Biology subjects

Londin, E.

Publications and source records attributed to Londin, E..

6 recordsLinked to original sources

bioRxiv2026

The SEA-AD DREAM Challenge: Community benchmarking human and AI agent solutions for Alzheimer's disease neuropathology prediction from single-nucleus transcriptomics

Single-nucleus transcriptomic atlases offer an unprecedented opportunity to connect cellular molecular states with Alzheimer's disease (AD) neuropathology, but whether these profiles encode reproducible, predictive information about pathological burden remains unclear. We present the SEA-AD DREAM Challenge, an open, international, model-to-data competition built on the Seattle Alzheimer's Disease Brain Cell Atlas to predict Alzheimer's disease neuropathological severity from single-nucleus RNA-sequencing data. Participants developed containerized models to predict categorical neuropathological staging, including overall Alzheimer's disease neuropathologic change, Braak stage, Thal phase, and CERAD score, as well as quantitative amyloid-{beta} and phospho-tau burden measured by 6E10 and AT8 immunohistochemistry. Across 17 eligible teams from 15 countries, the crowdsourcing framework enabled systematic comparison of diverse computational approaches and surfaced a broad landscape of modeling strategies and candidate predictive features. Top-performing methods achieved near-perfect prediction of categorical staging, with the best submission reaching a quadratic weighted kappa of 1.0 for the Overall AD Neuropathological Change score (ADNC), and competitive prediction of quantitative pathological burden in held-out data, with a best concordance correlation coefficient of 0.48. Post hoc perturbation analyses revealed that top categorical-stage predictions relied heavily on donor-level metadata-driven signals rather than transcriptomic features, whereas quantitative pathology prediction was more robust and supported by transcriptomic and cell-type-associated features with potential biological relevance to AD progression. The challenge also introduced the first AI Agent Track in a DREAM Challenge, providing an early benchmark for autonomous and human-guided agentic model development in single-cell neuroscience. This work demonstrates that single-nucleus transcriptomes encode substantial information about Alzheimer's disease pathology, establishes a reproducible benchmark for molecular neuropathology prediction, and highlights critical principles for designing privacy-preserving, leakage-aware community challenges using deeply phenotyped human brain data.

neuroscience↗

bioRxiv2024

All ribosomal RNAs and 45S spacers from humans to worms are packed with organism-specific motifs whose other copies are found predominantly in numerous nervous system genes including many associated with human disorders

The nucleotide sequences of ribosomal RNAs (rRNAs) and the spacers of 45S are tuned to fulfill optimally their respective roles during ribosome biosynthesis and function. We report that these sequences satisfy additional genome-wide constraints in humans, mice, fruit flies, and worms. In all four organisms, the rRNAs and 45S spacers are densely packed with organism-specific nucleotide motifs with many additional identical copies throughout the genome. The human rRNAs and 45S spacers contain 1,723 motifs whose sequences are unique to the rRNAs/spacers of primates. These motifs have numerous additional exact intronic and exonic copies whose genomic placement is also unique to primates. Specific combinations of the motifs appear exclusively in 3,430 human nervous system and developmental genes, including 1,046 risk genes for autism, schizophrenia, and bipolar disorder. RNA/RNA crosslinking experiments show that the rRNA/spacer motifs are contact points for rRNA-mRNA and mRNA-mRNA heteroduplexes. RNA binding protein (RBP) assays show that these motifs are also in the binding sites of 113 RBPs. RNA sequencing reveals that rRNAs and spacers produce endogenous small non-coding RNAs (sncRNAs) that carry the same primate-specific motifs. Lastly, the motifs intergenic and intronic copies overlap 131 GWAS polymorphisms associated with neuropathologies (p-val<3.9e-12). The findings suggest that the motifs facilitate RNA/RNA and RBP/RNA interactions that are affected by polymorphisms and modulated by rRNA- and spacer-derived sncRNAs carrying the same motifs. Our study also genetically links for the first time rRNAs and 45S spacers to autism and other typically human neurological disorders. Mutation panels based on these motifs can lead to new molecular diagnostics for these disorders, whereas snRNAs carrying these motifs can serve as drugs or potential therapeutic targets. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/627812v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@146feadorg.highwire.dtl.DTLVardef@1fa501corg.highwire.dtl.DTLVardef@a17f14org.highwire.dtl.DTLVardef@9e2053_HPS_FORMAT_FIGEXP M_FIG C_FIG The human ribosomal RNAs and the 45S spacers share primate-specific motifs with thousands of nervous system genes, including risk genes for autism and other neurological disorders. Similar links between rRNAs/spacers and nervous system genes exist in mice, fruit flies, and worms but are achieved through motifs that are unique to each organism. In humans, the motifs are at the contact points of endogenous gene-gene and rRNA-gene heteroduplexes, as well as the binding sites of RNA binding proteins (RBPs) in genes and rRNAs/spacers. Endogenous small RNAs carrying these shared motifs modulate these endogenous interactions and are disrupted by mutations at the motifs genomic copies. Mutation panels based on these motifs can lead to new diagnostics for autism and other disorders, while the small RNAs carrying the motifs can serve as drugs or potential therapeutic targets.

neuroscience↗

bioRxiv2018

Unification of miRNA and isomiR research: the mirGFF3 format and the mirtop API

BackgroundMicroRNAs (miRNAs) are small RNA molecules ([~]22 nucleotide long) involved in post-transcriptional gene regulation. Advances in high-throughput sequencing technologies led to the discovery of isomiRs, which are miRNA sequence variants. While many miRNA-seq analysis tools exist, a lack of consensus on miRNA/isomiR analyses exists, and the resulting diversity of output formats hinders accurate comparisons between tools and precludes data sharing and the development of common downstream analysis methods.\n\nFindingsTo overcome this situation, we present here a community-based project, miRTOP (miRNA Transcriptomic Open Project) working towards the optimization of miRNA analyses. The aim of miRTOP is to promote the development of downstream analysis tools that are compatible with any existing detection and quantification tool. Based on the existing GFF3 format, we first created a new standard format, mirGFF3, for the output of miRNA/isomiR detection and quantification results from small RNA-seq data. Additionally, we developed a command line Python tool, mirtop, to manage the mirGFF3 format. Currently, mirtop can convert into mirGFF3 the outputs of commonly used pipelines, such as seqbuster, miRge2.0, isomiR-SEA, sRNAbench, and Prost!, as well as BAM files. Its open architecture enables any tool or pipeline to output results in mirGFF3.\n\nConclusionsCollectively a comprehensive isomiR categorization system, along with the accompanying mirGFF3 and mirtop API provide a complete solution for the standardization of miRNA and isomiR analysis, enabling data sharing, reporting, comparative analyses, and benchmarking, while promoting the development of common miRNA methods focusing on downstream steps to miRNA detection, annotation, and quantification.

bioinformatics↗

bioRxiv2018

Miniaturized Permeability Assay for CRISPR-Mediated Genome-Wide Screens

The impermeability of the luminal endothelial cell monolayer is crucial for the normal performance of the vascular and lymphatic systems. A key to this function is the integrity of the monolayers intercellular junctions. The known repertoire of junction-regulating genes is incomplete. Current permeability assays are incompatible with high-throughput genome-wide screens that could identify these genes. To overcome these limitations, we designed a new permeability assay that consists of cell monolayers grown on [~]150 m microcarriers. Each microcarrier functions as a miniature individual assay of permeability (MAP). We demonstrate that false-positive results can be minimized, and that MAP sensitivity to thrombin-induced increase in monolayer permeability is similar to the sensitivity of the measurement of impedance. We validate the assay by showing that the expression of single guide RNAs (sgRNAs) that target genes encoding known thrombin signaling proteins blocks effectively thrombin-induced junction disassembly, and that MAPs carrying such cells can be separated effectively by a fluorescent probe from those that carry cells expressing non-targeting sgRNAs. These results indicate that MAPs are suitable for high-throughput experimentation and for genome-wide screens for genes that mediate the disruptive effect of thrombin on endothelial cell junctions.

cell biology↗

bioRxiv2018

Murine MPDZ-Linked Hydrocephalus is Caused by Hyperpermeability of the Choroid Plexus

Though congenital hydrocephalus is heritable, it has been linked only to eight genes, one of which is MPDZ. Humans and mice that carry a truncated version of MPDZ incur severe hydrocephalus resulting in acute morbidity and lethality. We show by magnetic resonance imaging that contrast-medium penetrates into the brain ventricles of mice carrying a Mpdz loss-of-function mutation, whereas none is detected in the ventricles of normal mice, implying that the permeability of the choroid plexus epithelial cell monolayer is abnormally high. Comparative proteomic analysis of the cerebrospinal fluid of normal and hydrocephalic mice revealed up to a 53-fold increase in protein concentration, suggesting that transcytosis through the choroid plexus epithelial cells of Mpdz KO mice is substantially higher than in normal mice. These conclusions are supported by ultrastructural evidence, and by immunohistochemistry and cytology data. Our results provide a straight-forward and concise explanation for the pathophysiology of Mpdz-linked hydrocephalus.

neuroscience↗

bioRxiv2016

The presence or absence alone of miRNA isoforms (isomiRs) successfully discriminate amongst the 32 TCGA cancer types

Previously, we demonstrated that miRNA isoforms (isomiRs) are constitutive and their expression profiles depend on tissue, tissue state, and disease subtype. We have now extended our isomiR studies to The Cancer Genome Atlas (TCGA) repository. Specifically, we studied whether isomiR profiles can distinguish amongst the 32 cancers. We analyzed 10,271 datasets from 32 cancers and found 7,466 isomiRs from 807 miRNA hairpin-arms to be expressed above threshold. Using the top 20% most abundant isomiRs, we built a classifier that relied on \"binary\" isomiR profiles: isomiRs were simply represented as present or absent and, unlike previous methods, all knowledge about their expression levels was ignored. The classifier could label tumor samples with an average sensitivity of 93% and a False Discovery Rate of 3%. Notably, its ability to classify well persisted even when we reduced the set of used features (=isomiRs) by a factor of 10. A counterintuitive finding of our analysis is that the isomiRs and miRNA loci with the highest ability to classify tumors are not the ones that have been attracting the most research attention in the miRNA field. Our results provide a framework in which to study cancer-type-specific isomiRs and explore their potential uses as cancer biomarkers

bioinformatics↗