Biology subjects

Hacker, J.

Publications and source records attributed to Hacker, J..

4 recordsLinked to original sources

bioRxiv2026

Post-encoding slow-wave amplitude during a daytime nap predicts pattern completion from sparse visual cues

Pattern completion refers to the reinstatement of a stored memory representation from partial or degraded cues. In this sense, it enables a form of cue-based generalization: the same memory representation can be retrieved across different, incomplete versions of the original input. Sleep supports hippocampus-dependent memory consolidation and may facilitate such flexible retrieval, but it remains unclear whether post-encoding sleep improves visual pattern completion from degraded cues. Previous sleep studies have mainly examined mnemonic discrimination or relational memory, leaving open whether sleep directly enhances the recovery of learned visual scenes from sparse perceptual information. We tested this question using the Memory Image Completion (MIC) task in a polysomnographic within-subject sleep-wake design. Twenty-eight healthy young adults (14 female; mean age 23.4 {+/-} 3.1 years) encoded scene-label associations and were tested immediately and after either a 90-min daytime nap or a matched wake interval. During retrieval, learned and new scenes were presented at five levels of visual completeness. A separate pre-encoding baseline nap assessed individual sleep physiology without prior learning. Sleep did not generally improve performance across all retrieval conditions. Instead, it selectively enhanced consolidation of learned scenes when visual cues were maximally degraded (p = .001) indicating increased pattern completion. No corresponding sleep effect was found for new scenes (all p > .31), suggesting that the benefit was specific to the recovery of previously encoded scene representations. Slow-wave amplitude during the post-encoding nap predicted consolidation of learned scenes under the most degraded condition (p = .011; FDR-corrected p = .042), whereas baseline slow-wave amplitude did not (p > .11). These findings suggest that post-encoding sleep facilitates cue-based recovery of learned visual representations from strongly degraded input, and that this benefit is linked to slow-wave amplitude during post-encoding sleep. Together, these results link sleep-dependent consolidation to visual pattern-completion-like retrieval and extend previous work on sleep-related memory transformation from verbal and relational paradigms to the recovery of learned scene representations from degraded cues.

neuroscience↗

bioRxiv2024

Effective Gene Therapy for Metachromatic Leukodystrophy Achieved with Minimal Lentiviral Genomic Integrations

Metachromatic leukodystrophy (MLD) is a fatal lysosomal storage disease (LSD) characterized by the deficient enzymatic activity of arylsulfatase A (ARSA). Combined autologous hematopoietic stem cell transplant (HSCT) with lentiviral (LV) based gene therapy has great potential to treat MLD. However, if enzyme production is inadequate, this could result in continued loss of motor function, implying a high vector copy number (VCN) requirement for optimal enzymatic output. This may place children at increased risk for genomic toxicity due to higher VCN. We increased the expression of ARSA cDNA at single integration by generating novel LVs, optimizing ARSA expression, and enhancing safety. In addition, our vectors achieved optimal transduction in mouse and human HSC with minimal multiplicity of infection (MOI). Our top-performing vector (EA1) showed at least 4X more ARSA activity than the currently EU-approved vector and a superior ability to secrete vesicle-associated ARSA, a critical modality to transfer functional enzymes from microglia to oligodendrocytes. Three-month-old Arsa-KO MLD mice transplanted with Arsa-KO BM cells transduced with 0.6 VCN of EA1 demonstrated behavior and CNS histology matching WT mice. Our novel vector boosts efficacy while improving safety as a robust approach for treating early symptomatic MLD patients.

molecular biology↗

bioRxiv2023

Increased epithelial mTORC1 activity in chronic rhinosinusitis with nasal polyps

BackgroundThe airway epithelium plays a central role in the pathogenesis of chronic respiratory diseases such as asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), but the mechanisms by which airway epithelial cells (EpCs) maintain inflammation are poorly understood. ObjectiveWe hypothesized that transcriptomic assessment of sorted airway EpCs across the spectrum of differentiation would allow us to define mechanisms by which EpCs perpetuate airway inflammation. MethodsEthmoid sinus EpCs from adult patients with CRS were sorted into 3 subsets, bulk RNA sequenced, and analyzed for differentially expressed genes and pathways. Single cell RNA-seq (scRNA-seq) datasets from eosinophilic and non-eosinophilic CRSwNP and bulk RNA-seq of EpCs from mild/moderate and severe asthma were assessed. Immunofluorescent staining and ex vivo functional analysis of sinus EpCs were used to validate our findings. ResultsAnalysis within and across purified EpC subsets revealed an enrichment in glycolytic programming in CRSwNP vs CRSsNP. Correlation analysis identified mammalian target of rapamycin complex 1 (mTORC1) as a potential regulator of the glycolytic program and identified EpC expression of cytokines and wound healing genes as potential sequelae. mTORC1 activity was upregulated in CRSwNP, and ex vivo inhibition demonstrated that mTOR is critical for EpC generation of CXCL8, IL-33, and CXCL2. Across patient samples, the degree of glycolytic activity was associated with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in severe asthma. ConclusionsTogether, these findings highlight a metabolic axis required to support epithelial generation of cytokines critical to both chronic T2 and non-T2 inflammation in CRSwNP and asthma. KEY MESSAGESO_LIEpithelial mTORC1 activity is upregulated in CRSwNP. C_LIO_LImTOR regulates EpC cytokine generation. C_LIO_LIEpithelial metabolic reprograming correlates with T2 inflammation in CRSwNP, and with both T2 and non-T2 inflammation in asthma. C_LI CAPSULE SUMMARYmTORC1 mediates EpC cytokine generation in CRSwNP.

immunology↗

bioRxiv2022

mRNA-based vaccines against SARS-CoV-2 do not stimulate interferon stimulatory gene expression in individuals affected by Aicardi Goutieres Syndrome.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses threats to individuals with rare disease, in part because so little is known about the impact of COVID-19 infection and vaccination safety in rare disease populations. Of particular concern, given the overlap in disease manifestations and interferon dysregulation, are a group of heritable autoinflammatory conditions called type I interferonopathies. The most common of these, Aicardi Goutieres Syndrome (AGS), is caused by altered nucleic acid metabolism and sensing, resulting in additional concerns surrounding the use of mRNA vaccination approaches. To determine whether mRNA vaccines induce an interferon response in AGS, we applied mRNA SARS-CoV-2 vaccines to whole blood samples and assessed internalization and interferon signaling gene expression responses to the mRNA. In all cases (11 AGS and 11 control samples), interferon signatures did not significantly increase from baseline, regardless of baricitinib treatment status in the AGS subjects, and were even decreased, when using codon optimized SARS-CoV-2 di-proline modified spike sequence (S2P). Internalization of S2P in human dendritic cells was verified by Western Blot, and in control and AGS blood cells was verified by Luciferase activity. Although numbers of tested samples in this rare disease are small, based on these findings, we suggest that COVID vaccination is unlikely to directly stimulate the interferon signaling gene expression in AGS patients via response to mRNA internalization. The in vitro nature of this study cannot exclude an exaggerated interferon response to spike protein production at a systemic level in individuals with a primary heritable interferonopathy. In the context of continued SARS-CoV-2 spread in the community, we do not recommend withholding vaccination in this rare disease group. However, we recommend that vaccinations for AGS patients are provided in a controlled setting with appropriate observation and used with caution in individuals with prior vaccine associated adverse events.

immunology↗