Biology subjects

Yi, N.

Publications and source records attributed to Yi, N..

7 recordsLinked to original sources

bioRxiv2026

SorCS1 promotes synaptic and cognitive resilience despite amyloid pathology in Alzheimer's disease model mice

Alzheimer's disease (AD) lacks effective therapies despite extensive efforts targeting amyloid {beta} (A{beta}) and its precursor processing. Synapse loss is the strongest correlate of cognitive decline, driven partly by A{beta} oligomers (A{beta}Os), which bind multiple synaptic membrane proteins including the synaptic organizer neurexin and disrupt synaptic integrity and function. The protein sorting receptor SorCS1 blocks interactions between A{beta}Os and {beta}-isoforms of neurexins ({beta}-Nrxns), but its therapeutic relevance in vivo remains unclear. Using 5xFAD mice, which overproduce A{beta}Os, combined with forebrain specific neuronal SorCS1 overexpression, we show that SorCS1 preserves working memory, synaptic integrity, and basal excitatory transmission without altering amyloid deposition, in part by restoring synaptic {beta}-Nrxn expression. SorCS1 also reduces tau hyperphosphorylation in 5xFAD synaptosomes and binds the tau kinase GSK3{beta}. These results identify SorCS1 as an AD resilience promoting factor that maintains synaptic connectivity and attenuates tau pathology, revealing a therapeutic strategy that operates independently of amyloid reduction.

neuroscience↗

bioRxiv2025

Bayesian Cooperative Learning for Multimodal Integration

Bayesian multimodal models that integrate data from multiple sources, studies, or modalities have garnered considerable attention in recent years. However, existing methods either rely on computationally expensive Markov chain Monte Carlo (MCMC) schemes or adopt variational approaches that forgo principled uncertainty quantification. To address this limitation and cater to practical needs, we abandon the MCMC framework and turn to resampling-based posterior inference for multimodal integration. Our method, Bayesian Cooperative Learning (BayesCOOP), embeds fast maximum a posteriori (MAP) estimation within a Bayesian bootstrap, combining a novel jittered group spike-and-slab prior with an efficient expectation-maximization (E M) coordinate descent algorithm under randomly weighted data perturbations. Averaging posterior summaries (MAP estimates) across bootstrap replicates yields approximate posterior samples that retain Bayesian interpretability while avoiding the computational burden of traditional sampling-based inference. We establish theoretical connections between BayesCOOPs pseudo-posterior averaging and posterior contraction principles, demonstrating near-optimal posterior consistency under sparsity. Extensive simulation studies and analyses of pregnancy multi-omics datasets demonstrate that BayesCOOP substantially outperforms state-of-the-art early, intermediate, and late fusion approaches in estimation, prediction, and uncertainty assessment. The open-source implementation of BayesCOOP is available at https://github.com/himelmallick/BayesCOOP.

bioinformatics↗

bioRxiv2025

TREM2 macrophages are associated with enhanced response to PD-1 blockade in human hepatocellular carcinoma

Macrophages are known to dampen tumor immunity. However, identifying druggable targets that modulate these cells to improve existing immunotherapies has been limited by a dearth of studies identifying macrophages that associate with pathological response to immune checkpoint blockade. To fulfill this unmet clinical need, we leveraged transcriptional and spatial profiling of specimens collected from a Phase II clinical trial studying neoadjuvant PD-1 blockade in patients with hepatocellular carcinoma (HCC). We determined that the intratumoral abundance of TREM2-expressing macrophages and serological levels of soluble TREM2 are elevated in patients who responded to PD-1 blockade, compared to non-responders. We validated these findings in a second HCC cohort and in the IMbrave150 trial. These highlight the robust potential for TREM2 macrophages to predict therapeutic responses of HCC to immunotherapy. Therefore, our study provides a novel basis for the use of TREM2 macrophages to strategize treatment for patients with HCC to maximize therapeutic benefit.

immunology↗

bioRxiv2025

Geographic distribution of genetic diversity of Heterocephalus glaber analyzed using whole genome sequencing and a chromosome-scale genome assembly

Naked mole-rats (Heterocephalus glaber) are a species of rodent endemic to the Horn of Africa, notable among mammals for their long lifespans, resistances to a variety of stresses, and eusocial mating behavior. Though their natural range extends across large portions of Kenya, Ethiopia, Somalia, and Djibouti, the large majority of genetic and genomic analyses focus on Kenyan specimens. Here, we constructed a chromosome-scale reference genome assembly for H.glaber, along with new reference assemblies of both the Damaraland mole-rat (Fukomys damarensis) and guinea pig (Cavia porcellus) genomes to aid annotation. We leveraged our H.glaber assembly, along with modern whole-genome sequencing, to characterize the genetic diversity of specimens deriving from Kenya, southern Ethiopia, and eastern Ethiopia. We found the Kenyan and southern Ethiopian specimens to be closely related to each other and highly diverged from eastern Ethiopian specimens. We also found specimens collected from nearby locations in southern Ethiopia to be more closely related to Kenyan specimens than to each other. This unexpected distribution of shared genetic diversity highlights the importance of local migration barriers to gene flow in wild H.glaber populations.

ecology↗

bioRxiv2022

SorCS1 inhibits amyloid-β binding to neurexin and rescues amyloid-β-induced synaptic pathology

Amyloid-{beta} oligomers (A{beta}Os), toxic peptide aggregates found in Alzheimers disease (AD), cause synapse pathology. A{beta}Os interact with Neurexins (NRXs), key synaptic organizers, and this interaction dampens normal trafficking and function of NRXs. Axonal trafficking of NRX is in part regulated by its interaction with SorCS1, a protein sorting receptor, but the impact of SorCS1 regulation of NRXs in A{beta} pathology was previously unstudied. Here, we show competitive interaction of SorCS1 and A{beta}Os with {beta}-NRXs and rescue effects of SorCS1 on A{beta}O-induced synaptic pathology. Like A{beta}Os, SorCS1 binds to NRX1{beta} through the histidine-rich-domain (HRD) of NRX1{beta}, and SorCS1 and A{beta}Os compete for NRX1{beta} binding. In cultured hippocampal neurons, SorCS1 colocalizes with NRX1{beta} on the axon surface, and axonal expression of SorCS1 rescues A{beta}O-induced impairment of NRX-mediated presynaptic organization and presynaptic vesicle recycling as well as A{beta}O-induced structural defects in excitatory synapses. Thus, we reveal a role of SorCS1 in the rescue of A{beta}O-induced NRX dysfunction and synaptic pathology, providing the basis for a novel potential therapeutic strategy for AD.

neuroscience↗

bioRxiv2018

Pre-implantation genetic diagnosis for a family with Usher syndrome through targeted sequencing and haplotype analysis

ObjectiveOur objective was to investigate the applicability of targeted capture massively parallel sequencing in developing personalized pre-implantation genetic diagnosis (PGD) assay.\n\nMethodsOne couple at risk of transmitting Usher Syndrome to their offspring was recruited to this study. The genomics DNA (gDNA) was extracted from the peripheral blood and underwent in vitro fertilization (IVF)-PGD. Prenatal molecular diagnosis was performed in the 20th week of gestation and the chromosomal anomaly was analyzed.\n\nResultsCustomized capture probe targeted at USH2A gene and 350kb flanking region were designed for PGD. Eleven blastocysts were biopsied and amplified by using multiple displacement amplification (MDA) and capture sequencing. A HMM-based haplotype analysis was performed to deduce embryos genotype by using SNPs identified in each sample. Four embryos were diagnosed as free of fathers rare mutation, two were transferred and one achieved a successful pregnancy. The fetal genotype was confirmed by Sanger sequencing of fetal genomic DNA obtained by amniocentesis. The PGD and prenatal diagnosis results were further confirmed by the molecular diagnosis of the babys genomic DNA sample. The auditory test showed that the hearing was normal.\n\nConclusionTargeted capture massively parallel sequencing (MPS) is an effective and convenient strategy to develop customized PGD assay.\n\nKey pointsGenetic counseling session was conducted with a family having Usher patient who was molecularly diagnosed, and a healthy baby was born with the help of successful PGD assay. This is of vast importance in management plans since it is the first report of PGD in Usher syndrome based on targeted capture MPS.

genetics↗

bioRxiv2018

Quantifying Heterogeneity in the Genetic Architecture of Complex Traits Between Ethnically Diverse Groups using Random Effect Interaction Models

In humans, most genome-wide association studies have been conducted using data from Caucasians and many of the reported findings have not replicated in other populations. This lack of replication may be due to statistical issues (small sample size, confounding) or perhaps more fundamentally to differences in the genetic architecture of traits between ethnically diverse subpopulations. What aspects of the genetic architecture of traits vary between subpopulations and how can this be quantified? We consider studying effect heterogeneity using random-effect Bayesian interaction models. The proposed methodology can be applied using shrinkage and variable selection methods and produces useful information about effect heterogeneity in the form of whole-genome summaries (e.g., SNP-heritability and the average correlation of effects) as well as SNP-specific attributes. Using simulations, we show that the proposed methodology yields (nearly) unbiased estimates of genomic heritability and of the average correlation of effects between groups when the sample size is not too small relative to the number of SNPs used. Subsequently, we used the proposed methodology for the analyses of four complex human traits (standing height, high-density lipoprotein, low-density lipoprotein, and serum urate levels) in European-Americans (EAs) and African-Americans (AAs). The estimated correlations of effects between the two subpopulations was well below unity for all the traits, ranging from 0.73 to 0.50. The extent of effect heterogeneity varied between traits and SNP-sets. Height showed less differences in SNP effects between AAs and EAs whereas HDL, a trait highly influenced by life-style, exhibited greater extent of effect heterogeneity. For all the traits we observed substantial variability in effect heterogeneity across SNPs, suggesting it varies between regions of the genome.

genetics↗