Biology subjects

Nazeraj, I.

Publications and source records attributed to Nazeraj, I..

3 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

Comprehensive profiling of small RNAs and their changes and linkages to mRNAs in schizophrenia and bipolar disorder

We investigated small non-coding RNAs (sncRNAs) from the prefrontal cortex of 93 individuals diagnosed with schizophrenia (SCZ) or bipolar disorder (BD) and 77 controls. We uncovered recurring complex sncRNA profiles, with 98% of all sncRNAs being accounted for by miRNA isoforms (60.6%), tRNA-derived fragments (17.8%), rRNA-derived fragments (11.4%), and Y RNA-derived fragments (8.3%). In SCZ, 15% of all sncRNAs exhibit statistically significant changes in their abundance. In BD, the fold changes (FCs) are highly correlated with those in SCZ but less acute. Non-templated nucleotide additions to the 3'-ends of many miRNA isoforms determine their FC independently of miRNA identity or genomic locus of origin. In both SCZ and BD, disease- and age-associated sncRNAs and mRNAs reveal accelerated aging. Co-expression modules between sncRNAs and mRNAs align with the polarities of SCZ changes and implicate sncRNAs in critical processes, including synaptic signaling, neurogenesis, memory, behavior, and cognition.

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↗