Search bioRxiv⌕ Search

Biology subjects

Varela, M. C.

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

2 recordsLinked to original sources
bioRxiv2025

Robust Production of Parvalbumin Cortical Interneurons and Fast-Spiking Neurons from Human Medial Ganglionic Eminence Organoids

The medial ganglionic eminence (MGE) gives rise to parvalbumin (PV)-and somatostatin (SST)-expressing cortical interneurons essential for regulating cortical excitability. Although PV interneurons are linked to various neurodevelopmental and neurodegenerative disorders, reliably generating them from human pluripotent stem cells (hPSCs) has been extremely challenging. We present a robust, reproducible protocol for generating single-rosette MGE organoids (MGEOs) from hPSCs. Transcriptomic analyses reveal that MGEOs exhibit MGE regional identity and faithfully model the developing human fetal MGE. As MGEOs mature, they generate abundant PV-expressing cortical interneurons, including putative basket and axoaxonic cells, at a scale not previously achieved in vitro. When fused with human cortical organoids (hCOs), these interneurons rapidly migrate into the hCOs, integrate into excitatory networks, and contribute to complex electrophysiological patterns and the emergence of large numbers of fast-spiking neurons. Using this model, we uncover a previously unreported migration deficit of MGE interneurons in a disease model of SLC6A1 developmental and epileptic encephalopathy, offering potential insights into the developmental contributions to epileptogenesis. MGEOs thus offer a powerful in vitro approach for probing human MGE-lineage cortical and subcortical GABAergic neuron development, modeling various neuropsychiatric disorders, and advancing cell-based therapies for neurodevelopmental and neurodegenerative disorders. HighlightsO_LIGeneration of subpallial organoids highly enriched for MGE lineages C_LIO_LIMGE organoids (MGEOs) robustly produce parvalbumin-expressing cortical interneurons C_LIO_LIComplex network activity and fast-spiking neurons are generated in assembloids C_LIO_LIImpaired interneuron migration in SLC6A1 knockout and patient-derived MGEOs C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/662594v2_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@1fce574org.highwire.dtl.DTLVardef@3c28d2org.highwire.dtl.DTLVardef@19bf737org.highwire.dtl.DTLVardef@834f2b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗
bioRxiv2018

Activity of Telavancin against S. aureus isolated from cystic fibrosis patients including those with decreased susceptibility to Ceftaroline

Methicillin-resistant Staphylococcus aureus (MRSA) acquisition in cystic fibrosis (CF) patients confers a worse clinical outcome with increased rate of declined lung function. Telavancin, an approved lipoglycopeptide used to treat infections due to S. aureus has a dual mode of action causing inhibition of the peptidoglycan synthesis and membrane depolarization. CF-associated MRSA infections remain an important problem with no foreseeable decline in prevalence rates. Although telavancin is currently in clinical use for complicated skin infections and hospital-acquired pneumonia, the activity against CF-associated S. aureus infections has not been investigated. In this work, we studied the activity of telavancin against CF S. aureus strains collected from diverse geographical CF centers in the USA. We found that telavancin-MIC90 was 0.06 g/ml, 8-fold lower than ceftaroline or daptomycin and 25-fold lower than linezolid and vancomycin. We demonstrate that telavancin at serum-free concentrations has rapid bactericidal activity with a decrease of more than 3 log10 CFU/ml during the first 4 to 6 hours of treatment, performing better in this assay than vancomycin and ceftaroline, including S. aureus resistant to ceftaroline.\n\nTelavancin resistance was infrequent (0.3%), although we found that it can occur in-vitro in both CF-and non-CF S. aureus strains by progressive passages with sub-inhibitory concentrations. Genetic analysis of telavancin in-vitro mutants showed gene polymorphisms in cell wall and virulence genes, and increased survival in a Galleria mellonella infection model. Thus, we conclude that telavancin represents a promising therapeutic option for CF infections with potent in-vitro activity and low resistance potential.

microbiology↗