Twenty-Year Survival Analysis of Adeno-Associated Virus Vector Serotype 2-Mediated Gene Therapy to the Central Nervous System for CLN2 Disease.

CLN2 disease (late infantile neuronal ceroid lipofuscinosis) is an autosomal recessive, neurodegenerative lysosomal storage disease that results from loss of function mutations in the gene, which encodes tripeptidyl peptidase 1. It affects the central nervous system (CNS) with progressive neurodegeneration and early death, typically at ages from 8 to 12 years. Twenty years ago, our phase I clinical trial treated subjects with CLN2 disease by a catheter-based CNS administration of an adeno-associated virus vector serotype 2 (AAV2) expressing the gene.

Serial Sampling of the Small Airway Epithelium to Identify Persistent Smoking-dysregulated Genes.

The small airway epithelium (beyond the sixth generation), the initiation site of smoking-induced airway disorders, is highly sensitive to the stress of smoking. Because of variations over time in smoking habits, the small airway epithelium transcriptome is dynamic, fluctuating not only among smokers but also within each smoker. To perform accurate assessment of the smoking-related dysregulation of the human small airway epithelium despite the variation of smoking within the same individual and of the effects of smoking cessation on the dysregulated transcriptome.

Oral epithelium response of electronic cigarette users to electronic cigarette.

Background: Electronic cigarettes are increasing in popularity, but there is only little information on their biologic effects on the oral epithelium, the initial site exposed to electronic cigarette smoke.

Methods: We assessed the oral epithelium response to electronic cigarettes by comparing the histology and RNA transcriptome (mRNA and miRNA) of healthy electronic cigarette vapers to nonsmokers. mRNA was assessed based on: (1) genome-wide; (2) genes previously identified as dysregulated in the oral epithelium of electronic cigarette vapers versus nonsmokers; (3) immune and inflammatory-related genes previously identified as dysregulated in the nasal epithelium of electronic cigarette vapers compared to nonsmokers; (4) genes previously identified as dysregulated in the small airway epithelium of nonsmokers following an acute exposure to electronic cigarette; and (5) genes related to the initial steps of COVID-19 infection.

The QChip1 knowledgebase and microarray for precision medicine in Qatar.

Risk genes for Mendelian (single-gene) disorders (SGDs) are consistent across populations, but pathogenic risk variants that cause SGDs are typically population-private. The goal was to develop "QChip1," an inexpensive genotyping microarray to comprehensively screen newborns, couples, and patients for SGD risk variants in Qatar, a small nation on the Arabian Peninsula with a high degree of consanguinity. Over 10 variants in 8445 Qatari were identified for inclusion in a genotyping array containing 165,695 probes for 83,542 known and potentially pathogenic variants in 3438 SGDs.

The derepression of transposable elements in lung cells is associated with the inflammatory response and gene activation in idiopathic pulmonary fibrosis.

Background: Transposable elements (TEs) are repetitive sequences of viral origin that compose almost half of the human genome. These elements are tightly controlled within cells, and if activated, they can cause changes in both gene regulation and immune viral responses that have been associated with several chronic inflammatory diseases in humans. As oxidants are potent activators of TEs, and because oxidative injury is a major risk factor in relation to idiopathic pulmonary fibrosis (IPF), we hypothesized that TEs might be involved in the regulation of gene expression and so contribute to inflammation in cases of IPF.

Dysregulation of club cell biology in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. "Bronchiolization", characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF.

Cell-specific expression of lung disease risk-related genes in the human small airway epithelium.

Background: The human small airway epithelium (SAE) plays a central role in the early events in the pathogenesis of most inherited and acquired lung disorders. Little is known about the molecular phenotypes of the specific cell populations comprising the SAE in humans, and the contribution of SAE specific cell populations to the risk for lung diseases.

Methods: Drop-seq single-cell RNA-sequencing was used to characterize the transcriptome of single cells from human SAE of nonsmokers and smokers by bronchoscopic brushing.

Expression of the SARS-CoV-2 Receptor in the Human Airway Epithelium.

Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19), a predominantly respiratory illness. The first step in SARS-CoV-2 infection is binding of the virus to (angiotensin-converting enzyme 2) on the airway epithelium. The objective was to gain insight into the expression of in the human airway epithelium.

Aggregate and Microcarrier Cultures of Human Pluripotent Stem Cells in Stirred-Suspension Systems.

Pluripotent stem cells can differentiate to any cell type and contribute to damaged tissue repair and organ function reconstitution. The scalable culture of pluripotent stem cells is essential to furthering the use of stem cell products in a wide gamut of applications such as screening of candidate drugs and cell replacement therapies. Human stem cell cultivation in stirred-suspension vessels enables the expansion of stem cells and the generation of differentiated progeny in quantities suitable for use in animal models and clinical studies.

Inverse problem analysis of pluripotent stem cell aggregation dynamics in stirred-suspension cultures.

The cultivation of stem cells as aggregates in scalable bioreactor cultures is an appealing modality for the large-scale manufacturing of stem cell products. Aggregation phenomena are central to such bioprocesses affecting the viability, proliferation and differentiation trajectory of stem cells but a quantitative framework is currently lacking. A population balance equation (PBE) model was used to describe the temporal evolution of the embryonic stem cell (ESC) cluster size distribution by considering collision-induced aggregation and cell proliferation in a stirred-suspension vessel.

Oxygen transport and stem cell aggregation in stirred-suspension bioreactor cultures.

Stirred-suspension bioreactors are a promising modality for large-scale culture of 3D aggregates of pluripotent stem cells and their progeny. Yet, cells within these clusters experience limitations in the transfer of factors and particularly O2 which is characterized by low solubility in aqueous media. Cultured stem cells under different O2 levels may exhibit significantly different proliferation, viability and differentiation potential.

Stem cell modeling: From gene networks to cell populations.

Despite rapid advances in the field of stem/progenitor cells through experimental studies, relevant modeling approaches have not progressed with a similar pace. Various models have focused on particular aspects of stem cell physiology including gene regulatory networks, gene expression noise and signaling cascades activated by exogenous factors. However, the self-renewal and differentiation of stem cells is driven by the coordinated regulation of events at the subcellular, intercellular and milieu levels.