Biology subjects

Goldschmidt, E.

Publications and source records attributed to Goldschmidt, E..

4 recordsLinked to original sources

bioRxiv2022

Heterogeneous migration of neuronal progenitors to the insula shapes the human brain

The human cerebrum consists of a precise and stereotyped arrangement of lobes, gyri, and connectivity that underlies human cognition. The development of this arrangement is less clear. Current models of radial glial cell migration explain individual gyral formation but fail to explain the global configuration of the cerebral lobes. Moreover, the insula, buried in the depths of the Sylvian fissure, belies conventional models. Here, we show that the insula has unique morphology in adults, that insular morphology and slow volumetric growth emerge during fetal development, and that a novel theory of curved migration is required to explain these findings. We calculated morphologic data in the insula and other lobes in adults (N=107) and in an in utero fetal brain atlas (N=81 healthy fetuses). In utero, the insula grows an order of magnitude slower than the other lobes and demonstrates shallower sulci, less curvature, and less surface complexity both in adults and progressively throughout fetal development. Novel spherical projection analysis demonstrates that the lenticular nuclei obstruct 60-70% of radial pathways from the ventricular zone (VZ) to the insula, forcing a curved migration path to the insula in contrast to a direct radial pathway. Using fetal diffusion tractography, we identify streams of putative progenitor cells that originate from the VZ and migrate tangentially around the lenticular nuclei to form the insula. These results challenge existing models of radial migration to the cortex, provide an alternative model for insular and cerebral development, and lay the groundwork to understand cerebral malformations, insular functional connectivity, and insular pathologies.

developmental biology↗

bioRxiv2021

Pan-cancer mapping of single T cell profiles reveals a TCF1:CXCR6-CXCL16 regulatory axis essential for effective anti-tumor immunity

Unleashing cytotoxic CD8+ T cells for effective cancer treatment requires understanding T cell states across different tumor microenvironments. Here, we developed an algorithm to recover both shared and tumor type specific programs and used it to analyze a scRNA-seq compendium of 38,852 CD8+ T cells from 141 patients spanning nine different human cancers. We uncovered a pan-cancer T cell dysfunction program that was predictive of clinical responses to immunotherapy and highlighted CXCR6 as a pan-cancer marker of dysfunctional T cells. In mouse models, CXCR6 increased following checkpoint blockade and was repressed by TCF1. Its ligand, CXCL16, was expressed primarily by myeloid cells, and was co-regulated with antigen presentation genes. CXCR6 deletion decreased Tox, CX3CR1, and Bcl2 expression, predisposing dysfunctional PD-1+Tim3+CD8+ T cells to apoptosis, and compromising tumor growth control. Our approach discovered a TCF1:CXCR6-CXCL16 regulatory axis essential for effective anti-tumor immunity, revealing a new perspective on T cell dysfunction and new opportunities for modulating this cell state.

immunology↗

bioRxiv2021

Frequent Aneuploidy in Primary Human T Cells Following CRISPR-Cas9 cleavage

Multiple ongoing clinical trials use site-specific nucleases to disrupt T cell receptor (TCR) genes in order to allow for allogeneic T cell therapy1-5. In particular, the first U.S. clinical trial using CRISPR-Cas9 entailed the targeted disruption of the TCR chains and programmed cell death protein 1 (PDCD1) in T cells of refractory cancer patients6. Here, we used the same guide RNA sequences and applied single-cell RNA sequencing (scRNAseq) to more than 7000 primary human T cells, transfected with CRISPR-Cas9. Four days post-transfection, we found a loss of chromosome 14, harboring the TCR locus, in up to 9% of the cells, and a chromosome 14 gain in up to 1.4% of the cells. We further identified truncations of chromosome 7, harboring the TCR{beta} locus, in 9.9% of the cells. Loss of heterozygosity (LOH) was further validated using fluorescence in situ hybridization (FISH) and the temporal dynamics of cleavage and incomplete repair were monitored using digital droplet PCR (ddPCR). Aneuploidy was found among all T cell subsets and was associated with transcriptional signatures of reduced proliferation and metabolism as well as with induced p53 activation and cell death. We conclude that aneuploidy and chromosomal truncations are frequent outcomes of CRISPR-Cas9 cleavage in clinical protocols. Monitoring and minimizing these aberrant products is crucial for future applications of genome editing in T cell engineering and beyond.

bioengineering↗

bioRxiv2019

Different principles govern different scales of brain folding

The signature folds of the human brain are formed through a complex and developmentally regulated process. In vitro and in silico models of this process demonstrate a random pattern of sulci and gyri, unlike the highly ordered and conserved structure seen in the human cortex. Here, we account for the large-scale pattern of cortical folding by combining advanced fetal MRI with nonlinear diffeomorphic registration and volumetric analysis. Our analysis demonstrates that in utero brain growth follows a logistic curve, in the absence of an external volume constraint. The Sylvian fissure forms from interlobar folding, where separate lobes overgrow and close an existing subarachnoid space. In contrast, other large sulci, which are the ones represented in existing models, fold through an invagination of a flat surface, a mechanistically different process. Cortical folding is driven by multiple spatially and temporally different mechanisms, therefore regionally distinct biological process may be responsible for the global geometry of the adult brain.

neuroscience↗