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Almeida, M. C.

Publications and source records attributed to Almeida, M. C..

4 recordsLinked to original sources

Comparative chromosome-scale genomics of the ayahuasca liana Banisteriopsis caapi reveals paleopolyploid ancestry and recent tandem-gene expansions as candidate signatures of ethnovariety differentiation

Background: Banisteriopsis caapi is the Amazonian liana that provides the {beta}-carboline-rich vine component of ayahuasca, a traditional Amazonian psychoactive preparation used in Indigenous and ceremonial contexts. The species encompasses culturally recognized ethnovarieties, some differing in stem architecture. Despite its cultural, ecological, and pharmacological importance, B. caapi remains largely unexplored at the genomic level. Here, we generated chromosome-scale genome assemblies for the caupuri and tucunaca ethnovarieties and used them to investigate genome evolution, structural variation, repeat composition, and candidate genomic features associated with ethnovariety-level differentiation. Results: Caupuri and tucunaca assemblies span 1.16 and 1.13 Gb, respectively, each organized into ten high-quality chromosome-scale pseudomolecules. Both genomes retain signatures of two ancient post-gamma duplication components, with related signals also detected in Malpighia emarginata, suggesting that at least part of this paleopolyploid history may predate the divergence of these Malpighiaceae lineages. Against this conserved chromosomal framework, the sampled caupuri and tucunaca genomes differ in structural variation, repeat composition, and gene-family profiles. Transposable element-associated insertions and deletions dominate the structural-variant landscape, while both genomes are highly repetitive, with approximately 78% of their assemblies composed of repetitive DNA largely shaped by LTR retrotransposons, including Gypsy/Retand and Copia/Ale, Copia/Tork, and Copia/Ivana lineages, together with non-autonomous large retrotransposon derivatives (LARDs). Most genes belong to shared orthogroups, indicating a largely conserved gene repertoire. However, candidate ethnovariety-biased differences emerge from the combined remodeling of gene families, LARD and LTR-associated genomic neighborhoods, and comparatively recent local expansions of tandem-duplicated gene arrays encoding signaling receptors, transporters, hormone-associated genes, cell wall and secondary wall functions, and meristem or organ-development pathways. Conclusions: These results indicate that the sampled caupuri and tucunaca genomes differ mainly through localized remodeling of shared genomic modules, including comparatively recent repeat turnover and local tandem-gene expansions. These assemblies provide the first large-scale nuclear genomic resource for B. caapi and a foundation for investigating paleopolyploid evolution in Malpighiaceae and candidate mechanisms of ethnovariety diversification.

genomics↗

Disrupted Brain Organoid Circuitry, Structural Organization, and Spine Morphology in 7q11.23 Copy Number Variant Syndromes

The 7q11.23 chromosomal region represents a model of gene dosage-dependence, where a hemizygous deletion causes Williams Syndrome (WS) and a duplication leads to 7q11.23 Duplication Syndrome (Dup7). It is not understood how these copy number variations (CNVs) disrupt development and functional cortical circuit assembly. Utilizing iPSC-derived cerebral organoids and longitudinal imaging from post-differentiation day 30 to 150, we characterized the aberrant neural rosette morphogenesis in WS and Dup7 during early stages, establishing an early structural divergence from control lines. We observed accelerated early cortical rosette morphogenesis in WS, characterized by a premature increase in both rosette number and layer thickness compared to controls. In contrast, Dup7 organoids consistently exhibit a significantly lower number and reduced thickness of rosettes from early stages onward. This early structural disruption progressively impacted synaptic-level architecture as the organoids matured. Dendritic spine characterization at later stages revealed Dup7 organoids exhibited a significantly higher dendritic spine density compared to WS. Pharmacological antagonism of CCR5 (C-C chemokine receptor type 5) with Maraviroc significantly enhanced dendritic spine density in control and WS organoids; however, this effect was absent in Dup7. To determine how these structural anomalies translate into circuit-level behavior, we performed longitudinal calcium imaging using GCaMP. Control organoids sustained synchronized activity and high spike correlations at all time points. This synchronization was delayed and highly transient in WS organoids, and completely abolished in Dup7 organoids, which exhibit significantly low spike correlations at all stages. Developmentally, GABA changes from acting as an excitatory signal in the immature brain to an inhibitory signal as the brain matures. As control lines matured gabazine-induced desynchronization progressively diminished, but persisted in WS organoids. Dup7 organoids failed to establish synchronization at any developmental time point, but displayed a negligible increased synchrony following gabazine treatment. These functional aberrations were paralleled by genotype-specific defects in structural organization, specifically in rosette morphogenesis and dendritic spine density. Collectively, our findings demonstrate that 7q11.23 CNVs trigger pathogenic neurodevelopmental defects by derailing the trajectories of structural organization, circuit assembly, and functional synchronization during cortical maturation.

neuroscience↗

BAG2 Condensates Couple Proteostasis to CD8+T Cell Surveillance

Protein aggregation, impaired degradation, and immune activation are central hallmarks of neurodegenerative diseases, yet how these processes are coordinated remains unclear. Here, we identify Immune-Protein Degradation Bodies (I-PDBs), a previously unrecognized class of BAG2-driven, phase-separated organelles that integrate protein quality control with adaptive immunity. IFN{gamma} induce I-PDB formation at the endoplasmic reticulum (ER), where they concentrate immunoproteasome components, MHC-I peptide-loading machinery, and ER-associated chaperones. I-PDBs redirect proteostatic cargo from centrosomal aggregation pathways to spatially restricted degradation sites optimized for antigenic peptide generation, coupling selective substrate clearance to CD8 T cell engagement. Using a cellular model of aggregation-prone tau, we show that I-PDBs capture pathological tau fibrils at ER-microtubule interfaces and process them into potentially antigenic peptides, thus reducing the load of aggregation-prone tau peptides. We term this mechanism the Proteostasis-Associated Immune Relay (PAIR), establishing I-PDBs as critical hubs linking proteostasis to immune surveillance with broad implications for disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/719751v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@16fa503org.highwire.dtl.DTLVardef@ba7607org.highwire.dtl.DTLVardef@19ae5bdorg.highwire.dtl.DTLVardef@60fdf7_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIFN{gamma} drives BAG2-dependent Immune-Protein Degradation Bodies (I-PDBs) C_LIO_LII-PDBs assemble at the endoplasmic reticulum and are enriched in immunoproteasome and MHC-I machinery C_LIO_LII-PDBs shunt misfolded proteins, including pathological tau, away from aggresomes C_LIO_LII-PDBs couple proteostasis to antigen presentation, enhancing CD8 T cell recognition C_LIO_LIThe Proteostasis-Associated Immune Relay (PAIR) defines a pathway linking proteostasis to adaptive immunity C_LI

cell biology↗

Progranulin loss induces mitochondrial dysfunction and ferroptosis in human cerebral organoids

Loss-of-function mutations in the granulin (GRN) gene cause frontotemporal dementia when the mutations are heterozygous and neuronal ceroid lipofuscinosis, a lysosomal storage disease, when homozygous. While it is well established that disease-causing GRN mutations decrease progranulin (PGRN) levels, leading to neurodegeneration, the cellular and molecular mechanisms underlying these conditions remain poorly understood. In this study, we utilized human induced pluripotent stem cell (iPSC) derived forebrain organoids to investigate the impact of PGRN homozygous deficiency on neuronal and glial cell populations. Through single-cell RNA sequencing, we identified robust downregulation of the mitochondrial oxidative phosphorylation pathway in PGRN KO organoids. In line with these results, PGRN KO organoids showed decreased mitochondrial respiration. Furthermore, our study demonstrated that PGRN loss induced increased levels of reactive oxygen species (ROS), lipid peroxidation and iron accumulation. Finally, we observed increased vulnerability to ferroptotic cell death in PGRN KO organoids. Our findings suggest that mitochondrial dysfunction and impaired responses to oxidative stress are early manifestations of PGRN loss, and offer insights into the molecular mechanisms driving neurodegeneration caused by PGRN deficiency. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/691344v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@c477e5org.highwire.dtl.DTLVardef@9b61eforg.highwire.dtl.DTLVardef@13aadeborg.highwire.dtl.DTLVardef@1702929_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO Proposed molecular mechanisms that lead to ferroptosis of PGRN KO cells. Created with BioRender.com. C_FIG

neuroscience↗