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Engineering transcriptional regulation for cell-based therapies.
Get PDFA major aim in the field of synthetic biology is developing tools capable of responding to user-defined inputs by activating therapeutically relevant cellular functions. Gene transcription and regulation in response to external stimuli are some of the most powerful and versatile of these cellular functions being explored. Motivated by the success of chimeric antigen receptor (CAR) T-cell therapies, transmembrane receptor-based platforms have been embraced for their ability to sense extracellular ligands and to subsequently activate intracellular signal transduction. The integration of transmembrane receptors with transcriptional activation platforms has not yet achieved its full potential. Transient expression of plasmid DNA is often used to explore gene regulation platforms in vitro. However, applications capable of targeting therapeutically relevant endogenous or stably integrated genes are more clinically relevant. Gene regulation may allow for engineered cells to traffic into tissues of interest and secrete functional proteins into the extracellular space or to differentiate into functional cells. Transmembrane receptors that regulate transcription have the potential to revolutionize cell therapies in a myriad of applications, including cancer treatment and regenerative medicine. In this review, we will examine current engineering approaches to control transcription in mammalian cells with an emphasis on systems that can be selectively activated in response to extracellular signals. We will also speculate on the potential therapeutic applications of these technologies and examine promising approaches to expand their capabilities and tighten the control of gene regulation in cellular therapies
Fundal Anterior to Posterior Hysterotomy and Cesarean Myomectomy in Fibroid Uterus
Get PDFFibroids are a common benign tumor located in the female reproductive tract and affect up to 10 percent of women, leading to challenges during cesarean section. Few cases of myomectomy at the time of cesarean section have been described and most describe uteri with only a few fibroids present. Our case describes a 39 year old G1P0101female with extensive fibroids including large fibroids located at the lower uterine segment. This patient underwent cesarean section and myomectomy at 27 weeks and five days gestation with a fundal, vertical hysterotomy, extending from the anterior to posterior wall of uterus. This is the first case described in the literature of a cesarean section performed on a uterus with innumerable intramural fibroids and first case documented of a fundal, anterior to posterior hysterotomy
FROM CRISIS TO AFTERMATH: THE ROLE OF NURSING PROFESSIONAL DEVELOPMENT EDUCATORS DURING THE COVID-19 PANDEMIC: A REALIST CASE STUDY
Get PDFThe purpose of this qualitative, realistic inquiry case study was to examine and understand the experiences of NPD educators as they assisted new graduate nurses transitioning into clinical nursing practice during the COVID-19 pandemic in acute care hospitals in the state of New York. Moreover, this research study sought to understand how the COVID-19 pandemic brought about changes to the NPD educator\u27s role and their ability to assist new graduate nurses transitioning into clinical practice post-pandemic. The sample included NPD educators from acute care hospitals in the state of New York. Data collection included semi-structured interviews and document collection. The study found that during the COVID-19 acute care hospitals were unprepared and NPD educators were required to take on additional role and responsibilities. Furthermore, the study found that NPD educators were unable to adequately support the new graduate nurses during the COVID-19 pandemic, yet new graduate nurses rose to the occasion and were willing to care for COVID-19 patients. Finally, the study found that new graduate nurses are less prepared to care for a diverse group of patients, and even though this was a stressful time, NPD educators remained motivated to provide care for patients and help the staff
DISCOVERY OF OLIGOMERIC STATES AND SMALL MOLECULES THAT AFFECT DEACYLASE ACTIVITIES OF HUMAN SIRTUIN-2 (SIRT2)
No full textHuman sirtuin isoform 2 (SIRT2) is an NAD+-dependent enzyme that removes various acyl modifications from lysine residues. SIRT2 is involved in many biological processes, such as transcription, DNA repair, cell proliferation, and metabolism. Due to its diverse functions, SIRT2 is implicated in various disease states, including cancers and neurodegenerative disorders. This dissertation aimed to understand the regulation of SIRT2’s deacylase activities and to discover small molecule modulators of SIRT2. In this work, we found that SIRT2 dimerized in solution, and the dimerization decreased the deacetylase activities without affecting the defatty-acylase activity of this protein. Dimerized SIRT2 dissociates into monomers upon binding long fatty acylated substrates but not acetylated substrate. In addition, SIRT2 dimerizes in cells, as evidenced by split GFP technology. Furthermore, SIRT2 dimerization can be disrupted genetically by point mutations and pharmacologically by ascorbyl palmitate. Our work also discovered a small molecule (8008-3660) (1) from a novel high-throughput screen that inhibits the enzyme’s deacetylase and defatty-acylase activities with potency comparable to known defatty-acylase inhibitors. Altogether, the genetic and pharmacological modulators discovered in this work have the potential to clarify different SIRT2’s deacylase activities in diseased and healthy cells and provide evidence that SIRT2 can be utilized as a therapeutic target for treating various diseases
Controls on Soft Tissue and Cellular Preservation in Late Eocene and Oligocene Vertebrate Fossils from the White River and Arikaree Groups of Nebraska, South Dakota, and Wyoming
Get PDFPrevious studies on microtaphonomy have identified multiple types of organic microstructures in fossil vertebrates from a variety of time periods and past environmental settings. This study investigates potential taphonomic, paleoenvironmental, and paleoclimatic controls on soft tissue and cellular preservation in fossil bone. To this end, fifteen vertebrate fossils were studied: eight fossils collected from the Oligocene Sharps Formation of the Arikaree Group in Badlands National Park, South Dakota, and seven fossils from formations in the underlying White River Group, including the Oligocene Brule Formation of Badlands National Park, and the Eocene Chadron Formation of Flagstaff Rim, Wyoming; Toadstool Geologic Park, Nebraska; and Badlands National Park, South Dakota. A portion of each fossil was demineralized to identify any organic microstructures preserved within the fossils. We investigated several factors which may have influenced cellular/soft tissue decay and/or preservation pathways, including taxonomic identity, paleoclimatic conditions, depositional environment, and general diagenetic history (as interpreted through thin section analysis). Soft tissue microstructures were preserved in all fossil samples, and cellular structures morphologically consistent with osteocytes were recovered from 11 of the 15 fossil specimens. Preservation of these microstructures was found to be independent of taxonomy, paleoclimate regime, apatite crystallinity, depositional environment, and general diagenetic history, indicating that biogeochemical reactions operating within microenvironments within skeletal tissues, such as within individual osteocyte lacunae or Haversian canals, may exert stronger controls on soft tissue and biomolecular decay or stabilization than external environmental (or climatic) conditions
Assessing the Usability and Feasibility of Digital Assistant Tools for Direct Support Professionals: Participatory Design and Pilot-Testing
Get PDFBackground: The United States is experiencing a direct support professional (DSP) crisis, with demand far exceeding supply. Although generating documentation is a critical responsibility, it is one of the most wearisome aspects of DSPs’ jobs. Technology that enables DSPs to log informal time-stamped notes throughout their shift could help reduce the burden of end-of-shift documentation and increase job satisfaction, which in turn could improve the quality of life of the individuals with intellectual and developmental disabilities (IDDs) whom DSPs support. However, DSPs, with varied ages, levels of education, and comfort using technology, are not likely to adopt tools that detract from caregiving responsibilities or increase workload; therefore, technological tools for them must be relatively simple, extremely intuitive, and provide highly valued capabilities. Objective: This paper describes the development and pilot-testing of a digital assistant tool (DAT) that enables DSPs to create informal notes throughout their shifts and use these notes to facilitate end-of-shift documentation. The purpose of the pilot study was to assess the usability and feasibility of the DAT. Methods: The research team applied an established user-centered participatory design process to design, develop, and test the DAT prototypes between May 2020 and April 2023. Pilot-testing entailed having 14 DSPs who support adults with IDDs use the first full implementation of the DAT prototypes during 2 or 3 successive work shifts and fill out demographic and usability questionnaires. Results: Participants used the DAT prototypes to create notes and help generate end-of-shift reports. The System Usability Scale score of 81.79 indicates that they found the prototypes easy to use. Survey responses imply that using the DAT made it easier for participants to produce required documentation and suggest that they would adopt the DAT if this tool were available for daily use. Conclusions: Simple technologies such as the DAT prototypes, which enable DSPs to use mobile devices to log time-stamped notes throughout their shift with minimal effort and use the notes to help write reports, have the potential to both reduce the burden associated with producing documentation and enhance the quality (level of detail and accuracy) of this documentation. This could help to increase job satisfaction and reduce turnover in DSPs, both of which would help improve the quality of life of the individuals with IDDs whom they support. The pilot test results indicate that DSPs found the DAT easy to use. Next steps include (1) producing more robust versions of the DAT with additional capabilities, such as storing data locally on mobile devices when Wi-Fi is not available; and (2) eliciting input from agency directors, families, and others who use data about adults with IDDs to help care for them to ensure that data produced by DSPs are relevant and useful
The Academic System Influence on Instructional Change: A Conceptual Systems Dynamics Model of Faculty Motivation to Adopt Research-Based Instructional Strategies (RBIS)
Get PDFMany universities have implemented initiatives to drive instructional change, yet their success has often been limited due to a lack of recognition of academia as a complex dynamic system. This paper explores how the interconnected and dynamic nature of academic systems influences faculty motivation to adopt instructional innovations, such as project-based learning (PBL) and small group collaborations (SGCs). We present a Conceptual Systems Dynamics Model (CSDM) that illustrates these interconnections, demonstrating how systemic factors create feedback loops that either reinforce or hinder faculty motivation, as well as other related factors. These loops, represented as Causal Loop Diagrams (CLDs), were derived from literature reviews and qualitative data obtained from interviews and focus groups involving 17 faculty and administrators within an Engineering Department at a research university in South America. The paper identifies thirteen CLDs, comprising seven reinforcing dynamics that positively influence faculty motivation and six balancing dynamics that exert negative pressure. Using empirical evidence and analysis, we describe how the systemic factors influence faculty motivation, and how shifts in motivation reciprocally impact these interconnected factors. By elucidating the complex dynamics at play, this research contributes to a deeper understanding of how to promote sustainable instructional change within academic institutions
Repetitive thinking, social connectedness, and distressing sexual experiences in autistic and non-autistic students: Examining social-cognitive risk factors and mental health during the college transition
Get PDFThe prevention and treatment of mental health concerns are consistently named among autistic adults’ highest clinical and research priorities. While several theories have been proposed to explain the high prevalence of depression and anxiety in autistic populations, virtually no longitudinal research has evaluated causal mechanisms. The first study in this dissertation aims to explore how known contributors to depression and anxiety identified by general population research – namely, rumination, dissatisfaction with social connectedness, and distressing sexual experiences – relate to the development of internalizing symptoms in autistic individuals during the transition to college. The second study explores potential contributors to sexual risk, through investigating differences in sexual consent understanding and experiences in autistic and non-autistic undergraduates. Results suggest that hypothesized predictors tend to primarily contribute to depression and anxiety symptoms during the transition to college through a) a baseline tendency that seems to have some persisting, longer-term influence throughout the semester and b) a synchronous, short-term risk that may contribute to symptoms in the moment. Findings also support prior literature that autistic adults endorse more childhood experiences of sexual abuse and unsatisfying sexual education experiences
READING INTERVENTIONISTS USING INDIVIDUALIZED LEARNING PLANS AND INSTRUCTION: A DISTRICT LEADER’S RESPONSE TO ADDRESS UNFINISHED TEACHING OPPORTUNITIES IN READING
Get PDFThis action-research study explores a district leader’s experience implementing district-wide individualized learning plans (ILPs) and individualized instruction to enhance student outcomes in reading. The study utilizes collective leadership practices by collaborating with reading interventionists throughout. In addition, this study provides an alternative to the technology-based personalized learning and high-dosage tutoring models
TRANSFORMING ORTHOPEDIC SURGERY: AUTONOMOUS IMAGE-GUIDED TECHNIQUES FOR FEMUR FRACTURE ROBOTIC SURGERY
No full textLong-bone fractures, particularly femur fractures, are prevalent and necessitate surgical intervention due to traumatic forces. Manual reduction procedures pose challenges, including excessive traction forces and reliance on limited X-ray imaging, resulting in malalignment-related complications and repeated surgeries. Current methods for femur fracture reduction are prone to inaccuracies, prolonged surgical times, and postoperative complications. This research introduces image-guided methods to automate a surgical robotic system, Robossis, to enhance femur alignment accuracy, reduce procedure times, and improve patient outcomes. To address these challenges, a marker-based approach utilizing a few X-ray images is developed to detect the spatial relative position of the femur fragments. This information plays a key role in guiding surgical robots for femur fracture alignment surgeries. Utilizing machine learning techniques, a U-Net model is tailored and trained on a cutting-edge dataset to delineate distinct femur landmarks, serving as critical guides for the robot’s navigation and aiding in alignment assessments. The developed Robossis system integrates optical tracking with a 6-DOF parallel robot, allowing real-time spatial data acquisition and automated alignment. Laboratory and cadaver experiments demonstrate its submillimeter accuracy in achieving femur alignment. This integrated approach advances femur fracture surgery by automating alignment, reducing intraoperative radiation exposure, and improving surgical precision