Biology subjects

Goldschmidt, E.

Publications and source records attributed to Goldschmidt, E..

6 recordsLinked to original sources

bioRxiv2026

Brain folding as a Fourier series yields a developmental clock

The human fetal cortex begins as a smooth spheroid and progressively folds into a stereotypical sulcal and gyral pattern that defines the final brain geometry. Two centuries ago, Joseph Fourier showed that any function on a bounded domain can be built from oscillations at successive frequencies, and that truncating the series at some maximum frequency yields a smoothed version of the original. Here I show the natural closed surface generalization of Fouriers construction, the spherical harmonic expansion, reproduces brain fetal developmental sequence in reverse: truncation of the fully formed cortex at low harmonic degree (L_max) recovers a younger fetal brain; at higher L_max, the primary, secondary and tertiary folds appear. The maximum harmonic degree is, therefore, a clock. From this observation, I obtained a closed-form 23-dimensional descriptor. The descriptor predicts gestational age from a single fetal MRI at 0.13 and 0.38 weeks across the two leading public atlases after a linear cross-cohort alignment (1.07 and 1.51 weeks without alignment); it orders all 28 longitudinal pairs of a modality- mismatched cohort; and it discriminates pathological from neurotypical fetuses at AUC 0.80 while resolving three biometrically concordant pathology subtypes. The equation also accounts for large- and small-scale brain folding mechanisms under one descriptor that become distinguishable as two distinct spectral signatures on the same curve. The descriptor is a new analytical dimension of brain folding. SignificanceJoseph Fouriers 1822 discovery, a sum of oscillations at successive frequencies, unexpectedly reproduces the temporal sequence in which the fetal cortex folds. The closed-surface generalization of Fouriers series truncated at low harmonic degrees recovers a younger fetal brain; and increasing the degree of truncation yields the primary, secondary and tertiary sulci. The truncation degree functions as a developmental clock and can be used as a descriptor that locates any fetal brain on the developmental curve, predicts gestational age, and discriminates pathological from neurotypical fetuses. The descriptor is a new analytical dimension of brain folding, and an unexpected application of an old mathematical principle.

developmental biology↗

bioRxiv2026

A single-cell and spatial atlas of prostate cancer reveals the combinatorial nature of gene modules underlying lineage plasticity and metastasis

Prostate cancer encompasses a spectrum of disease states driven by complex cellular heterogeneity. To delineate the transcriptional programs underlying lineage plasticity and metastasis, we constructed a comprehensive single-cell atlas of 128 patients, spanning localized, castration-resistant, and metastatic disease. Lineage plasticity was prevalent in localized disease, with subsets of tumor cells adopting distinct basal-like and club-like states. Luminal-like cancer cells also displayed extensive lineage infidelity, defined not by a binary loss of identity but by the combinatorial erosion of luminal gene modules associated with higher grade and stage. In the metastatic setting, gene program association analysis (GPAS) identified a broad induction of cell-cycle gene modules across organ sites as well as an induction of organ-specific gene modules, including osteomimetic signaling in bone, neuro-migratory genes in brain, and erythroid-like transitions in liver. Neuroendocrine prostate cancers (NEPCs) were not monolithic but defined by combinations of NE-associated gene modules including a novel HES6 program. Notably, these modules were detected at intermediate levels in localized samples, suggesting molecular plasticity precedes histological transformation. We also developed a refined NE signature that could distinguish NEPC tumors more accurately than previously published signatures. Within the tumor microenvironment (TME), we observed an elevation of pro-inflammatory Th17 T-cells in African American patients and identified a rare Schwann cell population. Finally, we present PCformer, a transformer-based foundation model trained on >500,000 cells to automate cell-state classification. Together, this comprehensive atlas demonstrates the complex nature of gene modules underlying lineage infidelity and plasticity in cancer cells and highlights distinct immune and stromal populations within the tumor ecosystem.

genomics↗

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↗