Biology subjects

Smits, M.

Publications and source records attributed to Smits, M..

7 recordsLinked to original sources

bioRxiv2026

Lineage origin of spinal cord cell type diversity

The complexity and specificity of movement in vertebrates is driven by a rich diversity of spinal motor and interneuron cell types. During development, eleven spinal cord progenitor domains generate an equivalent number of cardinal neuron types. How progenitor domains, individual progenitors, and post-mitotic diversity relate is still unknown. We performed high-resolution, single-progenitor cell lineage tracing in the embryonic mouse spinal cord using mosaic analysis with double markers (MADM). Our quantitative study of lineage progression revealed that spinal cord progenitors undergo highly variable numbers of proliferative, neurogenic, and gliogenic cell divisions. The nascent clonally-related neurons migrate radially over large distances, span the dorsoventral axis, and even cross the midline, demonstrating striking bilaterality. Molecular and morphometric analysis indicate high levels of progenitor multipotency, with an individual progenitor capable of producing several molecularly and morphologically distinct neuron types, as well as astrocytes. These findings redefine spinal cord development as a process in which lineage variability--rather than rigid progenitor identity--drives the generation of cellular diversity.

neuroscience↗

bioRxiv2026

A dual-clam species 63K SNP array for sustainable production and conservation of wild resources

Bivalves play an essential role in coastal ecosystems and their aquaculture represents an important economic sector in Europe playing a pivotal role within the EU Blue Growth Strategy. Among clam species, the Manila clam, Ruditapes philippinarum, and the grooved carpet shell, R. decussatus, are within the top five species in terms of production volume and economic value. In this study we designed and validated the first medium-density 63K single nucleotide polymorphism (SNP) array for these two commercially important species. By leveraging a new chromosome-level genome assembly for R. philippinarum and that of R. decussatus, we identified over 300 million SNPs through whole-genome resequencing and genotyping-by-sequencing strategies. After stringent filtering, we selected 49,392 high-quality SNPs for R. philippinarum and 14,193 for R. decussatus to construct a dual-species array. Array validation was carried out by genotyping 384 individuals across multiple wild populations and hatchery samples, demonstrating excellent performance, with 67.7% and 67.5% of SNPs classified as high-quality polymorphic markers for R. philippinarum and R. decussatus, respectively. Minor allele frequency, missing data rate, and inter-marker distance met stringent quality thresholds, confirming the array robustness for clam population genetics. Parentage analysis in R. philippinarum families highlighted significant power for pedigree reconstruction in breeding programs. This publicly available genomic resource provides a reliable, cost-effective genotyping platform to enable population genomics and advanced selective breeding, genome-wide association studies, and genetic monitoring, ultimately strengthening management of genetic diversity and sustainable farming for two key clam species.

genomics↗

bioRxiv2024

Mobile Human Brain Imaging using Functional Ultrasound

Imagine being able to study the human brain in real-world scenarios while the subject displays natural behaviors such as locomotion, social interaction, or spatial navigation. The advent of ultrafast ultrasound imaging brings us closer to this goal with functional Ultrasound imaging (fUSi), a new mobile neuroimaging technique. Here, we present real-time fUSi monitoring of brain activity during walking in a subject with a clinically approved sonolucent skull implant. Our approach utilizes personalized 3D-printed fUSi-helmets for stability, optical tracking for cross-modal validation with fMRI, advanced signal processing to estimate hemodynamic responses and facial tracking of a lick licking paradigm. These combined efforts allowed us to show consistent fUSi signals over 20 months, even during high-motion activities like walking. These results demonstrate the feasibility of fUSi for monitoring brain activity in real-world contexts, marking an important milestone for fUSi-based insights in clinical and neuroscientific research.

neuroscience↗

bioRxiv2024

Evolutionary trajectories of IDH-mutant astrocytoma identify molecular grading markers related to cell cycling

1To study the evolutionary processes that drive malignant progression of IDH-mutant astrocytomas, we performed multi-omics on a large cohort of matched initial and recurrent tumor samples. The overlay of genetic, epigenetic, transcriptomic and proteomic data, combined with single-cell analysis, have identified overlapping features associated with malignant progression. These features are derived from three molecular mechanisms and provide a rationale of the underlying biology of tumor malignancy: cell-cycling, tumor cell (de-)differentiation and remodeling of the extracellular matrix. Specifically, DNA-methylation levels decreased over time, predominantly in tumors with malignant transformation and co-occurred with poor prognostic genetic events. DNA-methylation was lifted from specific loci associated with DNA replication and was associated with an increased RNA and protein expression of cell cycling associated genes. All results were validated on samples of newly diagnosed IDH-mutant astrocytoma patients included the CATNON randomized phase 3 clinical trial. Importantly, malignant progression was hardly affected by radio- or chemotherapy, indicating that treatment does not affect the course of disease. Our results culminate in a DNA-methylation based signature for objective tumor grading.

cancer biology↗

bioRxiv2021

The epigenetic evolution of gliomas is determined by their IDH1 mutation status and treatment regimen

Tumor adaptation or selection is thought to underlie therapy resistance of gliomas. To investigate the longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 143 matched initial and recurrent patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) gliomas. IDHwt gliomas showed a longitudinally stable epigenome with relatively low levels of global methylation, whereas the epigenome of IDHmut gliomas showed initial high levels genome-wide of DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. By integrating DNA methylation and gene expression data, adaptive changes of putative master regulators of the cell cycle and of differentiation were seen in IDHmut recurrent tumors. Furthermore, relapses of IDHmut tumors were accompanied by histological progression which in turn influenced survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment differed between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neo-angiogenesis and T-cell infiltration upon treatment for IDHmut gliomas. Our study provides one of the largest cohorts of paired glioma samples profiled with epigenomics, transcriptomics and genomics; and our results demonstrate that the treatment of IDHmut gliomas reshapes the epigenome towards an IDHwt-like phenotype. Accordingly, the prevalent practice of early genotoxic treatment in this patient population may need to be revisited.

genomics↗

bioRxiv2021

Cornering an Ever-Evolving Coronavirus: TATX-03, a fully human synergistic multi-antibody cocktail targeting the SARS-CoV-2 Spike Protein with in vivo efficacy

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has created an ongoing global human health crisis and will likely become endemic, requiring novel sustainable therapeutic strategies. We report on the discovery of a fully human multi-antibody cocktail (TATX-03) targeting diversified non-overlapping epitopes on the SARS-CoV-2 spike protein that suppressed replication-competent viral titers to undetectable levels in the lungs of SARS-CoV-2 challenged hamsters upon both prophylactic and therapeutic administration. While monotherapy with two of the individual cocktail components also showed clear in vivo protection, neither recapitulated the efficacy of TATX-03. This synergistic effect was further supported by examining in vivo efficacy of these individual antibodies and corresponding combination therapy at a lower dose. Furthermore, in vitro screenings using VSV-particles pseudo-typed with spike proteins representing the SARS-CoV-2 variants of concern Alpha, Beta, and Delta showed that TATX-03 maintained its neutralization potency. These results merit further development of TATX-03 as a potential therapy for SARS-CoV-2 infection with resistance to mutagenic escape.

immunology↗

bioRxiv2019

The genomic landscape of metastatic castration-resistant prostate cancers using whole genome sequencing reveals multiple distinct genotypes with potential clinical impact

Here we present whole-genome sequencing (WGS) analysis of fresh-frozen metastatic biopsies from 197 castration-resistant prostate cancer patients. Using hierarchical unsupervised clustering based on genomic aberrations only, we defined eight different clusters. We detected four distinct and potentially clinically relevant genotypes harboring unique genomic features, including: 1) Microsatellite Instability; 2) Homologous Recombination Deficiency (HRD) with enriched genomic deletions and BRCA2 aberrations; 3) tandem duplication phenotype associated with biallelic CDK12 mutations; and 4) a subgroup enriched for chromothripsis events. Our data suggest that classifying patients using WGS characteristics may improve classification of HRD patients. Moreover, we confirmed that important regulators of AR-mediated signaling are located in non-coding regions. Using ChIP sequencing data, we showed that the amplified AR and MYC promoter regions contain open chromatin and bind AR, suggesting a role in AR mediated biology. Thus, high-resolution WGS may be used to improve patient stratification.

cancer biology↗