhanced tools for browsing genome (JBrowse), downloading sequences, mining complex data (AllianceMine), visualizing pathways, full-text searching literature (Textpresso), sequence similarity (SequenceServer). We existing interactive tables table paralogs complement our representation orthology. To support organism communities, implemented species-specific “landing pages” will add disease-specific portals soon; addition, common forum Discourse software. describe progress toward central persistent database curation, modeling that underpins harmonization, state-of-the-art curation system integrated artificial intelligence machine learning (AI/ML).

Language: Английский

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Identification of secretory autophagy as a mechanism modulating activity-induced synaptic remodeling

Proceedings of the National Academy of Sciences, Journal Year: 2024, Volume and Issue: 121(16)

Published: April 8, 2024

The ability of neurons to rapidly remodel their synaptic structure and strength in response neuronal activity is highly conserved across species crucial for complex brain functions. However, mechanisms required elicit coordinate the acute, activity-dependent structural changes synapses are not well understood, as neurodevelopment plasticity tightly linked. Here, using an RNAi screen Drosophila against genes affecting nervous system functions humans, we uncouple cellular processes important synapse development. We find mutations associated with neurodegenerative mental health disorders 2-times more likely affect activity-induced remodeling than report that while both development at fly NMJ require macroautophagy (hereafter referred autophagy), bifurcation autophagy pathway differentially impacts plasticity. demonstrate enhances activation but diminishes degradative autophagy, thereby driving towards autophagy-based secretion. Presynaptic knockdown Snap29, Sec22, or Rab8, proteins implicated secretory pathway, sufficient abolish remodeling. This study uncovers a transsynaptic signaling mechanism modulating

Language: Английский

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COG database update 2024

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 53(D1), P. D356 - D363

Published: Nov. 4, 2024

The Clusters of Orthologous Genes (COG) database, originally created in 1997, has been updated to reflect the constantly growing collection completely sequenced prokaryotic genomes. This update increased genome coverage from 1309 2296 species, including 2103 bacteria and 193 archaea, most cases, with a single representative per genus. set covers all genera archaea that included organisms 'complete genomes' as NCBI databases November 2023. number COGs expanded 4877 4981, primarily by protein families involved bacterial secretion. Accordingly, COG pathways functional groups now include secretion systems types II through X, well Flp/Tad type IV pili. These groupings allow straightforward identification examination lineages encompass-or lack-a particular system. Other developments improved annotations for rRNA tRNA modification proteins, multi-domain signal transduction some previously uncharacterized families. new version is available at https://www.ncbi.nlm.nih.gov/research/COG, on FTP site https://ftp.ncbi.nlm.nih.gov/pub/COG/, which also provides archived data previous releases.

Language: Английский

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Deregulated ion channels contribute to RHOBTB2-associated developmental and epileptic encephalopathy

Human Molecular Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 24, 2025

Abstract While de novo missense variants in the BTB domains of atypical RhoGTPase RHOBTB2 cause a severe developmental and epileptic encephalopathy, GTPase domain or bi-allelic truncating are associated with more variable neurodevelopmental seizure phenotypes. Apart from observation abundance resulting BTB-domain increased susceptibility Drosophila overexpressing RhoBTB, our knowledge on RHOBTB2-related pathomechanisms is limited. We now found enrichment for ion channels among differentially expressed genes RNA-Seq fly heads RhoBTB. Subsequent genetic interaction experiments confirmed functional link between RhoBTB paralytic, orthologue human sodium channels, including epilepsy SCN1A, vivo. then performed patch-clamp recordings mature neurons differentiated induced pluripotent stem cells either homozygous frameshifts patient-specific heterozygous domains. This revealed significantly altered neuronal activity excitability but not upon complete loss RHOBTB2. Our study indicates role deregulated pathogenesis encephalopathy points to specific underlying observed genotype–phenotype correlations regarding variant zygosity, location nature.

Language: Английский

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Drosophila Heart as a Model for Cardiac Development and Diseases

Cells, Journal Year: 2021, Volume and Issue: 10(11), P. 3078 - 3078

Published: Nov. 8, 2021

The Drosophila heart, also referred to as the dorsal vessel, pumps insect blood, hemolymph. bilateral heart primordia develop from most dorsally located mesodermal cells, migrate coordinately, and fuse form cardiac tube. Though much simpler, fruit fly displays several developmental functional similarities vertebrate and, we discuss here, represents an attractive model system for dissecting mechanisms of aging failure identifying genes causing congenital diseases. Fast imaging technologies allow characterization heartbeat parameters in adult there is growing evidence that dysfunction human diseases could be reproduced analyzed Drosophila, discussed here defects associated with myotonic dystrophy type 1. Overall, power genetics unsuspected conservation pathways puts at fundamental applied research.

Language: Английский

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Live-cell imaging of RNA Pol II and elongation factors distinguishes competing mechanisms of transcription regulation

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(15), P. 2856 - 2869.e9

Published: Aug. 1, 2024

Language: Английский

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DRscDB: A single-cell RNA-seq resource for data mining and data comparison across species

Computational and Structural Biotechnology Journal, Journal Year: 2021, Volume and Issue: 19, P. 2018 - 2026

Published: Jan. 1, 2021

With the advent of single-cell RNA sequencing (scRNA-seq) technologies, there has been a spike in studies involving scRNA-seq several tissues across diverse species including Drosophila. Although few databases exist for users to query genes interest within studies, search tools that enable find orthologous and their cell type-specific expression patterns are limited. Here, we built new database, DRscDB (https://www.flyrnai.org/tools/single_cell/web/), address this need. serves as comprehensive repository published datasets Drosophila relevant from human other model organisms. is based on manual curation various tissue types corresponding analogous vertebrates zebrafish, mouse, human. Of note, our database provides most literature-derived marker genes, thus preserving original analysis datasets. Finally, web-based user interface allows mine gene data perform cluster enrichment analyses pertaining both species.

Language: Английский

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TBK1 interacts with tau and enhances neurodegeneration in tauopathy

Journal of Biological Chemistry, Journal Year: 2021, Volume and Issue: 296, P. 100760 - 100760

Published: Jan. 1, 2021

One of the defining pathological features Alzheimer's disease (AD) is deposition neurofibrillary tangles (NFTs) composed hyperphosphorylated tau in brain. Aberrant activation kinases AD has been suggested to enhance phosphorylation and toxicity tau, making responsible attractive therapeutic targets. The full complement tau-interacting brain their activity remains incompletely defined. Here, immunoaffinity enrichment coupled with mass spectrometry (MS) identified TANK-binding kinase 1 (TBK1) as a partner human cortical tissues. We validated this interaction AD, familial frontotemporal dementia parkinsonism linked chromosome 17 (FTDP-17) caused by mutations MAPT (R406W & P301L) corticobasal degeneration (CBD) postmortem tissues well cell lines. Further, we document increased TBK1 both FTDP-17 map sites on based vitro assays MS. Lastly, Drosophila tauopathy model, activating expression conserved ortholog triggers hyperphosphorylation enhanced neurodegeneration, whereas knockdown had reciprocal effect, suppressing toxicity. Collectively, our findings suggest that may promote neuronal loss related tauopathies. Deposition extracellular amyloid-β (Aβ) plaque accumulation intracellular microtubule-binding protein are major hallmarks (1Alonso A.d.C. Grundke-Iqbal I. Iqbal K. sequesters normal into filaments disassembles microtubules.Nat. Med. 1996; 2: 783-787Crossref PubMed Scopus (630) Google Scholar, 2Bancher C. Brunner Lassmann H. Budka Jellinger Wiche G. Seitelberger F. Wisniewski Accumulation abnormally phosphorylated τ precedes formation disease.Brain Res. 1989; 477: 90-99Crossref (673) 3Goedert M. Spillantini Jakes R. Rutherford D. Crowther Multiple isoforms microtubule-associated tau: Sequences localization disease.Neuron. 3: 519-526Abstract Full Text PDF (1703) Scholar). degree NFT burden closely associated synaptic cognitive decline, therefore, target (4Arriagada P.V. Growdon J.H. Hedley-Whyte E.T. Hyman B.T. Neurofibrillary but not senile plaques parallel duration severity disease.Neurology. 1992; 42: 631-639Crossref 5Bierer L.M. Hof P.R. Purohit D.P. Carlin L. Schmeidler J. Davis K.L. Perl Neocortical correlate disease.Arch. Neurol. 1995; 52: 81-88Crossref (378) Tau required for binding stabilization microtubules under physiological conditions (6Alonso A.C. (641) 7Alonso Zaidi T. Role breakdown Alzheimer disease.Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 5562-5566Crossref (553) 8Kopke E. Tung Y.C. Shaikh Alonso Microtubule-associated tau. Abnormal non-paired helical filament pool disease.J. Biol. Chem. 1993; 268: 24374-24384Abstract In undergoes among other posttranslational modifications (PTMs), leading NFTs 9Wesseling Mair W. Kumar Schlaffner C.N. Tang Beerepoot P. Fatou B. Guise A.J. Cheng Takeda Muntel Rotunno M.S. Dujardin Davies Kosik K.S. et al.Tau PTM profiles identify patient heterogeneity stages disease.Cell. 2020; 183: 1699-1713.e13Abstract (55) regulated phosphatases, aberrant levels which have impact aggregation (10Gong C.X. Wang J.Z. Phosphatase toward τ: Decrease brain.J. Neurochem. 65: 732-738Crossref (393) 11Liu S.J. Zhang A.H. Li H.L. Q. Deng H.M. Netzer W.J. Xu Overactivation glycogen synthase kinase-3 inhibition phosphoinositol-3 C leads impairment spatial memory.J. 2003; 87: 1333-1344Crossref (211) Toward end, identification new could reveal potential targets pathways contribute further development drugs treatment Mass (MS)-based proteomics emerged powerful approach define global changes abundance PTMs mechanisms (12Ong S.-E. Mann spectrometry–based turns quantitative.Nat. 2005; 1: 252-262Crossref (1273) MS-based can also be combined affinity strategies, such immunoprecipitation (IP), interacting partners key proteins pathogenesis (13Ewing R.M. Chu Elisma Taylor Climie McBroom-Cerajewski Robinson M.D. O'Connor Large-scale mapping protein–protein interactions spectrometry.Mol. Syst. 2007; 3Crossref (715) 14Gingras A.-C. Gstaiger Raught Aebersold Analysis complexes using spectrometry.Nat. Rev. Mol. Cel. 8: 645Crossref (521) others co-immunoprecipitation (co-IP) MS quantify (i.e., interactome) (15Drummond Pires MacMurray Askenazi Nayak Bourdon Safar Ueberheide Phosphorylated interactome brain.Brain. 143: 2803-2817Crossref (17) 16Hsieh Guo Yalamanchili H.K. Abreha Al-Ouran Y. Dammer E.B. Lah J.J. Levey A.I. Bennett D.A. De Jager P.L. Seyfried N.T. Liu Z. Shulman J.M. Tau-mediated disruption spliceosome cryptic RNA splicing neurodegeneration disease.Cell Rep. 2019; 29: 301-316.e310Abstract (40) 17Meier Bell Lyons D.N. Ingram Chen Gensel J.C. Zhu Nelson P.T. Abisambra J.F. Identification novel endoplasmic reticulum Alzheimers Dis. 2015; 48: 687-702Crossref (26) This highlighted diversity having functional roles beyond microtubule assembly, including binding/splicing, translation, autophagy, ubiquitin-proteasome system To kinases, analyzed previously reported co-IP datasets from control (16Hsieh led 21 18 described interact or directly phosphorylate (18Martin Latypova X. Wilson C.M. Magnaudeix Perrin M.L. Yardin Terro kinases: Involvement disease.Ageing 2013; 12: 289-309Crossref (315) 19Cavallini Brewerton Sargent Glover Hardy Moore Calley Ramachandran Poidinger An unbiased identifying at 288: 23331-23347Abstract (63) prioritized TBK1, serine threonine belonging noncanonical IKK family (20Ahmad S.Y. Casanova J.L. Sancho-Shimizu V. Human TBK1: A gatekeeper neuroinflammation.Trends 2016; 22: 511-527Abstract (83) 21Oakes J.A. M.C. Collins M.O. player ALS linking autophagy neuroinflammation.Mol. Brain. 2017; 10: 5Crossref (125) Scholar), best characterized its role innate immunity signaling (22Fitzgerald K.A. McWhirter S.M. Faia Rowe D.C. Latz Golenbock D.T. Coyle Liao S.-M. Maniatis IKKε essential components IRF3 pathway.Nat. Immunol. 4: 491Crossref (1924) 23Hemmi Takeuchi O. Sato Yamamoto Kaisho Sanjo Kawai Hoshino Akira two IκB kinase-related lipopolysaccharide double stranded viral infection.J. Exp. 2004; 199: 1641-1650Crossref (448) 24Tanaka Z.J. STING specifies cytosolic DNA pathway.Sci. signaling. 2012; 5: ra20Crossref (549) 25Weidberg Elazar mediates crosstalk between immune response autophagy.Sci. 2011; pe39Crossref (103) 26Yu Yi Y.S. Yang Oh Jeong Cho J.Y. pivotal inflammatory responses mediated macrophages.Mediators Inflamm. 2012: 979105Crossref (120) selective (27He TBK1-OPTN Axis mitophagy response: neurodegenerative diseases.Neurosci. Bull. 33: 354-356Crossref (10) 28Heo J.-M. Ordureau Paulo Rinehart Harper J.W. PINK1-PARKIN mitochondrial ubiquitylation pathway drives program OPTN/NDP52 recruitment mitophagy.Mol. 60: 7-20Abstract (420) 29Matsumoto Shimogori Hattori N. Nukina controls autophagosomal engulfment polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation.Hum. Genet. 24: 4429-4442Crossref (160) energy metabolism (30Reilly Chiang S.-H. Decker Chang Uhm Larsen M.J. Rubin J.R. Mowers White N.M. Hochberg inhibitor IKK-ϵ improves obesity-related metabolic dysfunctions mice.Nat. 19: 313Crossref (285) 31Zhao Wong K.I. Sun Reilly Skorobogatko Saltiel A.R. crossroads inflammation homeostasis adipose tissue.Cell. 2018; 172: 731-743.e712Abstract (95) tumorigenesis (32Ou Y.H. Torres Ram Formstecher Roland Brekken Wurz Tasker Polverino Tan S.L. M.A. engages Akt/PKB survival support oncogenic transformation.Mol. Cell. 41: 458-470Abstract dynamics (33Pillai Nguyen Johnson Haura Coppola Chellappan Tank centrosome-associated necessary mitosis.Nat. Commun. 6: 1-14Crossref (58) Notably, genetic studies gene causal diseases (FTD) amyotrophic lateral sclerosis (ALS) (34Borghero Pugliatti Marrosu M.G. Murru M.R. Floris Cannas Occhineri Cau T.B. Loi Ticca Traccis Manera Canosa Moglia al.TBK1 ALS-FTD Sardinian patients.Neurobiol. Aging. 43: 180.e1-180.e5Crossref 35Freischmidt Müller Ludolph Weishaupt Andersen P.M. Association sporadic dementia.JAMA 74: 110-113Crossref (48) 36Freischmidt Wieland Richter Ruf Schaeffer Marroquin Nordin Hübers Weydt Haploinsufficiency causes fronto-temporal dementia.Nat. Neurosci. 18: 631Crossref (470) 37Gijselinck Van Mossevelde van der Zee Sieben Philtjens Heeman Engelborghs Vandenbulcke Baets Bäumer Loss frequent cause Belgian cohort.Neurology. 85: 2116-2125Crossref (106) 38Williams McCann E.P. Fifita Duncan E.L. Leo P.J. Marshall D.B. Nicholson G.A. Blair I.P. Novel truncating mutation Chinese origin.Neurobiol. 36: 3334.e1-3334.e5Crossref (29) However, modifying tauopathies known. Here report (FTDP-17). predominant overexpression cells neurons confirmed model systems. Finally, reciprocally increase decrease tau-induced neurodegeneration. Together these data hypothesis tightly regulate phosphorylation, (11Liu 39Cruz Tseng H.-C. Goldman Shih Tsai L.-H. Cdk5 p25 events tangles.Neuron. 40: 471-483Abstract (477) Currently, performed quantitative analysis more than 500 Gene Ontology (GO) proteins, revealed significant terms (e.g., "kinase signaling" binding") (Fig. 1A). Consistently, mapped GO were several well-established 3β (GSK3β) cyclin dependent 5 (CDK5) (40Paudel Lew Ali Brain proline-directed phosphorylates paired filaments.J. 23512-23518Abstract mitogen-activated (MAPK1 MAPK15) (19Cavallini calcium/calmodulin-dependent (CAMK2A, CAMK2B, CAMK2D, CAMK2G) (41Litersky G.V. Goedert Michael Seubert cyclic AMP-dependent II within domains Ser-262 Ser-356.Biochem. 316: 655-660Crossref (119) TAOK1 (42Giacomini Koo C.Y. Yankova Tavares I.A. Wray Noble Hanger Morris J.D.H. TAO reduces tauopathies.Acta Neuropathol. 37Crossref (21) Scholar) 1B). signal intensities measured significantly compared knowledge, TNIK, DAPK3, (log2 fold-changes 5.32, 3.96, 5.32 –log10 p values 5.99, 6.02, 1.62, respectively) validate lysates Tau5 antibody used IP-MS As expected, input appear stronger showed higher- lower-molecular-weight species observed, due proteolysis, respectively (43Alonso Novak Hyperphosphorylation induces self-assembly filaments/straight filaments.Proc. 2001; 98: 6923-6928Crossref (699) 44Takeda Wegmann DeVos Commins Roe A.D. Nicholls S.B. Carlson Pitstick Nobuhara C.K. Costantino Frosch M.P. Muller D.J. Irimia Neuronal uptake propagation rare high-molecular-weight derived brain.Nat. 8490Crossref (170) 1C). western blot GAPDH highlights equal loading across inputs. Assessment DAPK3 inputs similar samples indicating steady-state unchanged 1C, bottom panels). contrast, co-IPs strong bands (∼52 kDa) (∼84 suggesting consistent 1, B D). 22Fitzgerald (25Weidberg 45Pilli Arko-Mensah Ponpuak Roberts Master Mandell Dupont Ornatowski Jiang Bradfute TBK-1 promotes autophagy-mediated antimicrobial defense controlling autophagosome maturation.Immunity. 37: 223-234Abstract (401) focused attention FTD (35Freischmidt established. Given interacts yet remain unchanged, hypothesized elevated induced trans-autophosphorylation 172 (S172) loop domain (46Larabi Devos Ng Nanao M.H. Round Panne Crystal structure mechanism 1.Cell 734-746Abstract (114) 47Ma Helgason Phung Q.T. Quan C.L. Iyer R.S. Lee M.W. Bowman K.K. Starovasnik Dueber E.C. Molecular basis Tank-binding transautophosphorylation.Proc. 109: 9378-9383Crossref (123) Therefore, measure activated levels, pS172-TBK1 antibody. observed an 2A), quantification total shows statistically (Student's t-test, n = 3, value 0.0056) 2B). assess whether was unique shared tauopathies, first case missense (R406W) C-terminus cases particular exhibit AD-like clinical phenotype relatively late-onset amnestic longer (48Lindquist S.G. Holm I.E. Schwartz Law Stokholm Batbayli Waldemar Nielsen J.E. disease-like R406W mutation.Eur. 2008; 15: 377-385Crossref Like 2C). Furthermore, FTDP-17, following 2D). specificity additional (harboring P301L mutations) three (CBD), (49Kouri Carlomagno Baker Liesinger A.M. Caselli R.J. Wszolek Z.K. Petrucelli Boeve B.F. Parisi Josephs exon 13 (p. N410H) degeneration.Acta 2014; 127: 271-282Crossref (57) Western majority, all non-AD 2, E F), remained generally samples. 2F). suggests disease-specific and/or conformational changes. Thus, pathologic common brain, next sought determine substrate phosphorylation. putative directed reactions, whereby recombinant purified incubated reaction buffer ATP presence absence active (pS172-TBK1). Following tryptic digestion phosphopeptides corresponding nine (Table S1). These distributed N-terminal acidic (T30), proline-rich mid-domain (S191, S198, S214), repeat (MTBR) (S285, S289, S305, S324, S356) B). results, blotting reactions site-specific phospho-tau antibodies, gradual pS214-, pS324-, pS356-tau incubation times 3C). confirm specificity, added increasing concentrations small-molecule inhibitor, BX795 (50Lindwall Cole R.D. Phosphorylation affects ability assembly.J. 1984; 259: 5301-5305Abstract 51Brandt Teplow Shalloway Abdel-Ghany Differential effect modulation tau's growth nucleation.J. 269: 11776-11782Abstract

Language: Английский

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