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"Nguyen, Michelle"
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The Spitboy rule : tales of a Xicana in a female punk band
The story of a Chicana drummer who forged paths of feminism, freedom, and human rights into her all-girl punk rock band in the nineties.
Book
Landscape of stimulation-responsive chromatin across diverse human immune cells
A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells.
Analysis of gene expression and open chromatin regions in up to 32 immune cell populations under resting and stimulated conditions identifies widespread chromatin remodeling and shared response elements between stimulated B and T cells.
Journal Article
Functional CRISPR dissection of gene networks controlling human regulatory T cell identity
Human regulatory T (T
reg
) cells are essential for immune homeostasis. The transcription factor FOXP3 maintains T
reg
cell identity, yet the complete set of key transcription factors that control T
reg
cell gene expression remains unknown. Here, we used pooled and arrayed Cas9 ribonucleoprotein screens to identify transcription factors that regulate critical proteins in primary human T
reg
cells under basal and proinflammatory conditions. We then generated 54,424 single-cell transcriptomes from T
reg
cells subjected to genetic perturbations and cytokine stimulation, which revealed distinct gene networks individually regulated by FOXP3 and PRDM1, in addition to a network coregulated by FOXO1 and IRF4. We also discovered that HIVEP2, to our knowledge not previously implicated in T
reg
cell function, coregulates another gene network with SATB1 and is important for T
reg
cell–mediated immunosuppression. By integrating CRISPR screens and single-cell RNA-sequencing profiling, we have uncovered transcriptional regulators and downstream gene networks in human T
reg
cells that could be targeted for immunotherapies.
T
reg
cells are essential for immune homeostasis, but the transcription factors controlling their cellular identity are incompletely understood. Schumann and colleagues use pooled and arrayed CRISPR screens and scRNA-seq to describe key gene networks in human T
reg
cells.
Journal Article
Enhancer connectome in primary human cells identifies target genes of disease-associated DNA elements
High-resolution contact maps of active enhancers and target genes generated by H3K27ac HiChIP in primary human cells provide rational guides to link noncoding disease-associated risk variants to candidate causal genes. Genes are validated by CRISPR activation and interference at connected enhancers and eQTL analysis, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.
The challenge of linking intergenic mutations to target genes has limited molecular understanding of human diseases. Here we show that H3K27ac HiChIP generates high-resolution contact maps of active enhancers and target genes in rare primary human T cell subtypes and coronary artery smooth muscle cells. Differentiation of naive T cells into T helper 17 cells or regulatory T cells creates subtype-specific enhancer–promoter interactions, specifically at regions of shared DNA accessibility. These data provide a principled means of assigning molecular functions to autoimmune and cardiovascular disease risk variants, linking hundreds of noncoding variants to putative gene targets. Target genes identified with HiChIP are further supported by CRISPR interference and activation at linked enhancers, by the presence of expression quantitative trait loci, and by allele-specific enhancer loops in patient-derived primary cells. The majority of disease-associated enhancers contact genes beyond the nearest gene in the linear genome, leading to a fourfold increase in the number of potential target genes for autoimmune and cardiovascular diseases.
Journal Article
“Good Care Is Slow Enough to Be Able to Pay Attention”: Primary Care Time Scarcity and Patient Safety
Background
There is growing, widespread recognition that expectations of US primary care vastly exceed the time and resources allocated to it. Little research has directly examined how time scarcity contributes to harm or patient safety incidents not readily capturable by population-based quality metrics.
Objective
To examine near-miss events identified by primary care physicians in which taking additional time improved patient care or prevented harm.
Design
Qualitative study based on semi-structured interviews.
Participants
Twenty-five primary care physicians practicing in the USA.
Approach
Participants completed a survey that included demographic questions, the Ballard Organizational Temporality Scale and the Mini-Z scale, followed by a one hour qualitative interview over video-conference (Zoom). Iterative thematic qualitative data analysis was conducted.
Key Results
Primary care physicians identified several types of near-miss events in which taking extra time during visits changed their clinical management. These were evident in five types of patient care episodes: high-risk social situations, high-risk medication regimens requiring patient education, high acuity conditions requiring immediate workup or treatment, interactions of physical and mental health, and investigating more subtle clinical suspicions. These near-miss events highlight the ways in which unreasonably large patient panels and packed schedules impede adequate responses to patient care episodes that are time sensitive and intensive or require flexibility.
Conclusions
Primary care physicians identify and address patient safety issues and high-risk situations by spending more time than allotted for a given patient encounter. Current quality metrics do not account for this critical aspect of primary care work. Current healthcare policy and organization create time scarcity. Interventions to address time scarcity and to measure its prevalence and implications for care quality and safety are urgently needed.
Journal Article
Multiplexed droplet single-cell RNA-sequencing using natural genetic variation
Droplet single-cell RNA-seq is applied to large numbers of pooled samples from unrelated individuals.
Droplet single-cell RNA-sequencing (dscRNA-seq) has enabled rapid, massively parallel profiling of transcriptomes. However, assessing differential expression across multiple individuals has been hampered by inefficient sample processing and technical batch effects. Here we describe a computational tool, demuxlet, that harnesses natural genetic variation to determine the sample identity of each droplet containing a single cell (singlet) and detect droplets containing two cells (doublets). These capabilities enable multiplexed dscRNA-seq experiments in which cells from unrelated individuals are pooled and captured at higher throughput than in standard workflows. Using simulated data, we show that 50 single-nucleotide polymorphisms (SNPs) per cell are sufficient to assign 97% of singlets and identify 92% of doublets in pools of up to 64 individuals. Given genotyping data for each of eight pooled samples, demuxlet correctly recovers the sample identity of >99% of singlets and identifies doublets at rates consistent with previous estimates. We apply demuxlet to assess cell-type-specific changes in gene expression in 8 pooled lupus patient samples treated with interferon (IFN)-β and perform eQTL analysis on 23 pooled samples.
Journal Article
Hepatic Dearterialization for Nonresectable Liver Tumors in Five Dogs and Two Cats
Introduction Some massive or nodular liver tumors can make surgical resection dangerous. Transarterial embolization and chemoembolization recently have been evaluated in dogs and cats, but multinodular or diffuse tumors make selective embolization difficult, impractical, and may require multiple anesthetic events. Hepatic dearterialization in humans has been shown to be safe and sometimes successful in promoting temporary tumor regression. Materials and Methods Retrospective review of patients with nodular, diffuse, or non‐resectable massive liver tumors that underwent transarterial coil embolization of the hepatic artery from the origin of the gastroduodenal artery to the proximal hepatic artery was performed. Data recorded included patient signalment, clinical signs, serum biochemical changes, cross‐sectional imaging results, complications, and response to treatment. Results Seven patients (five dogs and two cats) underwent transarterial hepatic dearterialization and were included. All patients had increased pretreatment hepatocellular enzyme activities 24 h after surgery. All patients survived to discharge and five were discharged within 24 h after treatment. Two patients experienced mild short‐term vomiting and anorexia, one of which required repeat hospitalization. Repeat laboratory testing approximately 6 weeks after treatment indicated decreased ALT and AST activities in 5/6 and 4/5 patients, respectively. Repeat imaging identified tumor regression in 3/4 patients evaluated by computed tomography (CT). Survival time ranged from 50 to 505 days. Conclusion Hepatic dearterialization should be further investigated as a palliative management option for multinodular and diffuse liver tumors because it may provide a minimally invasive, safe, and palliative option based on the observation that all patients survived to discharge and tumor regression was noted in three animals.
Journal Article
Unconventional Tissue Engineering Materials in Disguise
Tissue engineering faces a recurring challenge in the transformation of biomaterials into 3D constructs that mimic the biological, chemical, and mechanical features of native tissues. Some of the conventional approaches can be sophisticated and involve extensive material processing and high-cost fabrication procedures. Despite tremendous strides in biomaterials discovery and characterization, the functional and manufacturing limitations have led to the innovation of novel biomimetic techniques that borrow from nature, human-made commodities, and other parts of life to overcome the challenges in tissue engineering and regenerative medicine. This review explores engineering strategies that involve unusual materials for improved functionality, scalability, sustainability, and cost-efficiency. The biomaterials discussed are globally accessible resources and can serve across a wide spectrum of biomedical research areas.
Tissue engineering has demonstrated remarkable progress in facilitating regeneration in diseased or damaged tissues. The field suffers from lack of biomaterials that provide sufficient vascularization for proper integration with surrounding tissues. The development of functional materials can be an efficient approach to address this concern.New strategies involve the rethinking of unconventional materials. Using materials such as plants, paper, ice, textiles, marine organisms, and edible products in modified fabrication techniques also adds the aspect of sustainability in these fields.These approaches address the functional limitations in tissue engineering technologies and offer biological, chemical, and mechanical robustness. With increased utilization of abundant and sustainable resources, the potential of tissue engineering technologies can reach a global scale.
Journal Article
Satisfaction can co-exist with hesitation: qualitative analysis of acceptability of telemedicine among multi-lingual patients in a safety-net healthcare system during the COVID-19 pandemic
Background
The COVID-19 pandemic triggered unprecedented expansion of outpatient telemedicine in the United States in all types of health systems, including safety-net health systems. These systems generally serve low-income, racially/ethnically/linguistically diverse patients, many of whom face barriers to digital health access. These patients’ perspectives are vital to inform ongoing, equitable implementation efforts.
Methods
Twenty-five semi-structured interviews exploring a theoretical framework of technology acceptability were conducted from March through July 2020. Participants had preferred languages of English, Spanish, or Cantonese and were recruited from three clinics (general medicine, obstetrics, and pulmonary) within the San Francisco Health Network. Both deductive and inductive coding were performed. In a secondary analysis, qualitative data were merged with survey data to relate perspectives to demographic factors and technology access/use.
Results
Participants were diverse with respect to language (52% non-English-speaking), age (range 23-71), race/ethnicity (24% Asian, 20% Black, 44% Hispanic/Latinx, 12% White), & smartphone use (80% daily, 20% weekly or less). All but 2 had a recent telemedicine visit (83% telephone). Qualitative results revealed that most participants felt telemedicine visits fulfilled their medical needs, were convenient, and were satisfied with their telemedicine care. However, most still preferred in-person visits, expressing concern that tele-visits relied on patients’ abilities to access telemedicine, as well as monitor and manage their own health without in-person physical evaluation.
Conclusions
High satisfaction with telemedicine can co-exist with patient-expressed hesitations surrounding the perceived effectiveness, self-efficacy, and digital access barriers associated with a new model of care. More research is needed to guide how healthcare systems and clinicians make decisions and communicate about visit modalities to support high-quality care that responds to patients’ needs and circumstances.
Journal Article
Breathing life into engineered tissues using oxygen-releasing biomaterials
Engineering three-dimensional (3D) tissues in clinically relevant sizes have demonstrated to be an effective solution to bridge the gap between organ demand and the dearth of compatible organ donors. A major challenge to the clinical translation of tissue-engineered constructs is the lack of vasculature to support an adequate supply of oxygen and nutrients post-implantation. Previous efforts to improve the vascularization of engineered tissues have not been commensurate to meeting the oxygen demands of implanted constructs during the process of homogeneous integration with the host. Maintaining cell viability and metabolic activity during this period is imperative to the survival and functionality of the engineered tissues. As a corollary, there has been a shift in the scientific impetus beyond improving vascularization. Strategies to engineer biomaterials that encapsulate cells and provide the sustained release of oxygen over time are now being explored. This review summarizes different types of oxygen-releasing biomaterials, strategies for their fabrication, and approaches to meet the oxygen requirements in various tissue engineering applications, including cardiac, skin, bone, cartilage, pancreas, and muscle regeneration.
Journal Article