Biology subjects

Abel, B.

Publications and source records attributed to Abel, B..

6 recordsLinked to original sources

bioRxiv2026

Adrenomedullin Restores Mitochondrial Bioenergetics and Rescues Interneuron Phenotypes in Human Models of 22q11.2 Deletion Syndrome

22q11.2 deletion syndrome (22q11.2DS), also known as DiGeorge syndrome, is the strongest genetic risk factor for schizophrenia, yet the cellular mechanisms underlying this vulnerability remain incompletely understood. Using iPSC-derived human subpallial organoids (hSOs) and forebrain assembloids (hFAs), we identified key 22q11.2DS cellular and molecular phenotypes in migrating cortical interneurons and rescued them with Adrenomedullin (ADM), a 52-amino-acid peptide hormone that acts through the CLR/RAMP2 receptor complex. Specifically, we discover that 22q11.2DS interneurons exhibit impaired migration patterns, and that this is associated with excessive mitochondrial fragmentation, reduced oxidative phosphorylation, and dysregulated calcium signaling. Transcriptomic analysis reveals a glycolytic shift and widespread downregulation of oxidative phosphorylation genes. Next, we identify ADM as a potent rescue agent that restores mitochondrial morphology, membrane potential, respiration, calcium homeostasis, actin retrograde flow, and interneuron migration. Mechanistically, we find that ADM signals through two parallel pathways: PKA-mediated DRP1 Ser637 phosphorylation, which promotes mitochondrial fusion, and PLC-mediated calcium signaling, which normalizes actin dynamics. These phenotypes and their rescue are recapitulated in primary developing human cortical tissue carrying the 22q11.2 deletion. Overall, our study establishes a mitochondrial-cytoskeletal axis as a novel biological mechanism underlying the alterations observed in neuronal development in human preclinical models of 22q11.2DS and identifies possible therapeutic molecular targets for 22q11.2DS-associated neuropsychiatric pathology. HIGHLIGHTSO_LIInhibitory neurons in 22q11.2DS organoids and assembloids show mitochondrial fragmentation and impaired migration C_LIO_LIADM rescues mitochondrial morphology, respiration, and interneuron migration C_LIO_LIPKA and PLC pathways mediate separate arms of ADMs rescue mechanism C_LIO_LIPhenotypes and ADM rescue are validated in human cortical tissue C_LI

neuroscience↗

bioRxiv2025

Cell Type-Specific Effects of miR-21 Loss Attenuate Tumor Progression in MYC-Driven Prostate Cancer

Aberrant microRNA expression is common in cancer, yet cell-type-specific microRNA activity in the tumor microenvironment (TME) remains poorly understood. Here, we show that germline deletion of miR-21 significantly attenuated the progression of MYC-driven prostate cancer (PCa), reducing prostate weight, tumor burden, and proliferation index in Hi-Myc mice. In situ hybridization revealed elevated miR-21 expression in multiple cell types during disease progression. Inflammatory and premalignant lesions in mouse and human prostate showed increased miR-21 in both stroma and epithelium, with further enrichment in the stroma of invasive adenocarcinoma. In Hi-Myc mice, single cell RNA-sequencing revealed miR-21 gene regulation in neoplastic, stromal, and immune cells in a cell-type-specific manner, impacting both direct and indirect targets. Notably, miR-21 deletion reduced immune infiltration into the prostate TME, particularly Trem2-expressing macrophages and regulatory T cells. The Timp1-fibroblast gene signature in MYC-driven PCa was suppressed in miR-21 knockout prostates. Cell-cell communication analysis showed that miR-21 suppressed TGF-beta signaling in the TME, partially through Ski and Smad7 suppression in cancer-associated fibroblasts. These findings underscore the crucial role of miR-21 in PCa and provide some of the first in situ insights into cell-type-specific miRNA activity in solid tumors.

cancer biology↗

bioRxiv2022

Lipid Oxidation Controls Peptide Self-Assembly near Membranes

The self-assembly of peptides into supramolecular fibril structures has been linked to neurodegenerative diseases such as Alzheimers disease but has also been observed in functional roles. Peptides are physiologically exposed to crowded environments of biomacromolecules, and particularly membrane lipids, within a cellular milieu. Previous research has shown that membranes can both accelerate and inhibit peptide self-assembly. Here, we studied the impact of biomimetic membranes that mimic cellular oxidative stress and compared this to mammalian and bacterial membranes. Using molecular dynamics simulations and experiments, we propose a model that explains how changes in peptide-membrane binding, electrostatics, and peptide secondary structure stabilization determine the nature of peptide self-assembly. We explored the influence of zwitterionic (POPC), anionic (POPG) and oxidized (PazePC) phospholipids, as well as cholesterol, and mixtures thereof, on the self-assembly kinetics of the amyloid {beta} (1-40) peptide (A{beta}40), linked to Alzheimers disease, and the amyloid-forming antimicrobial peptide uperin 3.5 (U3.5). We show that the presence of an oxidized lipid had similar effects on peptide self-assembly as the bacterial mimetic membrane. While A{beta}40 fibril formation was accelerated, U3.5 aggregation was inhibited by the same lipids at the same peptide-to-lipid ratio. We attribute these findings and peptide-specific effects to differences in peptide-membrane adsorption with U3.5 being more strongly bound to the membrane surface and stabilized in an -helical conformation compared to A{beta}40. Different peptide-to-lipid ratios resulted in different effects. Molecular dynamics simulations provided detailed mechanistic insights into the peptide-lipid interactions and secondary structure stability. We found that electrostatic interactions are a primary driving force for peptide-membrane interaction, enabling us to propose a model for predictions how cellular changes might impact peptide self-assembly in vivo, and potentially impact related diseases.

biophysics↗

bioRxiv2021

Minimal cross-over between mutations associated with Omicron variant of SARS-CoV-2 and CD8+ T cell epitopes identified in COVID-19 convalescent individuals

There is a growing concern that ongoing evolution of SARS-CoV-2 could lead to variants of concern (VOC) that are capable of avoiding some or all of the multi-faceted immune response generated by both prior infection or vaccination, with the recently described B.1.1.529 (Omicron) VOC being of particular interest. Peripheral blood mononuclear cell samples from PCR-confirmed, recovered COVID-19 convalescent patients (n=30) infected with SARS-CoV-2 in the United States collected in April and May 2020 who possessed at least one or more of six different HLA haplotypes were selected for examination of their anti-SARS-CoV-2 CD8+ T-cell responses using a multiplexed peptide-MHC tetramer staining approach. This analysis examined if the previously identified viral epitopes targeted by CD8+ T-cells in these individuals (n=52 distinct epitopes) are mutated in the newly described Omicron VOC (n=50 mutations). Within this population, only one low-prevalence epitope from the Spike protein restricted to two HLA alleles and found in 2/30 (7%) individuals contained a single amino acid change associated with the Omicron VOC. These data suggest that virtually all individuals with existing anti-SARS-CoV-2 CD8+ T-cell responses should recognize the Omicron VOC, and that SARS-CoV-2 has not evolved extensive T-cell escape mutations at this time. ImportanceThe newly identified Omicron variant of concern contains more mutations than any of the previous variants described to date. In addition, many of the mutations associated with the Omicron variant are found in areas that are likely bound by neutralizing antibodies, suggesting that the first line of immunological defense against COVID-19 may be compromised. However, both natural infection and vaccination develop T-cell based responses, in addition to antibodies. This study examined if the parts of the virus, or epitopes, targeted by the CD8+ T-cell response in thirty individuals who recovered from COVID-19 in 2020 were mutated in the Omicron variant. Only one of 52 epitopes identified in this population contained an amino acid that was mutated in Omicron. These data suggest that the T-cell immune response in previously infected, and most likely vaccinated individuals, should still be effective against Omicron.

immunology↗

bioRxiv2021

Size Matters: A Mechanistic Model of Nanoparticle Curvature Effects on Amyloid Fibril Formation

The aggregation of peptides into amyloid fibrils is linked to ageing-related diseases, such as Alzheimers disease and type 2 diabetes. Interfaces, particularly those with large nanostructured surface areas, can affect the kinetics of peptide aggregation, ranging from a complete inhibition to strong acceleration. While a number of physiochemical parameters determine interface effects, we here focus on the role of nanoparticle curvature for the aggregation of the amyloidogenic peptides A{beta}40, NNFGAIL, GNNQQNY and VQIYVK. Nanoparticles (NPs) provided a surface for peptide monomers to adsorb, enabling the nucleation into oligomers and fibril formation. High surface curvature, however, destabilized prefibrillar structures, providing an explanation for inhibitory effects on fibril growth. Thioflavin T (ThT) fluorescence assays as well as dynamic light scattering (DLS), atomic force microscopy (AFM) and electron microscopy experiments revealed NP size-dependent effects on amyloid fibril formation, with differences between the peptides. While 5 nm gold NPs (AuNP-5) retarded or inhibited the aggregation of most peptides, larger 20 nm gold NPs (AuNP-20) tended to accelerate peptide aggregation. Molecular dynamics (MD) studies demonstrated that NPs ability to catalyze or inhibit oligomer formation was influenced by the oligomer stability at curved interfaces which was lower at more highly curved surfaces. Differences in the NP effects for the peptides resulted from the peptide properties (size, aggregation propensity) and concomitant surface binding affinities. The results can be applied to the design of future nanostructured materials for defined applications.

biochemistry↗

bioRxiv2020

CD8+ T cell responses in convalescent COVID-19 individuals target epitopes from the entireSARS-CoV-2 proteome and show kinetics of early differentiation

Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understanding its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. 132 distinct SARS-CoV-2-specific CD8+ T cell epitope responses across six different HLAs were detected, corresponding to 52 unique reactivities. T cell responses were directed against several structural and non-structural virus proteins. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.

immunology↗