Biology subjects

Yoo, A.

Publications and source records attributed to Yoo, A..

8 recordsLinked to original sources

bioRxiv2025

Transient Dietary Changes Modulate Inflammatory Disease Trajectory in the Lean State

Obesity potently alters immune responses across various inflammatory contexts1-7. However, it is unclear whether a transient high-fat diet (HFD) can affect immune function despite minimal effects on body weight. Here, we demonstrate that a short-term HFD regimen significantly exacerbates disease severity in a model of experimental psoriasis, comparable to what is observed in obese mice on long-term HFD. We find that a critical 4-day window of HFD coinciding with disease onset is sufficient to overactivate the immune response, leading to worsened disease outcomes. Mechanistically, we identify the CD4+ T cell compartment as an essential mediator of HFD-induced disease severity. Within the compartment, we functionally validate that disease exacerbation is driven by increased differentiation of a pathogenic population of T helper 17 (TH17) cells8 expressing IL1R1 (interleukin-1 receptor, type I)9, which is triggered by localized activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome10. This brief window of HFD at disease onset leads to immune-dependent sensitization, as disease severity is increased upon a subsequent flare, despite complete recovery and under a low-fat diet (LFD) regimen. Our data indicate that transient dietary changes during the initial stages of an inflammatory event can rewire the immune milieu, profoundly influencing disease progression and inflammatory memory11. This phenomenon may have broad implications for conditions where obesity, and not diet itself, is considered the primary risk factor.

immunology↗

bioRxiv2024

Loss of neurofibromin accelerates uveal and dermal melanoma formation driven by GNAQ

Neurofibromin is a very large and complex tumor suppressor, whose loss can synergize with other MAPK pathway mutations to promote melanoma in the skin. In this paper, we investigated whether NF1 loss has a role in other melanomas, such as those that form in the dermis or eye (uveal tract). We found that heterozygous 17q11.2 loss that includes the NF1 locus is an uncommon, but recurrent phenomenon in human dermal and uveal melanomas described previously. We studied the effects of Nf1 haploinsufficiency in mice expressing oncogenic GNAQQ209L in melanocytes and Schwann cells of peripheral nerves using the Plp1-creERT transgene, with tamoxifen given at 5 weeks of age. Nf1 haploinsufficiency accelerated dermal and uveal melanoma formation. We studied the effects of Nf1 loss in these melanomas using RNAseq. Many of the differentially expressed genes were homologous to genes whose expression correlates with prognosis in human uveal melanoma. Of particular interest was the up-regulation of cAMP signaling and its connection to protein kinase A, which is mutant in malignant melanotic nerve sheath tumors (MMNSTs). An unexpected finding was that oncogenic GNAQ was sufficient by itself to drive peripheral nerve sheath-like neoplasms in the mice. Hence, these studies reveal new insight into both melanocyte and Schwann cell transformation.

cancer biology↗

bioRxiv2024

Neural mechanisms of resource allocation in working memory

To mitigate capacity limits of working memory, people allocate resources according to an items relevance. However, the neural mechanisms supporting such a critical operation remain unknown. Here, we developed computational neuroimaging methods to decode and demix neural responses associated with multiple items in working memory with different priorities. In striate and extrastriate cortex, the gain of neural responses tracked the priority of memoranda. Higher-priority memoranda were decoded with smaller error and lower uncertainty. Moreover, these neural differences predicted behavioral differences in memory prioritization. Remarkably, trialwise variability in the magnitude of delay activity in frontal cortex predicted differences in decoded precision between low and high-priority items in visual cortex. These results suggest a model in which feedback signals broadcast from frontal cortex sculpt the gain of memory representations in visual cortex according to behavioral relevance, thus, identifying a neural mechanism for resource allocation.

neuroscience↗

bioRxiv2024

Notch Inhibition Enhances Morphological Reprogramming of microRNA-Induced Human Neurons

Although the importance of Notch signaling in brain development is well-known, its specific contribution to cellular reprogramming remains less defined. Here, we use microRNA-induced neurons that are directly reprogrammed from human fibroblasts to determine how Notch signaling contributes to neuronal identity. We found that inhibiting Notch signaling led to an increase in neurite extension, while activating Notch signaling had the opposite effect. Surprisingly, Notch inhibition during the first week of reprogramming was both necessary and sufficient to enhance neurite outgrowth at a later timepoint. This timeframe is when the reprogramming miRNAs, miR-9/9* and miR-124, primarily induce a post-mitotic state and erase fibroblast identity. Accordingly, transcriptomic analysis showed that the effect of Notch inhibition was likely due to improvements in fibroblast fate erasure and silencing of anti-neuronal genes. To this effect, we identify MYLIP, whose downregulation in response to Notch inhibition significantly promoted neurite outgrowth. Moreover, Notch inhibition resulted in cells with neuronal transcriptome signature defined by expressing long genes at a faster rate than the control, demonstrating the effect of accelerated fate erasure on neuronal fate acquisition. Our results demonstrate the critical role of Notch signaling in mediating morphological changes in miRNA-based neuronal reprogramming of human adult fibroblasts.

developmental biology↗

bioRxiv2023

The prevalence of Fusobacterium nucleatum subspecies in the oral cavity stratifies by local health status

The ubiquitous inflammophilic pathobiont Fusobacterium nucleatum is widely recognized for its strong association with a variety of human dysbiotic diseases such as periodontitis and oral/extraoral abscesses, as well as multiple types of cancer. F. nucleatum is currently subdivided into four subspecies: F. nucleatum subspecies nucleatum (Fn. nucleatum), animalis (Fn. animalis), polymorphum (Fn. polymorphum), and vincentii/fusiforme (Fn. vincentii). Although these subspecies have been historically considered as functionally interchangeable in the oral cavity, direct clinical evidence is largely lacking for this assertion. Consequently, we assembled a collection of oral clinical specimens to determine whether F. nucleatum subspecies prevalence in the oral cavity stratifies by local oral health status. Patient-matched clinical specimens of both disease-free dental plaque and odontogenic abscess were analyzed with newly developed culture-dependent and culture-independent approaches using 44 and 60 oral biofilm/tooth abscess paired specimens, respectively. Most oral cavities were found to simultaneously harbor multiple F. nucleatum subspecies, with a greater diversity present within dental plaque compared to abscesses. In dental plaque, Fn. polymorphum is clearly the dominant organism, but this changes dramatically within odontogenic abscesses where Fn. animalis is heavily favored over all other fusobacteria. Surprisingly, the most commonly studied F. nucleatum subspecies, Fn. nucleatum, is only a minor constituent in the oral cavity. To gain further insights into the genetic basis for these phenotypes, we subsequently performed pangenome, phylogenetic, and functional enrichment analyses of oral fusobacterial genomes using the Anvio platform, which revealed significant genotypic distinctions among F. nucleatum subspecies. Accordingly, our results strongly support a taxonomic reassignment of each F. nucleatum subspecies into distinct Fusobacterium species. Of these, Fn. animalis should be considered as the most clinically relevant at sites of active inflammation, despite being among the least characterized oral fusobacteria.

microbiology↗

bioRxiv2021

Genomic and Metabolic Hallmarks of SDH- and FH-Deficient Renal Cell Carcinomas

PurposeSuccinate dehydrogenase-deficient and fumarate hydratase-deficient renal cell carcinomas (SDHRCC and FHRCC) are rare kidney cancers driven by loss of metabolically proximal enzymes. We sought to define and compare the genomic and metabolomic hallmarks of these entities. Experimental DesignWe analyzed SDHRCC and FHRCC tumors with either immunohistochemical evidence of loss of protein expression or genomically-confirmed biallelic inactivation of SDHA/B/C/D/AF2 or FH. Somatic alterations were identified using clinical pipelines, and allele-specific copy number changes were identified using FACETS. Mass-spectrometry-based metabolomic profiling was performed on available SDHRCC and FHRCC tumors. ResultsForty two patients were analyzed (25 FHRCC, 17 SDHRCC). In the germline analysis, 16/17 SDHRCC harbored a germline alteration in SDHB, whereas only 17/22 FHRCC had pathogenic germline FH variants. SDHRCC had a lower mutation burden (p = 0.02) and copy number alteration burden (p = 0.0002) than FHRCC. All SDHRCC presented with deletion of chromosome 1p (overlapping SDHB), whereas FHRCC demonstrated high but not ubiquitous loss of 1q (FH locus). Both SDHRCC and FHRCC demonstrated significant, idiopathic accumulation of the metabolite guanine. FHRCC tumors had elevated levels of urea cycle metabolites (argininosuccinate, citrulline, and fumarate), whereas SDHRCC had elevation of numerous acylcarnitines. These characteristic metabolic changes enabled the identification of a previously unrecognized SDH-deficient RCC. ConclusionDespite sharing similar genetic etiology, SDHRCC and FHRCC represent distinct molecular entities with unique genetic and metabolic abnormalities. Translational RelevanceMutations to the TCA cycle enzymes Succinate Dehydrogenase (SDH) and Fumarate Hydratase (FH) predispose individuals to unique subtypes of renal cell carcinoma (SDHRCC and FHRCC, respectively). Defining the genetic and metabolic hallmarks of these diseases is critical for advancing new diagnostic and therapeutic approaches for these rare but biologically intriguing entities. Despite a superficially similar genetic etiology, SDHRCC and FHRCC demonstrated significantly fewer secondary mutations to other cancer-associated genes and copy number aberrations than FHRCC, and was distinguished by universal loss-of-heterozygosity of chromosome 1p. Metabolomic analysis identified pathways disrupted in both SDHRCC and FHRCC, including the massive accumulation of free guanine, as well as pathways uniquely disrupted in each of the two entities. These metabolomic findings enabled the identification of a previously unidentified case of unclassified RCC with SDH deficiency, suggesting that metabolomic profiling may aid in phenotypic classification of tumors and uncover novel therapeutic targets.

cancer biology↗

bioRxiv2021

Resource-efficient pooled sequencing expands translational impact in solid tumors

Intratumoral genetic heterogeneity (ITH) poses a significant challenge to utilizing sequencing for decision making in the management of cancer. Although sequencing of multiple tumor regions can address the pitfalls of ITH, it does so at a significant increase in cost and resource utilization. We propose a pooled multiregional sequencing strategy, whereby DNA aliquots from multiple tumor regions are mixed prior to sequencing, as a cost-effective strategy to boost translational value by addressing ITH while preserving valuable residual tissue for secondary analysis. Focusing on kidney cancer, we demonstrate that DNA pooling from as few as two regions significantly increases mutation detection while reducing clonality misattribution. This leads to an increased fraction of patients identified with therapeutically actionable mutations, improved patient risk stratification, and improved inference of evolutionary trajectories with an accuracy comparable to bona fide multiregional sequencing. The same approach applied to non-small-cell lung cancer data substantially improves tumor mutational burden (TMB) detection. Our findings demonstrate that pooled DNA sequencing strategies are a cost-effective alternative to address intrinsic genetic heterogeneity in clinical settings.

genomics↗

bioRxiv2021

Joint representation of working memory and uncertainty in human cortex

Neural representations of visual working memory (VWM) are noisy, and thus, decisions based on VWM are inevitably subject to uncertainty. However, the mechanisms by which the brain simultaneously represents the content and uncertainty of memory remain largely unknown. Here, inspired by the theory of probabilistic population codes, we test the hypothesis that the human brain represents an item maintained in VWM as a probability distribution over stimulus feature space, thereby capturing both its content and uncertainty. We used a neural generative model to decode probability distributions over memorized locations from fMRI activation patterns. We found that the mean of the probability distribution decoded from retinotopic cortical areas predicted memory reports on a trial-by-trial basis. Moreover, in several of the same mid-dorsal stream areas the spread of the distribution predicted subjective trial-by-trial uncertainty judgments. These results provide evidence that VWM content and uncertainty are jointly represented by probabilistic neural codes.

neuroscience↗