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Biomedical subjects

Sarah E Pierce

Publications and source records attributed to Sarah E Pierce.

10 recordsLinked to original sources
PubMed2026

Efficient prime editing in vivo and in vitro using lipid nanoparticles.

Prime editing is a versatile clinical genome editing method that enables precise substitutions, small insertions and deletions at specified locations in the genomes of living systems including human cells. Although non-viral lipid nanoparticle (LNP) delivery of RNA in vivo has become a preferred method for gene editing in animals and patients, its application to complex, three-component prime editing systems has yielded low editing efficiencies. Here we developed a systematic prime editing LNP (PE-LNP) optimization platform that addresses key bottlenecks in cargo design that limit editing efficiency. This generalizable workflow yielded PE-LNPs that can achieve 49% average in vivo prime editing in the bulk mouse liver with a single dose of 2 mg kg-1. We applied our workflow to the correction of PAH R408W, a cause of phenylketonuria, in a mouse model and achieved prime editing efficiencies and serum phenylalanine levels anticipated to be curative. We also show that PE-LNPs minimize off-target editing compared with DNA delivery methods, induce only transient elevation of liver enzymes and can be dosed repeatedly to improve editing efficiencies. These PE-LNP systems provide an attractive alternative to viral delivery by offering transient expression that minimizes off-target editing, no observed long-term toxicity and high levels of non-viral in vivo liver prime editing.

Animals↗
PubMed2025

Functional Mapping of Epigenomic Regulators Uncovers Coordinated Tumor Suppression by the HBO1 and MLL1 Complexes.

UNLABELLED: Epigenomic dysregulation is widespread in cancer. However, the specific epigenomic regulators and the processes they control to drive cancer phenotypes are poorly understood. We used a novel high-throughput in vivo method to perform iterative functional screens of >250 epigenomic regulators within autochthonous oncogenic Kras-driven lung tumors. We identified many previously unappreciated epigenomic tumor suppressor and tumor dependency genes. We show that a specific HBO1 complex and MLL1 complex are robust tumor suppressors in lung adenocarcinoma. Histone modifications generated by the HBO1 complex are frequently reduced in human lung adenocarcinomas and are associated with worse clinical features. HBO1 and MLL1 complexes co-occupy shared genomic regions, affect chromatin accessibility, and control the expression of canonical tumor suppressor genes and lineage fidelity. The HBO1 complex is epistatic with the MLL1 complex and other tumor suppressor genes in lung adenocarcinoma development. Collectively, these results provide a phenotypic roadmap of epigenomic regulators in lung tumorigenesis in vivo. SIGNIFICANCE: Using a novel functional genomics method in vivo, we investigated epigenomic regulators in lung tumorigenesis. We discovered multiple novel genes that affect tumor growth. We show that the HBO1 and MLL1 complexes interact to suppress lung adenocarcinoma. Our findings provide broad insights into the epigenomic regulatory landscape of lung cancer.

Humans↗
PubMed2006

Head tilt-translation combinations distinguished at the level of neurons.

Angular and linear accelerations of the head occur throughout everyday life, whether from external forces such as in a vehicle or from volitional head movements. The relative timing of the angular and linear components of motion differs depending on the movement. The inner ear detects the angular and linear components with its semicircular canals and otolith organs, respectively, and secondary neurons in the vestibular nuclei receive input from these vestibular organs. Many secondary neurons receive both angular and linear input. Linear information alone does not distinguish between translational linear acceleration and angular tilt, with its gravity-induced change in the linear acceleration vector. Instead, motions are thought to be distinguished by use of both angular and linear information. However, for combined motions, composed of angular tilt and linear translation, the infinite range of possible relative timing of the angular and linear components gives an infinite set of motions among which to distinguish the various types of movement. The present research focuses on motions consisting of angular tilt and horizontal translation, both sinusoidal, where the relative timing, i.e. phase, of the tilt and translation can take any value in the range -180 degrees to 180 degrees . The results show how hypothetical neurons receiving convergent input can distinguish tilt from translation, and that each of these neurons has a preferred combined motion, to which the neuron responds maximally. Also shown are the values of angular and linear response amplitudes and phases that can cause a neuron to be tilt-only or translation-only. Such neurons turn out to be sufficient for distinguishing between combined motions, with all of the possible relative angular-linear phases. Combinations of other neurons, as well, are shown to distinguish motions. Relative response phases and in-phase firing-rate modulation are the key to identifying specific motions from within this infinite set of combined motions.

Cybernetics↗
PubMed2006

Identification of the adduct between a 4-Aza-3-ene-1,6-diyne and DNA using electrospray ionization mass spectrometry.

The interactions between a novel enediyne [1-methyl-2-(phenylethynyl)-3-(3-phenylprop-2-ynyl)-3H-benzimidazolium] (1) and various cytosine-containing oligonucleotides were studied using electrospray ionization mass spectrometry (ESI-MS) in a flow injection analysis mode useful for small volumes. This enediyne ligand, developed as a potential alternative to the highly cytotoxic natural enediynes, some of which have been successfully used as anti-tumor agents, has previously been shown to interact with DNA through frank strand scission as well as via the formation of adducts that lead to 2'-deoxycytidine-specific cleavage. Through ESI-MS, the structures of these adducts were examined and a sequence dependence of the 2'-deoxycytidine-specific cleavage was noted. Collisionally activated dissociation of the observed adducts confirmed the strength of the interactions between the enediyne and DNA and supports a direct linkage between the enediyne and the cytosine nucleobase, likely the result of a nucleophilic attack of the phenylethynyl group by the cytosine amine.

Alkynes↗
PubMed2006

A unique and universal molecular barcode array.

Molecular barcode arrays allow the analysis of thousands of biological samples in parallel through the use of unique 20-base-pair (bp) DNA tags. Here we present a new barcode array, which is unique among microarrays in that it includes at least five replicates of every tag feature. The use of smaller dispersed replicate features dramatically improves performance versus a single larger feature and allows the correction of previously undetectable hybridization defects.

Base Sequence↗
PubMed2005

Give Wisconsin children a boost.

In the United States, more children die from motor vehicle crashes than any other cause. Research has demonstrated that children ages 4-8 have a significantly reduced risk of injury if they are restrained in booster seats rather than adult seatbelts. Despite current recommendations, few children in this age group are properly restrained. Health care providers can help increase booster seat use by educating parents, participating in community campaigns, and advocating for mandatory booster seat laws.

Accidents, Traffic↗
PubMed2005

Improving awareness and use of booster seats in Head Start families.

OBJECTIVES: To determine the knowledge level of Head Start providers, parents, and students about booster seats and to directly observe booster seat use before and after a combined educational program and booster seat giveaway. METHODS: Before and after a short educational session and child safety seat giveaway, Head Start providers and parents received a brief questionnaire on booster seats and the state child restraint law. Direct parking-lot observation of booster seat use was performed before and after the giveaway. RESULTS: Forty-three students were enrolled in the study, with 33 receiving booster seats and 5 receiving forward-facing car seats, dependent on the weight and age of the child. Before the study, 15 (35%) of the children had weight/age appropriate child safety seats; after the giveaway, this number increased to 42 (98%; P<0.001). The proportion of children observed using booster seats before the giveaway was 6%, which increased to 34% after the giveaway (P<0.001). CONCLUSIONS: This study indicates that a booster seat giveaway can be successful in increasing the number of children who use booster seats; however, the majority (66%) of participating children still rode inappropriately restrained after the giveaway. Steps beyond providing booster seats, such as combining this intervention with ongoing parent and community education efforts, as well as legislation and enforcement, are needed to bring booster seat use to a high level. The information from this study may be helpful in designing future programs intended to increase booster seat use, as well as emphasizing the need for booster seat legislation.

Accidents, Traffic↗
PubMed2005

The role of the health care professional in bicycle safety.

Learning to ride a bicycle and enjoying the pleasures of cycling are synonymous with childhood; unfortunately, cycling does not come without risk of serious injury. Children under 15 years old account for the majority of cycling time in the United States, and on average, 1 child dies every day from a bicycle-related injury. Health care professionals can play an important role in making cycling a safe activity by encouraging and advocating for safe bicycling practices. Specific areas for physicians and health care professionals to emphasize involve the cyclist, environmental factors, and equipment factors. Helmet use by cyclists, avoidance of risk-taking, safe cycling road behavior, and proper cycling equipment fit and usage are all areas in which health care professionals can instruct families during office visits. The physician and the health care community can also be advocates for mandatory helmet legislation in order to achieve higher helmet usage rates and decreased cycling injuries. The health care professional's role in bicycle safety is an important component in building a foundation for safe cycling.

Accident Prevention↗
PubMed2004

Increasing access to affordable contraception: a look at the Wisconsin Medicaid Family Planning Waiver.

Approximately half of all pregnancies in the United States are unintended. The purpose of the Family Planning Waiver, a Wisconsin Medicaid program implemented in 2003, is to expand access to contraceptive care and other reproductive health services. The waiver provides women with birth control services and supplies, emergency contraception, routine reproductive health exams, and diagnosis and treatment of sexually transmitted diseases. With greater availability of contraception, the expected outcome is a reduction of unintended pregnancies and subsequent therapeutic abortion, which results in a decreased financial burden to the state, as well as an opportunity for women to experience motherhood when they are emotionally prepared to do so.

Adolescent↗