The Annapolis Symphony Orchestra (ASO) has announced its 2025-26 season under Artistic Director José-Luis Novo, marking his 21st year leading the organization. Performances will be held at Maryland Hall and locations across Annapolis and Anne Arundel County The season includes a five-concert Signature Series now the longest-serving artistic leader in ASO history will conduct fifteen concerts featuring both classical and contemporary works and the Annapolis premières of pieces by Silvestre Revueltas Guest artists making their ASO debut include guitarist Pablo Sainz-Villegas and soprano Angel Blue Pianists Olga Kern and Pascal Rogé will return for featured performances Katie Edwards praised the upcoming season:“The 2025-26 season offers many exhilarating opportunities to celebrate and support our musicians including the extraordinary professionals on stage with the ASO and the promising young artists of the Annapolis Symphony Academy.” Two free Pops in the Park concerts will be held Labor Day weekend at Downs Park and Quiet Waters Park Novo emphasized their importance:“Pops in the Park is an opportunity to connect with our community It’s a celebration of music under the open sky where families and friends can experience the thrill of a live symphony in a relaxed Holiday Pops concerts will be presented at Maryland Hall and Severna Park High School The ASO will also offer school field trip concerts and a family concert in March 2026 The renamed Signature Series will include: Free pre-concert lectures with WBJC’s Jonathan Palevsky will continue at Maryland Hall performances The Annapolis Symphony Academy (ASA) will continue offering students performance opportunities alongside ASO musicians with free ensemble participation and scholarships available ASO Executive Director Erica Bondarev-Rapach commented:“Under Maestro Novo’s baton we have explored new musical horizons and engaged with themes that connect art More information about the 2025-26 season can be found at the Annapolis Symphony Orchestra’s official website Police Investigating Fatal Shooting in Glen Burnie Anne Arundel Community College Recognized as 2025-2026 Military Friendly® and Military Spouse Friendly School Eye On Annapolis is a community based site focusing strictly on Anne Arundel County These staff postings are general news postings made by our team of bloggers throughout the day and are not attributed to any one particular staff person Thank you for stopping by and hopefully for engaging with Eye On Annapolis with your comments and opinions both here and on our social channels There has never been a more critical time for community involvement than today–for any number of reasons Annapolis and Anne Arundel County are our homes and this site is about the quality of life we all share It is written for the local community by the local community July 18 is the deadline for artists 18 or older who reside in Arkansas Tennessee or Texas to submit entries -- traditional and digital artworks -- for the 2025 Irene Rosenzweig Biennial Juried Exhibition at the Arts & Science Center for Southeast Arkansas cultural worker and naturalist Eepi Chaad of Houston is the year's juror There are three $100 merit awards and $2,000 available in purchase awards Entry fee is $25 per, with a maximum of five entries per artist. Visit artx3.org/rosenzweig for submission guidelines and the entry portal. For more information about the exhibition or submission process, contact Matthew Howard, the center's visitor relations coordinator; call (870) 536-3375 or email [email protected] The Arkansas Symphony Orchestra hosts its Summer Strings Camp The program is designed for string students of all ages and skill levels; participants will engage in daily instruction from directors of the Arkansas Symphony Youth Orchestras Arkansas Symphony String Academy teachers and other members of the Arkansas Symphony Orchestra Campers will be placed in one of two orchestras; they'll receive music theory classes and/or All-Region prep courses and take part in instrument-specific ensembles The camp includes faculty performances and a final student recital ASO co-concertmaster Kiril Laskarov will lead a chamber music session during the second week Tuition is $350; scholarships are available. Register at arkansassymphony.org/summer-strings-camp. For more information, email camp director Katherine Williamson at [email protected] Fayetteville clarinetist Arissa Cholthitchanta was the grand prize winner April 26 of the Stella Boyle Smith Young Artists Competition at the Arkansas Symphony's Stella Boyle Smith Music Center in Little Rock performed the first movement of the Clarinet Concerto No Nine finalists performed concertos in the competition sponsored by the Arkansas Symphony Orchestra Guild took top honors and a $250 cash prize in the piano category performing the first movement Wolfgang Amadeus Mozart's Piano Concerto No And cellist Isabel Lopez Furlong of Hot Springs after performing the first movement of Edward Elgar's Cello Concerto in e minor theater and restaurants for the Arkansas Democrat-Gazette He joined the then-Arkansas Democrat on the copy desk in June 1977 and served for 17 years (including the entirety of the newspaper war) as the paper's entertainment editor before taking on his current role as features reporter He is also host of the weekly classical music show "Major and Minor Masterpieces" on public radio station KLRE-FM This document may not be reprinted without the express written permission of Northwest Arkansas Newspapers LLC Material from the Associated Press is Copyright © 2025 audio and/or video material shall not be published rewritten for broadcast or publication or redistributed directly or indirectly in any medium Neither these AP materials nor any portion thereof may be stored in a computer except for personal and noncommercial use The AP will not be held liable for any delays errors or omissions therefrom or in the transmission or delivery of all or any part thereof or for any damages arising from any of the foregoing Broadway Off-Broadway Off-Off Broadway Cabaret Dance Opera Classical Music Nashville Minneapolis / St. Paul Connecticut Atlanta Chicago Los Angeles WEST END UK Regional Canada Australia / New Zealand Europe Asia Latin America Africa / Middle East TV/Movies Music thanks to a generous grant from Impact 100 Greater Chesapeake Chapter concerts will also be offered at Chesapeake Arts Center in Brooklyn Park led by Artistic Director and Conductor José-Luis Novo will present two days of concerts for area schoolchildren followed by the Symphony’s highly anticipated annual Family Concert at Maryland Hall in Annapolis This dynamic collaboration features live dance performances by Ballet Theatre of Maryland’s professional company members creating a multi-sensory celebration of music and movement Maestro Novo has curated a lively program designed to introduce young audiences to the rich world of orchestral music blending iconic classical masterpieces with beloved Broadway tunes The selections showcase the fundamental building blocks of music: melody “Children are innately curious and open to new experiences,” said Maestro José-Luis Novo “By presenting both classical and Broadway pieces we hope to ignite their imaginations and show them that music speaks a universal language — one that is exciting Ballet Theatre of Maryland dancers Cindy Case, Karissa Kralik, Lauren Martinez, Victoria Siracusa, Isaac Martinez, Diego Sosa, and Michael West, Jr., will perform original choreography to works by Bach, Tchaikovsky, Strauss and Scott Joplin. The choreography was created by Isaac Martinez, Diego Sosa, and Michael West Jr “This collaboration is an extraordinary opportunity for young audiences to experience the synergy of live music and dance,” said Ballet Theatre of Maryland Artistic Director Nicole Kelsch “We are proud to join the Annapolis Symphony in bringing this rich cultural experience to families across our region.”  we wanted every movement to mirror the emotion and story within the music,” added choreographer Diego Sosa “It’s a celebration of how sound and motion come together to create something magical.” ● Antonín Dvořák: Slavonic Dance in G minor ● Johann Sebastian Bach: Orchestral Suite No BTM performance choreographed by Diego Sosa with dancers Cindy Case ● Pyotr Ilyich Tchaikovsky: Swan Lake Suite: Czardas  Staged by Nicole Kelsch after Petipa and Ivanov with dancers Karissa Kralik, Isaac Martinez, and Michael West Jr BTM performance choreographed by Isaac Martinez with dancers Victoria Siracusa and Diego Sosa  ● Igor Stravinsky: Pulcinella Suite: Tarantella ● Scott Joplin: Maple Leaf Rag  BTM performance choreographed by Michael West, Jr. with dancers Cindy Case, Isaac Martinez, and Michael West Jr ● Leonard Bernstein: West Side Story: Mambo  The ASO’s school concerts are more than delightful performances. They serve as a cornerstone for arts education, offering students from public, private, homeschool, and virtual learning environments an immersive experience in symphonic music. These performances align with STEAM (Science, Technology, Engineering, Arts, and Mathematics) curricula, fostering interdisciplinary learning. The concerts aim to inspire a lifelong love of the arts.  "Introducing young minds to the world of symphonic music is both a joy and a responsibility," says Maestro Novo. "By blending timeless classical pieces with the vibrant energy of Broadway tunes, we aim to ignite a lifelong passion for music in our young audiences."  This year, thanks to a generous grant from Impact 100 Greater Chesapeake Chapter, concerts will also be offered at Chesapeake Arts Center in Brooklyn Park, Maryland.  ● School Concerts at Maryland Hall: May 8, 2025, 10:00 AM & 11:30 AM  ● School Concerts at Chesapeake Arts Center: May 9, 2025, 10:00 AM & 11:30 AM  ● Family Concert at Maryland Hall: May 10, 2025, 11:00 AM  School concert tickets are $5 per person and must be reserved by calling the ASO Box Office at 410-263-0907. Title I schools are encouraged to inquire about financial assistance by contacting Julie Nolan at JNolan@AnnapolisSymphony.org.  HAIRSPRAY will take center stage at Dundalk Community Theatre (DCT) on May 9, 10, 16, 17 at 8 p.m. and May 11 & 18 (SOLD OUT) at 3 p.m.. Based on the New Line Cinema film written and directed by John Waters. The Annapolis Symphony Orchestra (ASO), led by Artistic Director and Conductor José-Luis Novo, will present two days of concerts for area schoolchildren, followed by the Symphony’s highly anticipated annual Family Concert at Maryland Hall in Annapolis. Everyman Theatre has announced the upcoming  production of Charles Ludlam's beloved comedy, The Mystery of Irma Vep: A Penny Dreadful,  running May 18 - June 22, 2025. Visit the Ferleman Gallery for a night of food, cocktails, music and fun benefitting The Cumberland Theatre. Enjoy the ambiance of the lovely Ferleman Gallery and music from some of our most talented local artists. and exclusive discounts on tickets to your favorite shows © 2025 - Copyright Wisdom Digital Media, all rights reserved. Privacy Policy Metrics details Personalized antisense oligonucleotides (ASOs) have achieved positive results in the treatment of rare genetic disease1 As clinical sequencing technologies continue to advance the ability to identify patients with rare disease harbouring pathogenic genetic variants amenable to this therapeutic strategy will probably improve Here we describe a scalable platform for generating patient-derived cellular models and demonstrate that these personalized models can be used for preclinical evaluation of patient-specific ASOs We describe protocols for delivery of ASOs to patient-derived organoid models and confirm reversal of disease-associated phenotypes in cardiac organoids derived from a patient with Duchenne muscular dystrophy (DMD) with a structural deletion in the gene encoding dystrophin (DMD) that is amenable to treatment with existing ASO therapeutics we designed novel patient-specific ASOs for two additional patients with DMD (siblings) with a deep intronic variant in the DMD gene that gives rise to a novel splice acceptor site incorporation of a cryptic exon and premature transcript termination We showed that treatment of patient-derived cardiac organoids with patient-specific ASOs results in restoration of DMD expression and reversal of disease-associated phenotypes The approach outlined here provides the foundation for an expedited path towards the design and preclinical evaluation of personalized ASO therapeutics for a broad range of rare diseases the overwhelming time and cost requirements for the design and preclinical evaluation of personalized ASOs currently precludes this strategy from more widespread adoption current approaches for establishing patient-derived iPS cell models can be time consuming and costly These limitations often prevent patient-derived models from reaching their full therapeutic potential with respect to the patients from which they were generated We address several of these challenges through the development of a rapid robust and scalable platform for the generation of patient-derived cell models We describe an iPS cell reprogramming pipeline that utilizes cryopreserved peripheral blood mononuclear cells (PBMCs) commonly available from previous genetic testing and requires only 3 weeks to establish iPS cell lines we demonstrate that three-dimensional organoid models generated from patient-derived iPS cells recapitulate disease-associated phenotypes that can be reversed using patient-specific ASOs from procurement of patient PBMCs to empirical analysis of ASO effects on organoid function requires no specialized equipment and less than 6 weeks of hands-on time We anticipate that implementation of the platform that we describe will lead to the rapid development of preclinical ASO leads for the treatment of many rare genetic diseases patients provided a standard blood draw for genome sequencing and residual PBMCs were cryopreserved for future research use We reasoned that these patient-specific PBMCs could be a valuable resource for building a biobank of patient-derived cellular models of rare genetic diseases requires several technical hurdles to be addressed Schematic of the iPS cell reprogramming workflow iPS cell marker expression in patient-derived iPS cells (patient 1) Representative karyotype of patient-derived iPS cells (patient 1) Differentiation of patient-derived iPS cells (patient 1) into ectoderm Embryoid body formation using patient-derived iPS cells (patient 1) Differentiation of patient-derived iPS cells (patient 1) into two-dimensional skeletal muscle Differentiation of patient-derived iPS cells (patient 1) into three-dimensional cardiac and brain organoids Reprogramming outcomes relative to PBMC input cell counts Data in b,d,f,g are representative of n = 3 biologically independent experiments The iPS cell reprogramming protocol that we outline does not require specialized equipment or high-cost reagents and can be easily implemented in any standard research laboratory We reasoned that inhibition of cardiac troponin T in iPS cell-derived cardiac models would provide an ideal system for evaluating ASO delivery and efficacy Schematic of the design strategy for ASOs targeting cardiac troponin T Cardiac troponin T expression in cardiac organoids treated with ASOs Western blot confirmation of cardiac troponin T expression in cardiac organoids treated with ASOs Contraction of individual cardiac organoids treated with ASOs as determined by intracellular calcium levels Summarized contraction of cardiac organoids treated with ASOs Data in panels b,c are representative of n = 3 biologically independent experiments Data in panel e are presented as mean ± s.d Error bars in e represent standard deviation for n = 3 counts of 100 independent organoids these data demonstrate that ASOs can achieve robust genetic perturbation in an iPS cell-derived organoid model Schematic of the design strategy to profile existing ASO therapeutics for the treatment of DMD Chromatogram validating structural deletion within the DMD gene in patient 1 Targeted RNA-seq validating missing exons in the expressed DMD transcript in patient 1 Dystrophin expression in cardiac organoids derived from a patient with DMD (patient 1) treated with ASOs matching the sequence of existing ASO therapeutics Quantification of dystrophin expression in cardiac organoids derived from a patient with DMD (patient 1) compared with unaffected cardiac organoids Western blot confirmation of dystrophin expression in cardiac organoids derived from a patient with DMD (patient 1) treated with ASOs matching the sequence of existing ASO therapeutics Efficiency of ASO transfection in patient-derived cardiac organoids (patient 1) Relative expression of exon 45-containing versus exon 45-skipped DMD transcripts in cardiac organoids derived from a patient with DMD (patient 1) treated with ASOs matching the sequence of existing ASO therapeutics Contraction of individual cardiac organoids derived from a patient with DMD (patient 1) treated with ASOs matching the sequence of existing ASO therapeutics Time-course analysis of restored contraction (based on visual assessment of contraction) in cardiac organoids derived from a patient with DMD (patient 1) treated with ASOs matching the sequence of existing ASO therapeutics Viability of cardiac organoids derived from a patient with DMD (patient 1) treated with ASOs Data in d,f are representative of n = 3 biologically independent experiments Data in e,g,h,k are presented as mean ± s.d Error bars in e,h represent standard deviation for n = 3 replicates Error bars in g,k represent standard deviation for n = 4 replicates These results indicate that patient-derived organoid models can be used to evaluate the efficacy of ASO therapeutics Schematic of the design strategy for preclinical evaluation of novel patient-specific ASOs Chromatogram validating intronic variant within the DMD gene in patient 2a Dystrophin expression in cardiac organoids derived from a patient with DMD (patient 2a) treated with patient-specific ASOs Quantification of dystrophin expression in cardiac organoids derived from a patient with DMD (patient 2a) compared with unaffected cardiac organoids Western blot confirmation of dystrophin expression in cardiac organoids derived from a patient with DMD (patient 2a) treated with patient-specific ASOs RT–PCR validating restored exon 43–44 splicing in cardiac organoids derived from a patient with DMD (patient 2a) treated with patient-specific ASOs Contraction of individual cardiac organoids derived from a patient with DMD (patient 2a) treated with patient-specific ASOs Time-course analysis of restored contraction (based on visual assessment of contraction) in cardiac organoids derived from a patient with DMD (patient 2a) treated with patient-specific ASOs Efficiency of ASO transfection in patient-derived cardiac organoids (patient 2a) Viability of cardiac organoids derived from a patient with DMD (patient 2a) treated with ASOs Data in panels c,e,f are representative of n = 3 biologically independent experiments Data in panels d,i,j are presented as mean ± s.d Error bars in panel d represent standard deviation for n = 3 replicates Error bars in panels i,j represent standard deviation for n = 4 replicates these data establish patient-derived organoid models as powerful systems for the design and characterization of personalized ASO therapeutics for the full potential of personalized ASOs to be realized an expedited process for the preclinical characterization of candidate ASOs is required robust and scalable platform for generating patient-derived cellular models and have validated the utility of these models in the evaluation of patient-specific ASOs Although substantial regulatory considerations remain with regards to the approval of personalized ASOs for use in the clinic the platform that we have described will facilitate widespread preclinical development of personalized ASOs Increases in the number of prospective patient-specific ASOs will encourage a modernized assessment of the approval process for this unique class of therapeutics the data described here demonstrate reduction to practice for the use of patient-derived organoid models in the evaluation of personalized therapeutics The methods and protocols generated in this study are accessible and can be implemented in any standard research laboratory without the need for specialized equipment or high-cost reagents The widespread ability to generate patient-derived cellular systems will have a substantial effect on the understanding of disease mechanisms as well as potential therapeutic avenues for the treatment of many rare diseases Patients profiled in this study are participants in the Genomic Answers for Kids (GA4K) program at the Children’s Mercy Research Institute (https://www.childrensmercy.org/childrens-mercy-research-institute/studies-and-trials/genomic-answers-for-kids/) Potential GA4K participants are informed of the program by clinicians in our health system Participants met with a member of the study team to ensure any questions they had were answered as a part of the informed written consent into GA4K Participants did not receive any form of compensation Genome sequencing data collected through GA4K has been de-identified and deposited in dbGaP (accession: phs002206.v2.p1) Biospecimens collected through GA4K cannot be distributed as general research reagents but can be shared in instances directly related to achieving diagnoses The Institutional Review Board of Children’s Mercy Research Institute gave ethical approval for this work (studies #00002465 and #11120514) All methods were carried out in accordance with relevant guidelines and regulations All iPS cell lines were cultured in mTeSR1 medium on Matrigel-coated flasks in an incubator at 37 °C at 5% CO2 until 60–80% confluency was reached at which point cells were split using ReLeSR ASOs were added at a final concentration of 10 µM which was introduced with the transfection reagent TransIT-TKO (MIR2250 TransIT-TKO was added to Opti-MEM (31985062 Thermo Fisher Scientific) and mixed gently by pipetting up and down The ASOs were then added to the Opti-MEM-TransIT-TKO mix at the desired concentration and mixed gently by pipetting and incubated at room temperature for 45 min the ASO transfection mix was added dropwise and gently shaken to evenly distribute the ASOs ASOs were added to cardiac organoids 14–22 days after the start of differentiation Secondary antibodies (goat anti-rabbit Alexa Fluor 488 and goat anti-mouse Alexa Fluor 594; A11034 and A11032 organoids were incubated with fructose–glycerol clearing solution (60% glycerol and 2.5 M fructose; 2 h at room temperature followed by overnight at 4 °C) to optically clear organoids before imaging Organoids were imaged using the Nikon W1 spinning disk confocal microscope Cardiac organoids were loaded with 10 µM Fluo-4 AM (F14217 Thermo Fisher Scientific) with 1.25 mM probenecid (P36400 Fisher) added directly to the maintenance media (RPMI 1640/B27 with insulin) for 45 min at 37 °C and maintenance media were added back and incubated at 37 °C for an additional 30 min before responses were measured using a fluorescence microscope (Keyence BZ-X810) using the FITC filter set Quantification of cardiac contraction was performed using Musclemotion Directed differentiation into all three germ layers (endoderm mesoderm and ectoderm) was achieved using the STEMdiff Trilineage Differentiation Kit (05230 StemCell Technologies) following the manufacturer’s instructions iPS cells were harvested using ReLeSR and single cells were generated by gentle pipetting up and down This was followed by counting and seeding with recommended cell densities onto Matrigel-coated 24-well plates Cells were maintained in lineage-specific medium with daily medium changes until day 5 for mesoderm and endoderm differentiation and until day 7 for ectoderm differentiation Immunofluorescence staining was performed to assess differentiation to the ectoderm (nestin and PAX6) endoderm (FOXA2 and SOX17) and mesoderm (Brachyury and NCAM) Genomic integrity was assessed by karyotyping with a standard 20 iPS cell analysis Karyotype services were provided by the Children’s Mercy Kansas City Hospital Genetics laboratory Stem Cell Technologies) was used to check chromosome abnormalities following the manufacturer’s instructions Cardiac organoid viability was determined using the CellTiter-Glo 3D Cell Viability Assay kit (G9682 Promega) following the manufacturer’s instructions ASOs were labelled using the Label IT Nucleic Acid Labeling Kit MFP488 (MIR7125 Mirus) following the manufacturer’s instructions the labelling reaction was assembled according to instructions and was incubated at 37 °C for 3 h followed by purification using G50 microspin purification columns and transfected into cardiac and brain organoids as described above The genomic DNA from iPS cell lines were extracted using the Nucleospin Blood Kit (740951.50 PCR samples were purified using the QIAquick PCR Purification Kit (28106 All product sizes were confirmed on a 2% agarose gel before Sanger sequencing (Genewiz/Azenta Life Sciences) and Amplicon-Ez Next Generation sequencing (Genewiz/Azenta Life Sciences) For visualization, raw sequencing data were aligned to the human genome using STAR with default settings and GENCODE Release 43 as the reference transcriptome47 sequencing reads containing exon 44–45 junctions or exon 44–54 junctions were enumerated and normalized to the total number of sequencing reads for the sample LV-TRE-WT human MyoD-dsRedExpress2 was a gift from C HEK293T cells (American Type Culture Collection) were seeded (1 × 106 cells per well) in a six-well dish and allowed to attach for 24 h A transfection mixture of 8.25 µl TransIT LT-1 reagent (Mirus Bio) with psPAX2 vector DNA (11260 Addgene; 125 ng) and LV-TRE-WT human MyoD-T2A-dsRedExpress2 DNA (96918 Addgene; 1,250 ng) was mixed and the volume brought up with OptiMEM The transfection mixture was allowed to incubate for 30 min at room temperature and added to the cells Lentiviral supernatant was collected 48 h post-transfection Skeletal muscle differentiation was based on previous published methods19 iPS cells used for skeletal muscle differentiation were maintained in growth medium containing Dulbecco’s modified eagle’s medium (DMEM)/F12 (21041025 1% MEM non-essential amino acids (11140050 Thermo Fisher) and 10 ng ml−1 bFGF (78003.1 StemCell Tech) supplemented with 0.4 µM PD0325901 To generate stable iPS cell lines with integrated Dox-inducible MYOD1 transgene iPS cells were infected with the MyoD lentivirus supplemented with 4 µg ml−1 polybrene (TR-1003-G Uninfected cells were removed by 3-day incubation with 2 µg ml−1 puromycin (AT1113803 Gibco) to obtain a pure population of transduced cells iPS cells were pooled and expanded in growth media with puromycin iPS cells were seeded on Matrigel-coated plates in iPS cell growth media without bFGF supplemented with ROCK inhibitor (Y-27632) the medium was changed to induction medium (DMEM and 15% FBS) containing 3 µg ml−1 doxycycline (D9891 Sigma) to induce MyoD transgene expression Medium was changed 4 days later to Dox-containing differentiation media (low-glucose DMEM (36253 Thermo Fisher) and 3 µg ml−1 doxycycline) and changed every 2 days iPS cells were dissociated and centrifuged at 300g for 3 min Cells were resuspended in mTeSR1 media plus 10 μM ROCK inhibitor and single celled by gentle pipetting Ten thousand cells were plated in a low-attachment 96-well plate followed by centrifugation at 100g for 3 min and placed in an incubator at 37 °C at 5% CO2 Medium was changed every other day for 6–7 days when embryoid bodies have smooth edges and begin to brighten the medium was changed to neural induction media (DMEM/F12 neuroepithelia became visible and aggregates were coated in a 1% diluted Matrigel–DMEM solution and incubated at 37 °C for at least 30 min to allow Matrigel polymerization Differentiation media without vitamin A (1:1 mixture of DMEM/F12 and neurobasal (21103049 Invitrogen) containing 1:200 N2 supplement 1:100 B27 supplement without vitamin A (12587010 1:100 Glutamax and 1:200 MEM-NEAA) were added and refed every other day differentiation media were changed to differentiation media with vitamin A (17504044 Cerebral organoids were ready for downstream analysis after 2–3 weeks Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article The BioProject accession number for the amplicon sequencing data described in this study is PRJNA1177506. 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Exp. https://doi.org/10.3791/54650 (2016) Human induced pluripotent stem cell production and expansion from blood using a non‐integrating viral reprogramming vector Generation of human induced pluripotent stem cells using a defined Going back and forth: episomal vector reprogramming of peripheral blood mononuclear cells to induced pluripotent stem cells and subsequent differentiation into cardiomyocytes and neuron–astrocyte co-cultures Generation of transgene-free human induced pluripotent stem cells from erythroblasts in feeder-free conditions Targeted disruption of the cardiac troponin T gene causes sarcomere disassembly and defects in heartbeat within the early mouse embryo Fluorescent-based methods for gene knockdown and functional cardiac imaging in zebrafish Troponin destabilization impairs sarcomere–cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients Novel approaches to corticosteroid treatment in Duchenne muscular dystrophy a novel 2′OMeRNA/ENA® chimera antisense oligonucleotide induces robust exon 45 skipping for dystrophin in vivo Intron mutations and early transcription termination in Duchenne and Becker muscular dystrophy Low dystrophin levels increase survival and improve muscle pathology and function in dystrophin/utrophin double‐knockout mice What is the level of dystrophin expression required for effective therapy of Duchenne muscular dystrophy Medical imaging in new drug clinical development Machine learning applications in drug development Paediatric genomics: diagnosing rare disease in children Robust cardiomyocyte differentiation from human pluripotent stem cells via temporal modulation of canonical Wnt signaling Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease Cardioids reveal self-organizing principles of human cardiogenesis Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature https://doi.org/10.1038/nature12517 (2013) Download references This study was supported by the US National Institutes of Health (R01HD110447 to S.T.Y.) and generous philanthropic contributions to the Children’s Mercy Research Institute and the GA4K program We thank all GA4K study team members and program participants for making this study possible University of Missouri-Kansas City School of Medicine All authors read and approved the final manuscript The authors declare no competing interests reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations a) Differentiation of patient-derived iPSCs (patient 1) into ectoderm b) Neuronal marker expression in patient-derived cerebral organoids (patient 1) c) RT-PCR confirmation of neuronal marker expression in patient-derived cerebral organoids (patient 1) d) Background staining from secondary antibodies in cardiac and brain organoids Data in c are representative of n = 3 biologically independent experiments b) A representative iPSC colony derived from patient fibroblasts c) iPSC marker expression in iPSCs derived from patient fibroblasts d) Differentiation of iPSCs derived from patient fibroblasts into ectoderm a) Cardiac marker expression in patient-derived cardiac organoids (patient 1) b) RT-PCR confirmation of cardiac marker expression in patient-derived cardiac organoids (patient 1) Data in b are representative of n = 3 biologically independent experiments a) iPSC marker expression in patient-derived iPSCs (patient 2a) b) Representative karyotype of patient-derived iPSCs (patient 2a) c) Embryoid body generated from patient-derived iPSCs (patient 2a) d) Differentiation of patient-derived iPSCs (patient 2a) into ectoderm a) iPSC marker expression in patient-derived iPSCs (patient 2a) after 30 passages b) iPSC marker expression in patient-derived iPSCs (patient 2a) after 5 and 30 passages c) Phase contrast imaging of patient-derived iPSC colonies (patient 2a) after 5 and 30 passages d) qPCR analysis of common karyotypic abnormalities in patient-derived iPSCs (patient 2a) after 5 and 25 passages e) Differentiation of late-passage (passage 30) patient-derived iPSCs (patient 2a) into ectoderm Error bars in d represent standard deviation for n = 3 replicates a) Cardiac marker expression in patient-derived cardiac organoids (patient 2a) b) RT-PCR confirmation of cardiac marker expression in patient-derived cardiac organoids (patient 2a) a) Schematic of design and delivery strategy for preclinical evaluation of novel patient-specific ASOs b) Chromatogram validating intronic variant within the DMD gene in patient 2b c) Dystrophin expression in DMD patient-derived cardiac organoids (patient 2b) treated with patient-specific ASOs d) Quantification of DMD expression in DMD patient-derived cardiac organoids (patient 2b) as compared to unaffected cardiac organoids e) RT-PCR validating restored exon 43:44 splicing in DMD patient-derived cardiac organoids (patient 2b) treated with patient-specific ASOs f) Contraction of individual DMD patient-derived cardiac organoids (patient 2b) treated with patient-specific ASOs g) Viability of DMD patient-derived cardiac organoids (patient 2b) treated with ASOs h) Efficiency of ASO transfection in patient-derived cardiac organoids (patient 2b) i) Time course analysis of restored contraction in DMD patient-derived cardiac organoids (patient 2b) treated with patient-specific ASOs Data in e are representative of n = 3 biologically independent experiments h represent standard deviation for n = 4 replicates a) iPSC marker expression in patient-derived iPSCs (patient 2b) b) Representative karyotype of patient-derived iPSCs (patient 2b) c) Embryoid body generated from patient-derived iPSCs (patient 2b) d) Differentiation of patient-derived iPSCs (patient 2b) into ectoderm a) iPSC marker expression in patient-derived iPSCs (patient 2b) after 30 passages b) iPSC marker expression in patient-derived iPSCs (patient 2b) after 5 and 30 passages c) Phase contrast imaging of patient-derived iPSC colonies (patient 2b) after 5 and 30 passages d) qPCR analysis of common karyotypic abnormalities in patient-derived iPSCs (patient 2b) after 5 and 25 passages e) Differentiation of late-passage (passage 30) patient-derived iPSCs (patient 2b) into ectoderm a) Cardiac marker expression in patient-derived cardiac organoids (patient 2b) b) RT-PCR confirmation of cardiac marker expression in patient-derived cardiac organoids (patient 2b) Summary reprogramming reagents and methods All ASOs in this study were synthesized as fully 2’-O-methyl-modified RNAs Download citation DOI: https://doi.org/10.1038/s41586-024-08462-1 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology conducting the Atlanta Symphony Orchestra must feel akin to wearing a long-cherished Under Spano’s baton for the second week as music director emeritus this season the ASO delivered a captivating performance on Thursday at Atlanta Symphony Hall featuring works by Jean Sibelius showcasing the orchestra’s virtuosic versatility and the talents of guest pianist Jae Hong Park in his ASO debut The concert opened with Jean Sibelius’ Tapiola a tone poem that conjures the spirit of the northern Nordic forest drawing inspiration from the mythic forest spirit Tapio of Finnish lore evoking the wild spirit of the piece that was to be Sibelius’ final significant composition composed in 1926 before three decades of creative silence American music critic Alex Ross has called Tapoila “Sibelius’s most severe and concentrated musical statement.” Given Spano’s well-known involvement with conducting Sibelius’ orchestral works it is surprising the program booklet notes claimed that this was the ASO’s first performance of Tapiola when in fact Spano and the ASO performed it first in March 2008 and again November 2012 and a recording by Spano and the ASO was released on 2013 on ASO media (CD-1004) along with Symphony No Spano and the ASO navigated the score’s darkly shifting textures with precision allowing the work’s organic ebb and flow to unfold naturally The climactic storm of sound gave way to a haunting resolution Jae Hong Park joined Spano and the ASO as soloist for Alexander Scriabin’s Piano Concerto in F-sharp minor it is his sole concerto and first orchestral piece It bears the unmistakable imprint of Frédéric Chopin’s influence alongside discernable echoes of other Romantic composers such as Tchaikovsky Chopin’s dominant influence is evident in the concerto’s lyrical which closely mirror the Polish composer’s style—think of the poetic fluidity in Chopin’s own piano concertos Scriabin’s training at the Moscow Conservatory and his own early reputation as a “Russian Chopin” reinforce this connection where he shaped Scriabin’s lyricism with a delicate touch The ASO provided a responsive accompaniment supporting Park’s nuanced phrasing without overpowering his pianistic subtleties introspective central “Andante” allowed Park to bring out the work’s rhapsodic qualities while the finale’s effervescent energy highlighted his dexterity earning an enthusiastic ovation from the audience Park returned to the stage for a contrasting intimate encore: a Prelude in B minor by J.S Bach arranged by the Russian pianist and composer Alexander Siloti (1863 – 1945) Bach aficionados might not have recognized it at first as a transcription of the E minor Prelude (No 10) from the first book of The Well-Tempered Clavier with the moving 16th notes transferred from the left hand to the right as well as the key change to B minor The program concluded with Rimsky-Korsakov’s Scheherazade unabashedly a staple of Spano’s repertoire as a conductor and his relationship to the Atlanta Symphony Orchestra ever since an electrifying live performance of Scheherazade in May 2000 which inspired the subsequent CD released Telarc in 2001 marking Spano’s debut recording with the orchestra following his appointment as music director starting in the 2001-2002 season The album was praised by the Atlanta Journal-Constitution ear-ringing excitement” of Spano’s approach it contributed to the Atlanta Symphony Orchestra’s strong reputation during Spano’s 20-year tenure Interestingly, the most recent ASO performance of Scheherazade before Thursday was also conducted by Spano just three years ago, in April 2022. And Spano recently led the Fort Worth Symphony Orchestra in a performance of Scheherazade in early February this year Spano and the ASO leaned into the work’s narrative flair painting a sonic tapestry of the legendary tales Concertmaster David Coucheron brought elegance and warmth to the copious violin solos capturing the essence of the storyteller with sinuous phrasing and a golden tone The performance reveled in the work’s lush orchestration with the brass and percussion lending a thrilling intensity to the stormy climaxes The second movement’s playful exchanges and the final movement’s sweeping grandeur were particularly effective culminating in a shimmering conclusion that drew an enthusiastic response from the audience Spano maintained a strong rapport with the orchestra throughout the concert showcasing the ASO’s skill and ability to bring color and narrative depth across the range of repertoire With Park’s poised debut and Spano’s assured leadership the program proved a fitting testament to the ensemble’s artistry and cohesion Mark Gresham is publisher and principal writer of EarRelevant He began writing as a music journalist over 30 years ago but has been a composer of music much longer than that He was the winner of an ASCAP/Deems Taylor Award for music journalism in 2003 Metrics details GPNMB has been discussed as a potential therapeutic target in GRN-mediated neurodegeneration based on the observed reproducible upregulation in FTD-GRN cerebrospinal fluid (CSF) and post-mortem brain the functional impacts of up-regulated GPNMB are currently unknown and it is currently unclear if targeting GPNMB will be protective or deleterious Increases in GPNMB seen in FTD-GRN are reproduced in brains of aged Grn-deficient mice although brains of young Grn-deficient mice do not exhibit upregulated Gpnmb expression peripheral immune cells of these mice exhibit increased Gpnmb expression as young as 5-to-6 months suggesting the effects of Grn-deficiency in the periphery proceed those in the brain Grn-deficiency is known to alter peripheral immune cell function including impaired autophagy and altered cytokine secretion GPNMB has potential effects on these processes but has never been studied in peripheral immune cells of patients or preclinical models Informing the functional significance of GPNMB upregulation in Grn-deficient states in myeloid cells has potential to inform GPNMB as a therapeutic candidate The effects of GPNMB knock-down via antisense oligonucleotide (ASO) were assessed in peripheral blood mononuclear cells (PBMCs) from 25 neurologically healthy controls (NHCs) and age- and sex-matched FTD-GRN patients as well as peritoneal macrophages (pMacs) from progranulin-deficient (Grn -/-) and B6 mice antigen presentation and MHC-II processing and recycling were assessed as well as cytokine release and transcription ASO-mediated knock-down of GPNMB increased lysosomal burden and IL1β cytokine secretion in FTD-GRN carriers and NHCs monocytes ASO-mediated knock-down of Gpnmb in Grn-deficient macrophages decreased lysosomal pan-cathepsin activity and protein degradation ASO-mediated knock-down of Gpnmb increased MHC-II surface expression which was driven by decreased MHC-II uptake and recycling ASO-mediated knock-down of Gpnmb dysregulated IFN\(\gamma\)-stimulated IL6 cytokine transcription and secretion by mouse macrophages due to the absence of regulatory actions of the Gpnmb extracellular fragment (ECF) Our data herein reveal that GPNMB has a regulatory effect on multiple immune effector functions including capping inflammation and immune responses in myeloid cells the marked upregulation in GPNMB transcript and protein may represent a compensatory mechanism to preserve lysosomal function in myeloid cells These novel findings indicate that targeted depletion of GPNMB in FTD-GRN would not be a rational therapeutic strategy because it is likely to dysregulate important immune cell effector functions mediated by GPNMB our data indicate that therapeutic strategies inhibiting GPNMB levels and/or activity may worsen the effects of GRN deficiency is associated with increased risk for neurodegenerative diseases and understanding mechanisms associated with GRN deficiency may aid in future therapeutic development highlighting that PGRN deficiency leads to early immune dysregulation in the periphery that pre-empts dysregulation in the CNS suggesting that the lysosomal dysfunction could be a proximal cause of GPNMB upregulation in Grn -/- mice and FTD-GRN patients that GPNMB may be upregulated to help curb or dampen inflammation which we posit may be due to an upregulation of compensatory genes in a Gpnmb-null environment IFNγ will be used to stimulate myeloid cell to assess immune responses such as cytokine release and antigen presentation which typically occur during an immune response to an inflammatory stimulus slowly added to 37 °C filter sterilized complete culture media (RPMI 1640 media 10% heat-inactivated fetal bovine serum (FBS) 1 mM Penicillin–Streptomycin) and pelleted via centrifugation at 90 × g for 10 min at room temperature The supernatant was removed and cells were resuspended in 37 °C MACS buffer (PBS pH 7.2) cell counting using Trypan blue exclusion C57BL/6 littermate controls were used for all studies with Grn -/- and C57BL/6 controls cohoused All animal procedures were approved by the University of Florida Institutional Animal Care and Use Committee (IACUC #201,910,870) and were in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No Male and female mice were aged to 5–6-months old and sacrificed via cervical dislocation or decapitation to a final concentration of 1 × 106 cells per 100 µL 100 µL of cells were transferred to each Nucleocuvette which was then placed into a 4D-Nucleofector® X Unit (Lonza) and pulsed using the CM 138 pulse code 400 µL of growth media (acclimated in incubator 1-h prior) was added to each Nucleocuvette and cells transferred to plates pre-coated with poly-D-Lysine (Sigma) cells washed and treatment started as previously described V-PLEX mouse pro-inflammatory panel 1 kit (MesoScaleDiscovery; K15048D) or V-PLEX human pro-inflammatory panel 1 kit (MSD; K15049D) was used to quantify cytokines in conditioned media from murine peritoneal macrophages (pMacs) and patient PBMCs Media was diluted 1:1 with MSD kit diluent and incubated at room temperature in the provided MSD plate with capture antibodies for 2 h as per manufacturer’s instructions Plates were then washed × 3 with PBS with 0.05% Tween-20 and detection antibodies conjugated with electrochemiluminescent labels were added and incubated at room temperature for another 2 h with shaking After 3 × washes with PBS containing 0.05% Tween-20 MSD read buffer was diluted to 2 × and added and the plates were loaded into the QuickPlex MSD instrument for quantification Results were normalized to total live cell counts as measured via flow cytometry MHC II Ea chain (Ea) (52–68) peptide (Anaspec) was reconstituted in sterile distilled H2O to a final concentrate of 1 mg/mL. Once peritoneal macrophages had adhered to plates, 5 µg per well was added in growth media. Cells were incubated for 18-h and taken forward for flow cytometry. Protocol available at https://dx.doi.org/10.17504/protocols.io.14egn3r3pl5d/v1 This step will label any primary antibody-labelled MHC-II that had been taken up in the first incubation step evading labelling with goat anti-mouse IgG-Alexa 647 in the blocking step and had been recycled back to the plasma membrane Cells were harvested and transferred to a v-bottom 96-well plate (Sigma CLS3896-48EA) and centrifuged at 300 × g for 5 min at 4 °C Cells were fixed in 50 µL of 1% PFA at 4 °C in the dark for 30 min Cells were centrifuged at 300 × g for 5 min and resuspended in 200 µL FACs buffer Cells were taken for flow cytometry on a Macs Quant Analyzer (Miltenyi) or BD LSR Fortessa™ Cell Analyzer A minimum of 100,000 events were captured per sample and data were analyzed using FlowJo version 10.6.2 software (BD Biosciences) The equation from the 4-PL curve was used to determine the concentration of Gpnmb ECF in the test samples Statistics and data analyses were performed using IBM SPSS statistics 27 or GraphPad Prism 9 When assessing differences between ASO treatment groups when optimizing ASO conditions (in both human PBMCs and murine pMacs) cytokine assessment and microscopy image analysis in pMacs where differences were assessed in 2 independent variables (mouse genotype and ex vivo treatment) For flow cytometry and cytokine assessment in human PBMCs where differences were assessed in 2 independent variables (disease status and ex vivo treatment) For flow cytometry-based pulse-chase assays in pMacs where differences were assessed in 3 independent variables (mouse genotype The normal distribution of the data in this study was determined using the Shapiro–Wilk test Homogeneity of Variance of the data in this study was determined using the Levene’s test In instances when data did not fit parametric assumptions (heterogeneity of variance and/or non-normally distributed data) with Dunn’s test used for post-hoc analysis with Bonferroni correction Post-hoc tests following ANOVAs were conducted using Bonferroni correction Two-tailed levels of significance were used and p < 0.05 was considered statistically significant Graphs are depicted by means ± standard error of the mean (SEM) When deciding if data points are true statistical outliers versus a reflection of biological variability we assume that data points that are ± 2 standard deviations of the mean of a data set are statistical outliers and are therefore excluded from data sets ASO-mediated knock-down of GPNMB increases HLA-DR expression and IL1β secretion in human PBMCs and imapirs lysosomal acidity in FTD-GRN monocytes PBMCs from NHCs and FTD-GRN patients were nucleofected with control or GPNMB-targeting ASO followed by 18-h incubation in presence or absence of 100 U IFNγ and cells assessed via flow cytometry and media taken for cytokine quantification GPNMB MFI was quantified in classical monocytes (A HLA-DR was quantified in classical monocytes (C normalized to live cell count (E) and fold-change from control ASO vehicle conditions calculated (F) Lysotracker MFI was quantified in classical monocytes (G Bars represent mean ± SEM (N = 20–25 participants per disease state) Similar patterns were observed with TNF (Sup FTD-GRN monocytes exhibit increased GPNMB expression that is accompanied by blunted responses to IFNγ as indicated by decreased HLA-DR expression and IL1β secretion To assess the effects of GRN mutations, MFI of Lysotracker DND-99, which will accumulate in and stain sufficiently acidic lysosomes within cells, was quantified in classical monocytes. Interestingly, no significant differences in Lysotracker MFI were exhibited between patient groups in control ASO conditions (Fig. 1G) GPNMB expression was quantified to assess the efficacy of ASO-mediated GPNMB knock-down in FTD-GRN patient PBMCs and those from NHCs. Indeed, GPNMB knock-down decreased GPNMB MFI levels in both vehicle and IFNγ treatments and patient groups in all cell types assessed (Fig. 1A no stimulation-dependent increase in HLA-DR was observed in classical monocytes from either FTD-GRN patients or NHCs due to a significant increase in HLA-DR expression in the vehicle GPNMB ASO conditions relative to control ASO that an increase in GPNMB levels is associated with suppressed stimulation-dependent changes in HLA-DR expression and that knock-down of GPNMB increases HLA-DR expression in classical monocytes IL1β fold-change from control ASO vehicle conditions was significantly increased in both patient groups suggesting that GPNMB may exert anti-inflammatory effects and knock-down of GPNMB increases the pro-inflammatory phenotype of PBMCs No significant effects of GPNMB knock-down were observed for any other cytokine (Sup Regarding lysotracker MFI, despite no significant differences being observed in control ASO conditions between FTD-GRN patient monocytes and those from NHCs, a significant decrease in Lysotracker MFI was observed in FTD-GRN classical monocytes relative to NHCs upon the knock down of GPNMB via ASOs in vehicle conditions (Fig. 1G Such data suggest that an upregulation of GPNMB may be a compensatory mechanism to protect lysosomal function in FTD-GRN monocytes with the subsequent loss of GPNMB predisposing patient cells to a disruption in proper lysosomal acidity No significant differences were observed between non-nucleofected cells and those nucleofected with control ASO (Sup was used to quantify cathepsin activity in LPMs after nucleofection with a control ASO alongside non-nucleofected controls to assess effects of nucleofection on lysosomal function No significant differences were observed between non-nucleofected and control ASO conditions in either genotypes or sexes (Sup these data suggest that nucleofection with a control ASO at 1 µg does not significantly modify immune responses or lysosomal function in macrophages relative to non-nucleofected cells directly compare the effects of Gpnmb knock-down via ASO relative to control ASO Grn-deficient mouse macrophages display upregulation of Gpnmb protein and extracellular fragment (ECF) all of which are modulated by inflammatory insults and ASO-mediated knock-down male and female mice were nucleofected with control or Gpnmb-targeting ASO followed by 18-h incubation in presence or absence of 100 U IFNγ and cells assessed via flow cytometry or RNA extracted Gpnmb MFI was quantified in LPMs from male and female mice (A-D) Total Gpnmb transcript levels were quantified in pMacs from male and female mice (E Gpnmb ECF was quantified in media from pMacs from male and female mice (G Bars represent mean ± SEM (N = 5–6 mice per genotype) ASO-mediated knock-down of Gpnmb decreases lysosomal protein degradation in Grn-deficient macrophages from female mice plated and allowed to rest for 24 h and lysosomal function assessed via microscopy BMV109 and DQ-BSA MFI was quantified from microscopy images of pMacs from male mice (A BMV109 and DQ-BSA MFI was quantified from microscopy images of pMacs from female mice (D Bars represent mean ± SEM (N = 6 mice per genotype) ASO-mediated knock-down of Gpnmb increases MHC-II surface expression but not MHC-II processing in macrophages from Grn-deficient females followed by 18-h incubation in presence or absence of 100 U IFNγ and cells assessed via flow cytometry MHC-II MFI was quantified in MHC-II + LPMs from male and female mice (A Cells were incubated with Eα peptide and peptide-bound MHC-II complexes at the plasma membrane were quantified in LPMs from male and female mice (C-F) LPMs from female Grn -/- mice exhibited decreased stimulation-dependent YAe MFI relative to B6 controls suggesting dysregulation of the antigen processing pathway in these cells when Gpnmb is reduced acutely ASO-mediated knock-down of Gpnmb decreases MHC-II uptake and recycling in macrophages from Grn-deficient females female mice were nucleofected with control or Gpnmb-targeting ASO they were assessed for MHC-II uptake utilizing a pulse-chase flow cytometry-based assay (A) MHC-II-488 MFI was quantified in LPMs from female mice over a 2-h time-course pMacs were assessed for MHC-II recycling utilizing a pulse-chase flow cytometry-based assay (D) Recycled MHC-II MFI was quantified in LPMs from female mice over an 18-h time-course (E ASO-mediated knock-down of Gpnmb dysregulates stimulation-evoked cytokine transcription and protein secretion pMacs from B6 and Grn -/- female and male mice were nucleofected with control or Gpnmb-targeting ASO they were subject to 18-h incubation in presence or absence of 100 U IFNγ and cell RNA extracted and conditioned media collected IL6 transcript levels were assessed in pMacs from male and female mice (A IL6 cytokine release in media was quantified in conditioned media and normalized to live cell count in pMacs from male and female mice (C loss of Gpnmb causes decreased MHC-II complex uptake and recycling presumably due to the lysosomal dysfunction induced by acute removal of Gpnmb causing MHC-II complexes to accumulate on the cell surface increases in GPNMB leads to a decrease in stimulation-dependent Il1β and IL6 cytokine secretion in GRN-FTD PBMCs and Grn -/- pMacs with GPNMB knock-down increasing expression and secretion of these cytokines This increase in pro-inflammatory cytokine secretion may be driven by the decrease Gpnmb ECF and its immunosuppressive function taken together our data suggest that Gpnmb upregulation may be a compensatory mechanism to rescue and protect the lysosome in the absence of PGRN and that this occurs much earlier in the peripheral immune system than in the CNS Although it was demonstrated that altered lysosomal acidity (a reliable indicator of lysosomal health) was observed upon GPNMB knock-down in GRN-FTD patient monocytes it was not possible to confirm lysosomal dysfunction with an orthogonal assay (such as BMV109 or DQ-BSA) as was done here in murine macrophages due to a limited supply of cryopreserved cells available Future studies will be needed to confirm lysosomal dysfunction in GRN-FTD patient monocytes upon GPNMB knock-down knock-down of Gpnmb also mediated MHC-II complex cell surface expression and the ability of these Grn -/- macrophages to engage in antigen presentation From our findings it is difficult to discern whether the accumulation of MHC-II at the cell surface upon Gpnmb knock-down in Grn -/- macrophages from female mice represent newly synthesized MHC-II complexes or peptide-bound MHC-II; however given that a decrease in Eα peptide-bound MHC-II expression was observed in Grn -/- macrophages from female mice upon Gpnmb knock-down but further research is required to conclusively distinguish between these two possibilities We have observed that the upregulation of GPNMB in Grn -/- mice does not occur in the periphery until 5-to-6 months of age and cannot be observed in 2-to-3-month-old mice (Sup that studies utilizing macrophages will not detect the immunosuppressive effects of Gpnmb in young Grn-deficient mice as Gpnmb becomes upregulated at later ages Future studies will be needed to determine the extent to which strategies to increase GPNMB levels using small molecules or gene therapy may serve to rescue or protect the lysosome from further dysfunction and cap or curtail detrimental chronic inflammatory responses centrally and peripherally The datasets generated and analyzed during the current study are available in the Zenodo repository, https://doi.org/10.5281/zenodo.12773066 National Centralized Repository for Alzheimer’s Disease and Related Dementias a novel protein architecture for a new family of protein growth factors The interaction between progranulin and prosaposin is mediated by granulins and the linker region between saposin B and C Secreted progranulin is a homodimer and is not a component of high density lipoproteins (HDL) Intracellular Proteolysis of Progranulin Generates Stable Lysosomal Granulins that Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by<i>GRN</i>Mutations Highlights on Genomics Applications for Lysosomal Storage Diseases Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17 Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21 Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease Novel exon 1 progranulin gene variant in Alzheimer’s disease A novel progranulin mutation associated with variable clinical presentation and tau Rs5848 variant influences GRN mRNA levels in brain and peripheral mononuclear cells in patients with Alzheimer’s disease Progranulin plasma levels as potential biomarker for the identification of GRN deletion carriers A case with atypical onset as clinical amnestic Mild Cognitive Impairment converted to Alzheimer’s disease Progranulin plasma levels in the diagnosis of frontotemporal dementia Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members Network analysis of the progranulin-deficient mouse brain proteome reveals pathogenic mechanisms shared in human frontotemporal dementia caused by GRN mutations Investigating the role and regulation of GPNMB in progranulin-deficient macrophages Progranulin and GPNMB: interactions in endo-lysosome function and inflammation in neurodegenerative disease Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages The glycoprotein GPNMB is selectively elevated in the substantia nigra of Parkinson’s disease patients and increases after lysosomal stress Lysosomal Dysfunction at the Centre of Parkinson’s Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models Progranulin mutations result in impaired processing of prosaposin and reduced glucocerebrosidase activity Progranulin deficiency leads to reduced glucocerebrosidase activity Gpnmb is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses Glycoprotein Nonmetastatic Melanoma Protein B (GPNMB) Ameliorates the Inflammatory Response in Periodontal Disease Peripheral Innate Immune Activation Correlates With Disease Severity in GRN Haploinsufficiency and neuropathology in progranulin-deficient mice Core features of frontotemporal dementia recapitulated in progranulin knockout mice Genetic ablation of Gpnmb does not alter synuclein-related pathology Monitoring Protein Endocytosis and Recycling Using FACS-Based Assays Revisiting Mouse Peritoneal Macrophages: Heterogeneity Progranulin loss results in sex-dependent dysregulation of the peripheral and central immune system Tumor associated microglia/macrophages utilize GPNMB to promote tumor growth and alter immune cell infiltration in glioma Quantitating MHC class II trafficking in primary dendritic cells using imaging flow cytometry ASO-mediated knockdown or kinase inhibition of G2019S-Lrrk2 modulates lysosomal tubule-associated antigen presentation in macrophages increased mortality and FTLD-TDP-associated neuropathology in progranulin knockout mice Core neuropathological abnormalities in progranulin-deficient mice are penetrant on multiple genetic backgrounds Accelerated Lipofuscinosis and Ubiquitination in Granulin Knockout Mice Suggest a Role for Progranulin in Successful Aging Tubular lysosome morphology and distribution within macrophages depend on the integrity of cytoplasmic microtubules Tubulation of class II MHC compartments is microtubule dependent and involves multiple endolysosomal membrane proteins in primary dendritic cells mTOR controls lysosome tubulation and antigen presentation in macrophages and dendritic cells Systems level analysis of sex-dependent gene expression changes in Parkinson’s disease Sex differences in autophagy-mediated diseases: toward precision medicine Sex Differences in Autophagy Contribute to Female Vulnerability in Alzheimer’s Disease Differences Between Women and Men in Incidence Rates of Dementia and Alzheimer’s Disease The epidemiology of frontotemporal dementia Sex influences clinical phenotype in frontotemporal dementia Bone Marrow-Derived and Elicited Peritoneal Macrophages Are Not Created Equal: The Questions Asked Dictate the Cell Type Used GPNMB confers risk for Parkinson’s disease through interaction with α-synuclein Wallings R. The R1441C-LRRK2 mutation induces myeloid immune cell exhaustion in an age- and sex-dependent manner. 2023; Available from: https://www.biorxiv.org/content/10.1101/2023.10.12.562063v1 Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay Peripheral and central immune system crosstalk in Alzheimer disease — a research prospectus Download references we thank contributors who collected samples used in this study whose help and participation made this work possible We thank members of the Tansey lab for useful discussions and edits of the manuscript We thank Professor Jessica Rexach (Dept of Neurology UCLA) for useful discussions and edits of the manuscript We thank Biogen/Ionis for supplying all GPNMB and control ASOs We thank the UF Interdisciplinary Center for Biotechnology Research (UF | ICBR) for use of flow cytometry facilities and advice Partial funding for this work was derived from a Bright Focus Foundation Post-Doctoral Award (RLW) and a Moonshot Award from the Fixel Institute for Neurological Diseases (RLW) Samples from the National Centralized Repository for Alzheimer’s Disease and Related Dementias (NCRAD) which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA) Samples received from NCRAD were collected under the following funding sources; ALLFTD The ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study receives support through a National Institute of Aging (NIA) and National Institute of Neurological Disorders and Stroke (NINDS) grant U19AG063911 The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) study receives support through a U.S Department of Health and Human Services (DHHS) and the National Institute of Neurological Disorders and Stroke (NINDS)/National Center for Advancing Translational Sciences (NCATS) grant U54NS092089 The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study was made possible through the support of the U.S Department of Health and Human Services (DHHS) and the National Institute on Aging (NIA)/National Institute of Neurological Disorders and Stroke (NINDS) grant U01AG045390 BrightFocus Foundation,National Institute of Neurological Disorders and Stroke,RF1NS128800,Malú Gámez Tansey,Parkinson's Disease Foundation,PF-LAUNCH-1263938,rebecca wallings Center for Translational Research in Neurodegenerative Disease Noelle Neighbarger & Malú Gámez Tansey Project administration and supervision: MGT All authors reviewed and approved the final manuscript This study was reviewed and approved by the University of Florida Institutional Review Board (IRB202101359) All patient samples were obtained from NCRAD (see funding details below) and all participants provided informed consent in their respective cohort studies This study was reviewed and approved by the University of Florida Institutional Animal Care and Use Committee (IACUC202200000114) MGT is a current or recent advisor/consultant for INmune Bio WDH is an employee of Biogen and HK is an employee of Ionis Pharmaceuticals where ASOs are currently under development for neurological indications All other authors hold no competing interests Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations unless otherwise stated in a credit line to the data Download citation DOI: https://doi.org/10.1186/s13024-025-00829-w Susanne Back explains the growing role of antisense oligonucleotides (ASOs) in neuroscience drug discovery and methods for assessing bioavailability in CNS disorders like ALS Associate Director of Central Nervous System (CNS) Pharmacology at Charles River Labs I earned my PhD in Pharmacology from the University of Helsinki in Finland and since then have spent the last 15 years developing and working with preclinical models for neurological illnesses such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS) I lead and oversee preclincal studies for our clients employing in vivo models to assist drug development programs in neuroscience synthetic sequences of single-stranded DNA that alter RNA expression or splicing in the process of translation where genetic code (DNA) is used to produce proteins restore or modify the expression of a protein ASOs are described as a gene therapy as they alter translation but the processes involved in their drug discovery and manfacture are more similar to small molecule drug development There are several reasons why there is increasing interest in ASOs to treat CNS disorders Firstly there are already examples of ASOs that have been approved by the FDA for the treatment of rare diseases 'designed' nature means they can be targeted to a specific RNA transcript related to disease-causing genes This makes them particularly attractive in diseases where there is a strong genetic link and a wide range of rare and ultra-rare diseases When transitioning an ASO program into an in vivo environment the first thing to consider is the amount of evidence supporting the involvement of a target in the disease Strong evidence for ALS often comes from familial forms of the disease where specific gene mutations— for example in the SOD1 or TDP-43 genes —are directly linked to the disease These genetic insights help guide our choice of preclinical models and readouts in the pharmacology phase It is also crucial to prioritize the studies that will move the drug discovery program forward as efficiently as possible ALS is a disease where time is of the essence so we need to focus on studies that help us avoid unnecessary delays pharmacodynamic readouts—whether the ASO leads to degradation how we implement these readouts can differ across programs like bio-distribution and immunostimulatory effects While animal models are critical for understanding disease mechanisms and testing therapeutic approaches they do not always fully mimic the human condition even the best animal models may not capture the entire complexity of the disease as it occurs in patients meaning that results from animal studies do not always predict what we will see in human trials there is a growing interest in human-based in vitro models especially in certain situations where animal models may not be relevant The challenge is balancing these different models to ensure we get the most accurate and predictive data as we advance ASO therapies to reduce failure rates and get life-altering therapies to patients faster One key difference between small molecule drugs and ASOs is that ASOs do not freely cross the blood brain barrier This means they cannot be given systemically for example in a pill format that is taken orally they need to be directly administered into the CNS Clinically the most common way of doing this is intrathecal injection injection into the space around the spinal cord meaning that in studies in animal models we can use the same method as would be used in the clinic in patients.  Other methods of administration are also under investigation for example conjugating an ASO to an antibody to enable transport through the blood brain barrier Disruption of the blood brain barrier with focused ultrasound is also used for gene therapy administration in the clinic and this is something we can use in animal models as well in drug discovery and safety studies.  There are a few established methods for this To measure ASO distribution in CNS tissues we often use tissue dissection followed by techniques like liquid chromatography-mass spectrometry which allow us to quantify ASO levels in different brain regions a repeated microsampling technique used in animal models which can enable measurement of ASO concentrations in plasma and cerebrospinal fluid (CSF) it is important to remember that ASOs act on intracellular targets so measurement of unbound ASOs in these fluids may not be the most accurate technique we can use PET imaging with radio-labeled ASOs to track their distribution in living animals PET imaging also allows for repeated measurement so tracking of distribution and bioavailability over time.  The half-life of ASOs can vary significantly depending on their chemistry and backbone we have seen knockdown effects lasting up to eight weeks after a single intrathecal injection knockdown effects were observed for up to 24 weeks after two injections their therapeutic effects last far longer than small molecules which is highly beneficial to patients.  Susanne Back obtained her PhD in pharmacology from the University of Helsinki where she investigated CNS diseases using rodent models to evaluate novel therapies and biomarkers She then spent three years as a postdoctoral researcher at the National Institute on Drug Abuse developing disease models in rodents and cell-based systems After working in CNS drug discovery at Orion Pharma She now leads a team specializing in preclinical in vivo models and pharmacology supporting drug discovery efforts in CNS and rare diseases At Charles River we are passionate about our role in improving the quality of people’s lives Our dedicated team of preclinical neuroscience CRO scientists want the same thing as you do: to find a cure for the devastating diseases of the central nervous system From basic research to regulatory approval and collaborative approach you need to discover and develop novel therapies.  We understand the challenges and complexities in the search of potential therapies for neurological disorders The combination of our comprehensive neuroscience drug discovery services and expertise supports the creation of customizable innovative and efficient solutions for your research Our team of neuroscientists continues to establish the most relevant in vitro and in vivo models and assays of acute and chronic neurological diseases to help our partners identify and test new compounds in this challenging field Sponsored Content Policy: News-Medical.net publishes articles and related content that may be derived from sources where we have existing commercial relationships provided such content adds value to the core editorial ethos of News-Medical.Net which is to educate and inform site visitors interested in medical research Posted in: Insights from Industry Please use one of the following formats to cite this article in your essay Charles River Labs - Neuroscience Discovery Services Considerations for taking ASO discovery programs into animal models 2025 from https://www.news-medical.net/news/20250224/Considerations-for-taking-ASO-discovery-programs-into-animal-models.aspx "Considerations for taking ASO discovery programs into animal models" <https://www.news-medical.net/news/20250224/Considerations-for-taking-ASO-discovery-programs-into-animal-models.aspx> https://www.news-medical.net/news/20250224/Considerations-for-taking-ASO-discovery-programs-into-animal-models.aspx you can trust me to find commercial scientific answers from News-Medical.net please log into your AZoProfile account first Registered members can chat with Azthena, request quotations, download pdf's, brochures and subscribe to our related newsletter content A few things you need to know before we start Read the full Terms & Conditions Gondolabio partner on therapies for genetic conditions The N-Lorem Foundation has partnered with Gondolabio to discover and advance novel antisense oligonucleotide (ASO) treatment options — medications that can correct genetic abnormalities in people — for nano-rare patients First, the California-based nonprofit will leverage its ASO discovery platform to identify new medicines to treat two genetic diseases with significant unmet needs. N-Lorem will “select ASO medicines to prespecified biological targets,” according to a press release from the new partners will develop any resulting therapies both clinically and commercially “We have been impressed with the vision and pioneering spirit of the Gondolabio team and are looking forward to working with them on these important programs,” said Stanley T ASOs can be designed to address specific genetic mutations, offering a personalized treatment option for people with rare or ultra-rare diseases, such as aromatic L-amino acid decarboxylase (AADC) deficiency In AADC deficiency, genetic mutations disrupt the production and/or function of the AADC enzyme, which is vital for producing several neurotransmitters — molecules that nerve cells use to communicate. A lack of functional AADC results in reduced neurotransmitter levels, ultimately leading to disease symptoms ASOs are small strands of lab-made DNA or RNA tailored to bind to specific messenger RNAs or mRNAs — the intermediate molecules that carry information from the DNA that’s used for protein production A specific ASO can be developed rapidly and inexpensively to target the mRNA of a defective gene to correct the abnormality N-Lorem’s mission is to develop ASOs free of charge for people with extremely rare diseases caused by a single genetic defect N-Lorem has received more than 300 applications for ASO treatment and has approved more than 140 patients we have industrialized the treatment of nano-rare patients and created an organization capable of scaling up to meet a growing demand while maintaining high quality at each step,” Crooke said “The efficiencies of our lab ensure that we can conduct the work in this collaboration in parallel with the ongoing efforts of our mission to help nano-rare patients.” This partnership will combine the category-defining expertise in antisense technology which … N-Lorem [has] developed with Gondolabio’s ability to rapidly and efficiently progress novel therapeutics in genetic diseases a clinical-stage biotechnology company founded in September 2024 The company will use its cutting-edge biological research to clinically and commercially develop N-Lorem’s ASOs “This partnership will combine the category-defining expertise in antisense technology which Stan and N-Lorem have developed with Gondolabio’s ability to rapidly and efficiently progress novel therapeutics in genetic diseases,” said Morgan Paull Gondolabio will give N-Lorem upfront payments and cover research and development expenses The foundation could also receive additional funds for each ASO that’s discovered and developed No specific dollar amounts were shared by the partners Such payments to N-Lorem will help fund the foundation’s other activities to provide ASO treatment to people with extremely rare diseases for free and for life “The funding we receive from these transactions will enable us to broaden our investment in nano-rare patients and create opportunities for sustainable revenues through potential milestone payments and equity as these programs advance,” Crooke said That’s important to Gondolabio as well “It is especially meaningful to us that in addition to the programs we develop together our collaboration will help to fund N-Lorem’s nonprofit mission to treat patients with nano-rare conditions — this is the best kind of win-win,” Paull said This site is strictly a news and information website about the disease This content is not intended to be a substitute for professional medical advice Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition Never disregard professional medical advice or delay in seeking it because of something you have read on this website by Kylon Williams | Isley Gooden | Kaelin Clay (KATV) — The Arkansas Symphony Orchestra is hosting their annual ASO Giving Day the orchestra accepts donations that will allow them to continue bringing live music and music education to the state of Arkansas ASO is able to provide things like their String Academy where students aged 4-12 can take violin and cello lessons It is a program where ASO musician educators take 3rd grade students how to play the violin Those who would like to donate can do so here The relationship between Georgia State University (GSU) and the Atlanta Symphony Orchestra (ASO) continues to grow faculty and alumni unparalleled opportunities to engage with one of the nation’s premier orchestras educational outreach and professional development this partnership fosters artistic excellence and provides invaluable experiences for GSU musicians Spearheaded by GSU faculty member and flute professor Jessica Petrasek the Panthers at the Symphony initiative formalizes an exclusive relationship between GSU and the ASO Newly integrated into the performance syllabus for both undergraduate and graduate music degrees (with optional participation for other music majors) this program provides students with unique access to professional experiences made possible by GSU’s proximity to the ASO is an incredible recruitment tool and highlights the university’s direct access to world-class symphonic music clarinet student Jadyn Green conceived the name Panthers at the Symphony adding a student-driven touch to this exciting new program with the graduate orchestral conducting studio sitting down with Spano to discuss Rite of Spring further integrating GSU’s presence into ASO’s educational initiatives GSU alumnus and Grammy-nominated composer Carlos Simon frequently collaborates with the ASO Recent highlights include the orchestra’s performances of his works Fate Now Conquers and brea(d)th the latter of which was commissioned and premiered by the ASO whose music explores social justice and historical narratives with the ASO playing a key role in bringing his compositions to the concert stage The future is bright for this thriving partnership and we look forward to the incredible opportunities still to come Filed Under: Academic Unit News Mary Beth Corbett (J.D. ‘25): Tech + Teaching = Tax Law M.F.A. Film Candidate Deena Ramadan is Set to Embark on Creative Filmmaking Journey with Open Options CEHD Celebrates Student Achievement, Donor Impact at Annual Luncheon Bliss Honored for Outstanding Contribution to Clinical Legal Education Robinson's Take: Will Tariffs Ground Your Vacation? Trade War Uncertainty Hits Travel Plans Falling tree limbs in Birmingham kills one person the Alabama Symphony Orchestra will perform with Mariachi Cobre at the BJCC For ticket information visit alabamasymphony.org Themed around the "Genesis de L’Afrique," or "The Beginning of Africa," the show featured creative contemporary pieces consisting of distinct textiles and designs By - April 28 The African Student Organization hosted its annual fashion show in the Mandela Room this past Friday Themed “Threads of the Motherland: Genesis de L’Afrique,” which translates to “The Beginning of Africa,” the show honored centuries of African culture and fashion the organization’s educational coordinator and a sophomore majoring in philosophy shared the event’s significance to the African community at Binghamton University “The theme of the show is a tribute to not only the African continent but the African Diaspora who attend Binghamton,” Mwambwa wrote “A reminder that everything started from Africa and even something as modern [as] fashion shows can find its roots in African culture.” The show was separated into five scenes with distinct themes and feels — “Abstract Art,” “Jewels of Africa,” “A Night in Cairo,” “Detty December” and “ASO To The Wiase.” The scenes featured short performances with choreography and acting “ASO has different committees of E-board and Interns hard working together to put different parts of the show together,” Larry Ayiku ASO’s activities coordinator and a senior majoring in biology helping create walks for the models and making sure things are as good as they can be Our Threads of the Motherland fashion show is one of our biggest events every year so a lot of work goes into making sure every detail colorful light fixtures hung over the huge stage at the front of the venue Pieces of African art hung on the walls along with a photo backdrop featuring patterned and gold fabric music filled the room as the models took the stage “Abstract Art,” was inspired by the idea “a picture is worth a thousand words” — indicating how communicating through the art of clothing is a focal point of fashion lace and glitter mermaid gowns representing the many creative ways African culture shines setting the tone for the rest of the night a masculine-presenting and a feminine-presenting model took the stage together One of the models wore an intricately designed orange gown with a train Before the models came out for the next scene African Sounds of Healing put on a drum performance rhythmic Afro-Cuban melody divided into three sets to prelude “Jewels of Africa” as the impassioned beats of their drums pulsed through the room “Each scene we’ve put together represents a different part of African culture allowing our models to express different aspects of heritage and culture,” Ayiku wrote “We hope that as audience members are watching models walk “Jewels of Africa” featured jewel-toned deep purples greens and blues as models took to the runway One wore an electric blue satin outfit with a cape and jeweled collar and design on its front Another scene featured a pair walking down the runway the second theme focused on the clothing’s intricate stitching and artwork Owusu-Boamah explained that the scene aimed to honor Africa’s rich history through textiles with cultural significance “A Night in Cairo,” was a tribute to timeless fashion Models wore flowing floor-length gowns in shades of greens Runway walks for this scene were predominantly performed by models taking the stage by themselves The scene honored Egyptian culture and nodded to its traditional forms of dress the organization’s E-Board and interns were recognized for their contributions to the annual show the Binghamton Bhangra dance team performed bhangra Intermission was followed by “Detty December,” which highlighted Africa’s nightlife Three models wearing red and black outfits kicked the scene off “Detty December” showcased the diverse aspects of African culture and fashion One set included models in denim skirts and baby tees paired with black boots and heels Each model wore a rhinestone-embedded belt and some complemented it with tights to tie their look together Another set included a single model wearing a casual relaxed outfit featuring jeans and a white T-shirt paired with a colorful The final scene was titled “ASO to the Wiase.” “Wiase,” which translates to “world,” featured scenes futuristic in nature performing a choreographed “fight.” One model wore long while the other donned a gray fitted sweatsuit pointing to the fact that African culture and style are constantly evolving the show embraced many different styles of African culture and its continued legacy in shaping contemporary art “This theme serves as both a tribute and a journey celebrating Africa’s roots and the foundation from which its many cultures and innovations have risen from,” Ayiku wrote invites the audience to travel through time and enjoyment that have shaped the continent while also embracing the modern expressions that continue to redefine what it means to be African today.” New Role Highlights Pager Health's Supportive Partnership with Health Plans to Provide Scalable and Efficient Digitally Enabled Member Advocacy Solutions NEW YORK, April 28, 2025 /PRNewswire/ -- Pager HealthSM a connected health platform company serving more than 26 million members a seasoned healthcare executive and high-impact sales leader has been named Vice President of Health Plan Partnerships and Growth Her appointment is the first of many milestones in Pager Health's broader strategy to drive Administrative Services Only (ASO) profitability and market share for health plan partners Kirchner comes to Pager Health from Accolade where she served as Vice President of Partnerships leading the company's development of innovative distribution channels and alternate paths to revenue growth Kirchner leveraged multiple Accolade capabilities to develop several groundbreaking partnerships that drove revenue in embedded book-of-business solutions and expanded ASO membership retention and growth During her time as Senior Director of strategic contracting at BioTelemetry the company achieved $450 million in sales before being acquired by Philips' Connected Care business segment in 2021 Her more than two decades as a healthcare executive also include leadership roles in management and business development at Walgreens and Aetna Kirchner will lead Pager Health's ASO channel development initiative to support health plans seeking to grow and retain their ASO line of business Unlike other connected health platforms that compete directly with health plans for employer business in the ASO market Pager Health exclusively partners with health plans to enhance ASO services for self-insured employer groups through digital transformation "Jill is a dynamic leader with a proven track record of business development and revenue growth," said Walter Jin "Her appointment strengthens our ASO initiative adding new executive expertise that further enhances Pager Health's unique role as a partner who is always fully aligned with health plans as they expand their ASO business HIPAA-compliant approach ensures smooth integration to our solutions with minimal IT effort and no need for a full-system overhaul we are the ideal partner for health plans challenged by tech debt the accumulated cost and inefficiencies resulting from suboptimal technology solutions that may hinder their system scalability A Next-Generation Approach to ASO GrowthPager Health is redefining how health plans support members by providing purpose-built and digitally led member advocacy solutions that are white-labeled and embedded enabling health plans to retain their brand integrity and support the full member experience The company's solutions work behind the scenes with each health plan's existing systems to create a seamless member journey self-service and concierge-level care experiences that guide members to their personalized next best action By leveraging Pager Health's integration of AI-based member advocacy services with always-available human support differentiating their ASO offerings and attracting more employers to their services "Pager Health brings a new level of scalability and efficiency to the ASO market by offering the next generation of digitally enabled member advocacy solutions that fully leverage AI yet still provide access to human support throughout the entire member experience," said Kirchner "And because Pager Health offers a fully white-labeled member experience health plans that partner with us preserve their brand integrity while benefiting from an expanded and differentiated product suite I'm eager to share our unique ASO story with health plans." About Pager HealthPager Health is a connected health platform company that enables healthcare enterprises to deliver high-engagement intelligent health experiences for their patients members and teams through integrated technology Our solutions help people get the right care at the right time in the right place and stay healthy while simultaneously reducing system friction and fragmentation providers and employers representing more than 26 million individuals across the United States and Latin America Health Care & Hospitals Computer & Electronics Personnel Announcements Do not sell or share my personal information: In his first of two weeks of concerts this season with the Atlanta Symphony Orchestra music director laureate Robert Spano led the orchestra in a program featuring American and British works by Aaron Copland and Ralph Vaughan Williams at Symphony Hall on Thursday evening who was the ASO’s music director for 20 years became music director of the Fort Worth Symphony Orchestra in the summer of 2022 and has since added several additional titles to his resume: He was appointed music director of the Washington National Opera early last year and as music director designate led an acclaimed performance of Beethoven’s Fidelio with the company in the fall; his three-year term begins with the upcoming 2025-26 season He was also appointed as principal conductor of the Rhode Island Philharmonic and Music School in 2024 for one season and will continue as principal guest conductor with them this fall Spano also continues his role as music director of the Aspen Music Festival and School Thursday night’s concert opened with one of the most celebrated works in American classical music Originally composed for a chamber orchestra of 13 as a ballet for Martha Graham the orchestral suite distills the score’s essence into a concert form for the larger ensemble this performance began with a little feeling of uncertainty although Spano brought it quickly in line and ensured a sense of balance drawing a lean American sound from the orchestra the interpretation felt restrained and struggled to capture the full spark and vitality of its dance origins Moments that should have sparkled with energy and lift came across as earthbound; although individual moments of warmth and clarity emerged the overall reading never fully ignited as it ought The performance took a stronger turn with Jennifer Higdon’s Harp Concerto featuring the ASO’s longtime principal harpist who took an unusual stage position for a soloist to Spano’s right Although it is admittedly not my favorite Higdon composition the Harp Concerto is a work that exemplifies her skillful orchestration and natural affinity for instrumental color scored in a manner that ensures the solo instrument remains central rather than being overwhelmed by the ensemble and highlights the harp’s expressive range Johnson navigated her solo part with authority and elegance the first two movements were not the most captivating or adventurous of the bunch arguably the most compelling section of the concerto played to the harp’s strengths by incorporating dialogues with small instrumental groups Debussy-like transparency of chamber music With its colorful percussion and rhythmic vitality the final movement built to a grand conclusion Johnson and Spano maintained a strong rapport throughout The highlight of the evening was Vaughan Williams’ Symphony No a work that stands in stark contrast to the composer’s turbulent Fourth Symphony we finally experienced Spano at his best with the ASO whose affinity for this repertoire is well established delivered a reading that balanced the symphony’s dreamlike lyricism with a clear structural vision which can easily become dense and murky in the wrong hands remained luminous and transparent under his direction even as the ASO responded with remarkable warmth and cohesion With its rhythmic interplay and shifting harmonic colors the second movement retained a buoyant energy without becoming weighty one of the symphony’s most poignant movements the woodwinds and strings wove a seamless tapestry of sound The final “Passacaglia” unfolded with unhurried inevitability leading to a radiant conclusion that felt both expansive and intimate in its final moments Spano and the ASO musicians delivered an utterly exquisite performance bringing the evening to a satisfying close And one great additional note: the American String Teachers Association (ASTA) has been holding its “National Orchestra Festival 2025” this week down at the Hyatt Recency Hotel (March 19-22) and a large number of middle school and high school string players who came with their school orchestras from around the country for the festival were present at Symphony Hall on Thursday for the concert It’s absolutely fabulous that they got to hear it The final performance of this program takes place tonight at Symphony Hall (March 22) Spano returns to the ASO podium next week to lead a concert of music by Sibelius winner of the 2021 Busoni International Piano Competition 2025 (GLOBE NEWSWIRE) -- BBB National Programs’ National Advertising Division has referred ASO LLC to the Federal Trade Commission (FTC) and Food & Drug Administration (FDA) for failing to comply with its decision regarding advertising claims for its Hydrocolloid Gel Bandages (JJCI) challenged ASO’s claims that its Hydrocolloid Gel Bandages provide “2x faster healing.” NAD found that the “2x faster healing” claim was not supported and recommended its discontinuation ASO agreed to comply with NAD’s recommendations NAD initiated a compliance proceeding at the behest of JJCI based on their concerns about ASO’s compliance ASO indicated that it would remove the claims from its packaging “upon depletion of current inventories” and that it had limited control over third-party retailer compliance NAD found that while ASO had taken some steps to remove the “up to 2x faster healing” claim from online advertising noncompliant claims persisted on product packaging and third-party retail websites and it made the following recommendations based on its review: ASO refused to comply with NAD’s recommendations NAD has referred the matter to the appropriate government agencies and platforms where the advertising claims appear and with which NAD has a reporting relationship This press release shall not be used for advertising or promotional purposes About BBB National Programs: BBB National Programs currently operating more than a dozen globally recognized programs that have been helping enhance consumer trust in business for more than 50 years These programs provide third-party accountability and dispute resolution services that address existing and emerging industry issues create a fairer playing field for businesses BBB National Programs continues to evolve its work and grow its impact by providing business guidance and fostering best practices in arenas such as advertising About the National Advertising Division: The National Advertising Division of BBB National Programs provides independent self-regulation and dispute resolution services guiding the truthfulness of advertising across the U.S The National Advertising Division reviews national advertising in all media and its decisions set consistent standards for advertising truth and accuracy delivering meaningful protection to consumers and leveling the playing field for business – Today an Alachua County Jury awarded over $15 million to Alachua County Sheriff’s Deputy Kevin Davis who filed a lawsuit alleging that he was denied promotions due to racial discrimination and was retaliated against after he filed discrimination complaints the jury found that Davis had been denied a promotion and that the denial was based on race; they also found that the Sheriff would not have denied Davis a promotion if race had not been a factor in the promotion decision The jury found that Davis had engaged in protected activity by filing discrimination complaints and that the Sheriff took adverse employment action against him; they also found that the Sheriff would not have taken those adverse employment actions if race were not a factor The jury awarded $115,724 in damages to compensate for loss of wages and benefits plus $15 million for emotional pain and mental anguish “The jury spoke – and they said that when you make decisions based on race and you retaliate against the one person who stood up against your disgusting behavior you will be held accountable.”Regarding the amount of the award “We asked the jury to follow the law and compensate Kevin Davis up to $8 million The verdict shows that the jury believed Kevin Davis’ mental anguish was worth even more than that.” and we will update this as we receive additional information Complaint alleged racial discrimination in promotion process Davis described the promotion process at ASO: eligible employees may take a promotional exam and must achieve a minimum score to be placed on the eligibility list; the top candidates are given an opportunity to interview with either the Sheriff or Undersheriff; and the Sheriff or his designee makes the final decision based on relevant experience Davis claimed that after Sheriff Clovis Watson took office in January 2021 he and other Caucasian employees were “continuously passed over for promotion and transfer because of their race” and at the time the complaint was filed he had been third on the promotion list for lieutenant for 17 months Davis stated that he filed an internal complaint about racially-based discrimination in promotions at ASO but said he received no response Davis filed charges of discrimination with the U.S Equal Employment Opportunity Commission (EEOC) and the Florida Commission on Human Relations (FCHR) in February 2022 and received a Notice of Determination from FCHR in October and a Notice of Suit Rights from the EEOC in January 2023 that give him the right to sue A third charge of discrimination was filed in March 2024 with the EEOC and that charge is pending within the EEOC administrative process Davis provided several examples of minority candidates being “promoted or otherwise selected over a Caucasian candidate with the deciding factor being race.” One example was a black male who was ranked fifth on the Sergeant’s promotional list and was selected over four non-minority candidates and given a position that is highly unusual for newly-promoted Sergeants Another black male was named as “acting” lieutenant in spite of not being one of the top five candidates and not being eligible for promotion to lieutenant at the time Another black male was promoted to lieutenant over eligible non-minority candidates although he was not in the top five of the lieutenant promotional list A black female was hired in spite of a “known criminal history and numerous racially motivated social media posts.” Davis stated in the complaint that Watson required photos to be submitted with the paperwork for promotions and special assignments and that the photo “serves no other purpose than to confirm the race of the employee.” Davis submitted a complaint to Human Resources in August 2022 when a black male who was eighth on the promotion list was promoted to lieutenant over him two white males were promoted to lieutenant and Davis claimed that this was an act of retaliation and “an effort to conceal discriminatory intent” because both had lower test scores and less supervisory experience than Davis Thank you democrats for helping to get this incompetent idiot elected as our previous sheriff Emery Gainey did so much more in his short time in office Gainesville voters voted for Scott because he had a D after his name It’s just a matter of time that he too will be exposed I threw my vote at Scott because he had good white people smiling and waving his signs at the polls Better choice than GOP shoe shiner Uncle Emery Charlie Grapsky probably has an ear to ear grin over this Automatic voting for Dems will NEVER change in AC The Dems control the county and always will until someone steps up and really puts enough data out to convince independent voters to join with Repubs to vote out the Dem local career office holders (county biased AC county will continue to vote Dem and School Board with Alachua County voters Emery Gainey didn’t promote Kevin Davis either Sniff poor Clovie cried and wasted a Kleenex while his oversize ego got “impuned.” County should not have to pay the $15 million Judge should order Clovis to sell his large Faberge egg collection to pay off the $15 million Unfortunately the county and its idiot voters do need to pay it Perhaps we could create a Democrat only surtax for it these morons voted in Clovis over Sadie to make themselves feel better about Fentanyl Floyd’s untimely overdose Can’t people just work together to do good instead of all the name calling In this case it is on point to note that the Democratic operatives closed the primary and elected Clovis over Sadie without one Republican vote on the matter This fiasco is 100% the fault of the Alachua County Democratic Party Dem/Rep is apparently the dividing line between insane and sane And the insane/stupid people always insist on trying to boss everyone else around Doing good is permanently expelling them from public office hopefully for the remainder of their lives You can thank BLM and the ghost of George F Thanks for exposing this democrat corruption Sadly ppl vote for party/politics over merit in this county Bet he never expected to be the first 8 figure employee of the County Equally confident the liberal voters didn’t expect to have to fork over $15,000,000 of their tax dollars for their elected racist Sheriff either worked with him over 20 years ago when he returned to the jail after a civilian stint ASO could use a few solid supervisors to tighten things up this decision does nothing to reverse the DEI promotions currently enjoying someone more qualified’s paychecks Esp if people kept documentation and proof Remember..the person running the Clovis campaign used the prevailing law to get a nobody write-in candidate thereby closing the election NO REPUBLICANS got to vote in the election that put Clovis in office Republicans at the state level REFUSE to make any effort to change the law Maybe it will come out why his campaign headquarters burned to the ground after the election? Oh and where the missing million dollar check went frome the city of Alachua Time for an investigation into GPD’s decades of racial and gender discrimination in hiring and promotional practices Would make a good investigative journalism piece for the AC instead of copypasta press releases Our statement on investigative reporting from three years ago – and it still applies: https://alachuachronicle.com/if-you-want-more-investigative-work-we-need-your-support/ I found it funny how the City of Alachua made up a Captain position for Chad out of nowhere The entire senior staff including the director of planning have all resigned over the last couple weeks People have ZERO idea on the racial discrimination and promotions that happened under Tony Jones Until all the boxes are removed from employment applications https://www.gnvinfo.com/alachua-sheriff-clovis-watson-jr-resigns-leaving-behind-legacy-of-corruption/ It seems like the direct perpetrator of the discrimination should foot the bill Good for Kevin for standing up against the machine if we’re being real about racial profiling you would need to look no further than the jury box It would be fun to watch an inquiry into Gainesville Fire Rescue’s promotional behavior in this regard there should be zero discrimination against any race Merit is the only way to select for quality employees I see DEI just going thru a fast food drive thru and the rude treatment there For those who came in late: Other than women pump up that ego) and collect campaign donations from Big Sugar (money) cuz sugar cane is a big Alachua County crop In 2006 when Clovis was getting ready to enter politics he thought the upcoming Tea Party Republican movement was the wave of his future and stood on the courthouse steps Few years later he came slinking back to being a Dem once someone explained reality to him: how it hard it is to win an election in blue Alachua County if he was a Republican https://www.gainesville.com/story/news/2006/06/29/alachuas-watson-switches-parties-blasts-democrats/31488103007/ The racist proclivity of the Democrat Sheriff is funded to the tune of 15 million bucks by the taxpayers of Alachua County Whatever happened to not being judged by the color of your skin How bout that so called ‘content of character’ MLK was both an adulterer and a philanderer is this considered a crime by Clovis while he was in public office and is he looking at any jail time for it and will he have to pay some of that jury award because of HIS personal malfeasance Most jurisdictions have an immunity law that protects elected officials from lawsuits for actions performed “in the line of duty” a darling of the County’s brainwashed Left voters To some of you legal eagles out there- just exactly how will this be paid I’m really hoping this won’t be like many lawsuits where the plaintiff only recovers a fraction of the money owed them Davis has to do is say “I’m a “friend” of Celebration Pointe(nudge nudge wink wink)” and the county manager will write him a $15M check Monday and hand deliver it Is it true that Sheriff Watson gave 150 promotions to his employees: 120 were white and 30 were Black we don’t have reporters who can sit in a courtroom all day for a full week It’s just me and a part-time freelancer who covers the High Springs and Newberry governments Understood – my comment isn’t directed as much to AC as to media in general I read the data point in a one sentence “by the way” graph in an article but haven’t seen any details since I think detailing the facts is more helpful than not The problem with a trial is that you have to actually be there – the details aren’t in any documents few local outlets have the resources these days to send a reporter to sit in a courtroom for a whole week WUFT and The Alligator can sometimes send students you’re probably getting a different reporter every day but then I wouldn’t have been able to publish anything else the whole week Clovis Watson has a long and perverted history of getting away with physical and emotional terrorism Charles Grapski has waited far too long to see Watson experience the sting of justice for Grapski’s dear-death jail experience plus physical abuse by the City of Alachua Police while Watson was chief The video recordings of these events still exist as evidence Alachua is such a caring place for down and out creatures First there was the Retirment Home for Horses Now there is a brand new Retirement Home for Clovis https://alachuachronicle.com/pig-sanctuarys-mission-is-to-help-abandoned-surrendered-or-neglected-pigs/ Remember that 20 year road improvement plan that pretty much only included roads inside the Gainesville city limits the AC BOCC touted as a big step in support of ALL taxpayers in AC Road repair/improvement will be the 1st line item slashed by the Democratic (tax evading) AC BOCC and their General Contractor bought and paid for County Manager Oh no it’s only what blacks have dealt with since forever That’s quite a low IQ take of the incident you have there Take the judgement from Clovis’ retirement.If they did not rig the last election we would have had a good sheriff in town the Honorable Sheriff “Heriff” Gainey <#= ThriveComments.util.render_label('login_submit_comment') #> <#= ThriveComments.util.render_label('commenting_as',ThriveComments.current_user.display_name || ( ThriveComments.social_user && ThriveComments.social_user.name ) ) #> <#= ThriveComments.util.render_label('guest_comment') #> Huntington disease (HD) is a progressive and fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT) use an antisense oligonucleotide (ASO) to silence MSH3 a DNA mismatch repair protein that drives CAG repeat expansion suggesting a potential approach to address HD pathogenesis Prices may be subject to local taxes which are calculated during checkout doi: https://doi.org/10.1038/d41573-025-00042-w Antisense oligonucleotide–mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington’s disease iPSC–derived striatal neurons Download references POST-DOCTORAL RESEARCH FELLOW Post Summary of the role The Characterisation & Processing of Advanced Materials HT is an interdisciplinary research institute created and supported by the Italian government whose aim is to develop innovative strategies to pr.. UNIL is a leading international teaching and research institution with over 5,000 employees and 17,000 students split between its Dorigny campus Department of Energy and Environmental Materials and advance cancer research in a leading translational institute Olivia Newton-John Cancer Research Institute Sign up for the Nature Briefing newsletter — what matters in science Please enable JS and disable any ad blocker Academy Sports and Outdoors (Nasdaq: ASO) has announced its participation in the upcoming J.P Morgan Retail Roundup Conference in New York from April 2-3 CEO Steve Lawrence and CFO Carl Ford will engage in a fireside chat on April 2 The event will be accessible through a live webcast with a 30-day replay available on the company's investor relations website at investors.academy.com established in 1938 as a family business in Texas has expanded to over 300 stores across 21 states and footwear categories through national and private label brands Academy Sports and Outdoors (Nasdaq: ASO) ha annunciato la sua partecipazione alla prossima J.P Morgan Retail Roundup Conference che si terrà a New York dal 2 al 3 aprile 2025 Il CEO Steve Lawrence e il CFO Carl Ford parteciperanno a una conversazione informale il 2 aprile 2025 L'evento sarà accessibile tramite una diretta web con una riproduzione disponibile per 30 giorni sul sito web delle relazioni con gli investitori dell'azienda all'indirizzo investors.academy.com fondata nel 1938 come azienda familiare in Texas si è espansa a oltre 300 negozi in 21 stati e calzature attraverso marchi nazionali e privati Academy Sports and Outdoors (Nasdaq: ASO) ha anunciado su participación en la próxima J.P Morgan Retail Roundup Conference en Nueva York del 2 al 3 de abril de 2025 El CEO Steve Lawrence y el CFO Carl Ford participarán en una charla informal el 2 de abril de 2025 El evento será accesible a través de una transmisión en vivo con una repetición disponible durante 30 días en el sitio web de relaciones con inversores de la compañía en investors.academy.com establecida en 1938 como un negocio familiar en Texas se ha expandido a más de 300 tiendas en 21 estados y calzado a través de marcas nacionales y privadas Academy Sports and Outdoors (Nasdaq: ASO)는 2025년 4월 2일부터 3일까지 뉴욕에서 열리는 J.P Morgan Retail Roundup Conference에 참여한다고 발표했습니다 CEO 스티브 로렌스와 CFO 칼 포드는 2025년 4월 2일 오전 8시 동부 표준시 기준으로 대화형 세션에 참여할 예정입니다 회사의 투자자 관계 웹사이트인 investors.academy.com에서 30일 동안 재생할 수 있습니다 1938년 텍사스에서 가족 사업으로 설립된 Academy는 21개 주에 걸쳐 300개 이상의 매장으로 확장되었으며 신발 카테고리에 중점을 두고 국가 및 개인 브랜드를 통해 사업을 운영하고 있습니다 Academy Sports and Outdoors (Nasdaq: ASO) a annoncé sa participation à la prochaine J.P Morgan Retail Roundup Conference qui se tiendra à New York du 2 au 3 avril 2025 Le PDG Steve Lawrence et le directeur financier Carl Ford participeront à une discussion informelle le 2 avril 2025 à 8h00 L'événement sera accessible via un webinaire en direct avec une rediffusion disponible pendant 30 jours sur le site web des relations avec les investisseurs de l'entreprise à l'adresse investors.academy.com fondée en 1938 en tant qu'entreprise familiale au Texas s'est étendue à plus de 300 magasins dans 21 États en se concentrant sur les catégories de plein air ainsi que de chaussures à travers des marques nationales et de distributeurs Academy Sports and Outdoors (Nasdaq: ASO) hat seine Teilnahme an der bevorstehenden J.P Morgan Retail Roundup Conference in New York vom 2 CEO Steve Lawrence und CFO Carl Ford werden am 2 April 2025 um 8:00 Uhr Eastern Time an einem informellen Gespräch teilnehmen Die Veranstaltung wird über einen Live-Stream zugänglich sein die auf der Investor-Relations-Website des Unternehmens unter investors.academy.com verfügbar ist 1938 als Familienunternehmen in Texas gegründet hat sich auf über 300 Geschäfte in 21 Bundesstaaten ausgeweitet und konzentriert sich auf die Kategorien Outdoor Sport & Freizeit sowie Schuhe durch nationale und private Marken A live and replay webcast (for 30 days) of the fireside chat, will be made available on the Company's investor relations website at investors.academy.com Media inquiries: Meredith Klein, Vice President of Communications346.823.6615meredith.klein@academy.com Investor inquiries:Dan Aldridge, Vice President of Investor Relations832.739.4102dan.aldridge@academy.com  View original content to download multimedia:https://www.prnewswire.com/news-releases/academy-sports--outdoors-announces-participation-in-upcoming-investor-conference-302413343.html Already have an account? Login Metrics details A novel application of antisense oligonucleotide (ASO) technology adds to the growing number of ‘personalized’ therapies for rare diseases; but pathways to implementation and access are urgently needed Ziegler, A. Nat. Med. https://doi.org/10.1038/s41591-024-03197-y (2024) Download references The work by the authors is being supported by the European Rare Disease Research Alliance (ERDERA) program of the European Union Heidelberg University Hospital and Faculty of Medicine Center for Neurology and Hertie Institute for Clinical Brain Research German Center of Neurodegenerative Diseases (DZNE) Centre for Rare Diseases and Institute for Medical Genetics and Applied Genomics are members of the scientific advisory committee of N1C which has patents on exon-skipping technology some of which has been licensed to BioMarin and subsequently sublicensed to Sarepta further discloses serving as ad hoc consultant for PTC Therapeutics also performed ad hoc consulting for Alpha Anomeric also reports membership of the scientific advisory boards of Eisai was also a scientific advisory board member for ProQR Remuneration for A.A.R.’s consulting and advising activities is paid to LUMC LUMC also received speaker honoraria from PTC Therapeutics Italfarmaco and Pfizer and funding for contract research from Sapreme Project funding is received from Sarepta Therapeutics and Entrada via unrestricted grants has nothing to disclose in relation to the topics covered in this manuscript he has also received consultancy honoraria from UCB She has received speaker and/or consultancy honoraria or sponsoring contributions from Abbvie Reprints and permissions Download citation DOI: https://doi.org/10.1038/s41591-024-03217-x This website is using a security service to protect itself from online attacks The action you just performed triggered the security solution There are several actions that could trigger this block including submitting a certain word or phrase You can email the site owner to let them know you were blocked Please include what you were doing when this page came up and the Cloudflare Ray ID found at the bottom of this page.