Biology subjects

Baron, H.

Publications and source records attributed to Baron, H..

3 recordsLinked to original sources

bioRxiv2023

Improved Protocol for Reproducible Human Cortical Organoids Reveals Early Alterations in Metabolism with MAPT Mutations

Human pluripotent stem cell (hPSC)-derived cortical organoids are powerful models but are often limited by low efficiency, variability, and stress-related artifacts. To address these challenges, we developed a scalable organoid platform with end-to-end quality control (QC) metrics spanning manufacturing and single-cell RNA-sequencing (scRNA-seq), developed using eight MAPT mutation isogenic line sets relevant to frontotemporal dementia (FTD-tau). Using a 96 slit-well format, we achieved [~]100% production efficiency across 64 lines. Controlled-release FGF2 enhanced iPSC pluripotency and reduced mesendodermal contaminants, while optimized SB431542 dosing enhanced cortical patterning across lines with variable TGFBR1/ALK5 expression. The resulting organoids displayed transcriptomic profiles and low-stress signatures closely aligned with the developing human cortex. Applying a cortical organoid scRNA-seq index (CortiCOSI), we identified early dysregulation of phosphatase regulators (PPP2CA, ANP32A) and the prefoldin subunit PFDN6 in MAPT V337M excitatory neurons before tau hyperphosphorylation and oligomerization. This platform improves scalability, reproducibility, and mechanistic insight in cortical organoid studies.

neuroscience↗

bioRxiv2022

Proteome capacity constraints favor respiratory ATP generation

Cells face competing metabolic demands. These include efficient use of both limited substrates and limited proteome capacity, as well as flexibility to deal with different environments. Flexibility requires spare enzyme capacity, which is proteome inefficient. ATP generation can occur via fermentation or respiration. Fermentation is much less substrate-efficient, but often assumed to be more proteome efficient 1-3, thereby favoring fast-growing cells engaging in aerobic glycolysis 4-8. Here, however, we show that mitochondrial respiration is actually more proteome-efficient than aerobic glycolysis. Instead, aerobic glycolysis arises from cells maintaining the flexibility to grow also anaerobically. These conclusions emerged from an unbiased assessment of metabolic regulatory mechanisms, integrating quantitative metabolomics, proteomics, and fluxomics, of two budding yeasts, Saccharomyces cerevisiae and Issatchenkia orientalis, the former more fermentative and the latter respiratory. Their energy pathway usage is largely explained by differences in proteome allocation. Each organisms proteome allocation is remarkably stable across environmental conditions, with metabolic fluxes predominantly regulated at the level of metabolite concentrations. This leaves extensive spare biosynthetic capacity during slow growth and spare capacity of their preferred bioenergetic machinery when it is not essential. The greater proteome-efficiency of respiration is also observed in mammals, with aerobic glycolysis occurring in yeast or mammalian cells that maintain a fermentation-capable proteome conducive to both aerobic and anaerobic growth.

systems biology↗

bioRxiv2021

Palaeogenomic analysis of black rat (Rattus rattus) reveals multiple European introductions associated with human economic history

The distribution of the black rat (Rattus rattus) has been heavily influenced by its association with humans. The dispersal history of this non-native commensal rodent across Europe, however, remains poorly understood, and different introductions may have occurred during the Roman and medieval periods. Here, in order to reconstruct the population history of European black rats, we generated a de novo genome assembly of the black rat, 67 ancient black rat mitogenomes and 36 ancient nuclear genomes from sites spanning the 1st-17th centuries CE in Europe and North Africa. Analyses of mitochondrial DNA confirm that black rats were introduced into the Mediterranean and Europe from Southwest Asia. Genomic analyses of the ancient rats reveal a population turnover in temperate Europe between the 6th and 10th centuries CE, coincident with an archaeologically attested decline in the black rat population. The near disappearance and re-emergence of black rats in Europe may have been the result of the breakdown of the Roman Empire, the First Plague Pandemic, and/or post-Roman climatic cooling.

evolutionary biology↗