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Publications in Enabling & Strategic Technologies by NOMIS researchers

Fibroblast Growth Factor 2-Mediated Regulation of Neuronal Exosome Release Depends on VAMP3/Cellubrevin in Hippocampal Neurons

NOMIS Researcher(s)

Published in

March 1, 2020

Extracellular vesicles (EVs) are endogenous membrane-derived vesicles that shuttle bioactive molecules between glia and neurons, thereby promoting neuronal survival and plasticity in the central nervous system (CNS) and contributing to neurodegenerative conditions. Although EVs hold great potential as CNS theranostic nanocarriers, the specific molecular factors that regulate neuronal EV uptake and release are currently unknown. A combination of patch-clamp electrophysiology and pH-sensitive dye imaging is used to examine stimulus-evoked EV release in individual neurons in real time. Whereas spontaneous electrical activity and the application of a high-frequency stimulus induce a slow and prolonged fusion of multivesicular bodies (MVBs) with the plasma membrane (PM) in a subset of cells, the neurotrophic factor basic fibroblast growth factor (bFGF) greatly increases the rate of stimulus-evoked MVB-PM fusion events and, consequently, the abundance of EVs in the culture medium. Proteomic analysis of neuronal EVs demonstrates bFGF increases the abundance of the v-SNARE vesicle-associated membrane protein 3 (VAMP3, cellubrevin) on EVs. Conversely, knocking-down VAMP3 in cultured neurons attenuates the effect of bFGF on EV release. The results determine the temporal characteristics of MVB-PM fusion in hippocampal neurons and reveal a new function for bFGF signaling in controlling neuronal EV release.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Nanoscience & Nanotechnology

DOI
10.1002/advs.201902372

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy

NOMIS Researcher(s)

Published in

January 1, 2019

Motivation Multiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia. Results We performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified. Availability and implementation Datasets and scripts for reproduction of results are available through: Https://nalab.stanford.edu/multiomics-pregnancy/.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics

DOI
10.1093/bioinformatics/bty537

Predicting age from the transcriptome of human dermal fibroblasts

NOMIS Researcher(s)

Published in

December 20, 2018

Biomarkers of aging can be used to assess the health of individuals and to study aging and age-related diseases. We generate a large dataset of genome-wide RNA-seq profiles of human dermal fibroblasts from 133 people aged 1 to 94 years old to test whether signatures of aging are encoded within the transcriptome. We develop an ensemble machine learning method that predicts age to a median error of 4 years, outperforming previous methods used to predict age. The ensemble was further validated by testing it on ten progeria patients, and our method is the only one that predicts accelerated aging in these patients.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Bioinformatics

DOI
10.1186/s13059-018-1599-6

Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy δ7 mouse model phenotype

NOMIS Researcher(s)

Published in

March 1, 2014

Background Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile. Objective We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region. Methods We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features. Results We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment. Conclusion These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients. © 2014 Elsevier HS Journals, Inc.

Research field(s)
Applied Sciences, Enabling & Strategic Technologies, Optoelectronics & Photonics

DOI
10.1016/j.clinthera.2014.02.004

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